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Cancer immunotherapy has drawn much attention because it can restart the recognition and killing function of the immune system to normalize the antitumor immune response. However, the role of radiotherapy and chemotherapy in cancer treatment cannot be ignored. Due to cancer heterogeneity, combined therapy has become a new trend, and its efficacy has been confirmed in many studies. This review discussed the clinical implications and the underlying mechanisms of cancer immunotherapy in combination with radiotherapy or chemotherapy, offering an outline for clinicians as well as inspiration for future research.

PURPOSE: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with and without BRCA1 and BRCA2 mutations. METHODS: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas. RESULTS: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8(+) and PD-L1(+) cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1(+) and PD-L1(+)CD8(+) cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI: 0.21–0.79, p = 0.008 and HR: 0.49, 95% CI: 0.26–0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1(+) and FAP(+)PD-L1(+) cells (HR: 0.52, 95% CI: 0.28–0.96, p = 0.037 and HR: 0.27, 95% CI: 0.08–0.87, p = 0.029) and CD8(+) cells (HR: 0.51, 95% CI: 0.28–0.93, p = 0.027). CONCLUSIONS: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.

To understand how malignant tumors develop from single cells, we used long-term, time-lapse, live-cell imaging to track the dynamics of the cell membrane, nucleus, spindle, and cell cycle regulators during the development of high-grade, serous, carcinoma-derived organoids. Organoids are highly heterogeneous and include 2 major subtypes. Type-1 organoids are relatively homogeneous and develop via traditional mitosis, whereas type-2 organoids are highly heterogenous and are composed of differently sized polyploid giant cancer cells (PGCCs). Tracking the origin of PGCCs in type-2 organoids shows single cells first undergo asymmetric mitosis and nuclear fusion, followed by endoreplication, multipolar restitution mitosis, multipolar endomitosis, and karyokinesis. At the cellular level, the formation of PGCCs was associated with the formation of transient intracellular cells, termed fecundity cells. The fecundity cells underwent decellularization via the dissolution of the cell membrane, which allowed a giant nucleus to form via nuclear fusion. Different PGCCs underwent nuclear budding, decellularization, or entosis to form Russian doll-like tissue structures that facilitated rapid tumor growth and evolution. The uncoupling of nuclear augmentation from cytokinesis led to a rapid increase in the nuclear-to-cytoplasmic ratio and increased the genomic content of PGCCs, which facilitated macro-genomic evolution during tumor development. Our live-cell imaging evidence allows us to link nuclear replication and cancer evolution to the nuclear morphologies observed by pathologists under the microscope. PGCCs may be the central regulators of malignant histogenesis, cancer evolution, and physical barriers conferring resistance to immune therapy. Citation Format: Xiaoran Li, Yanping Zhong, Xudong Zhang, Anil Sood, Jinsong Liu. Spatio-temporal view of malignant histogenesis and cancer evolution via formation of polyploid giant cancer cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 108.

Mid-infrared spectroscopic imaging (MIRSI) is an emerging class of label-free techniques being leveraged for digital histopathology. Modern histopathologic identification of ovarian cancer involves tissue staining followed by morphological pattern recognition. This process is time-consuming, subjective, and requires extensive expertise. This paper presents the first label-free, quantitative, and automated histological recognition of ovarian tissue subtypes using a new MIRSI technique. This technique, called optical photothermal infrared (O-PTIR) imaging, provides a 10X enhancement in spatial resolution relative to prior instruments. It enables sub-cellular spectroscopic investigation of tissue at biochemically important fingerprint wavelengths. We demonstrate that enhanced resolution of sub-cellular features, combined with spectroscopic information, enables reliable classification of ovarian cell subtypes achieving a classification accuracy of 0.98. Moreover, we present statistically robust validation from 74 patient samples with over 60 million data points. We show that sub-cellular resolution from five wavenumbers is sufficient to outperform state-of-the-art diffraction-limited techniques from up to 235 wavenumbers. We also propose two quantitative biomarkers based on the relative quantities of epithelium and stroma that exhibits efficacy in early cancer diagnosis. This paper demonstrates that combining deep learning with intrinsic biochemical MIRSI measurements enables quantitative evaluation of cancerous tissue, improving the rigor and reproducibility of histopathology.

Triple negative breast cancer (TNBC) has very poor prognosis and no efficacious therapeutic options due to the absence of a validated molecular target. Therefore, novel therapeutic strategies against TNBC are urgently needed. Our team synthesized and screened a series of compounds derived from Rhein, of which 4F was selected for further analysis based on its ability to produce the vacuolated appearance of cells. Using Cell counting kit-8 assay, colony-formation assay, cell apoptosis and cell cycle assay, we compared the antitumor effects of 4F, Rhein and Cisplatin on a TNBC cell line MDA-MB-231 in vitro. The vacuoles in MDA-MB-231 cells were observed and analyzed by hematoxylin-eosin staining and transmission electron microscopy. Autophagy and apoptosis-related proteins including p62, Microtubule Light Chain 3 (LC3), Beclin-1 and Caspase-3 were determined by western blot. The tandem mRFP-GFP-LC3 Lentivirus was used for monitoring the maturation step of autophagosomes. Our data revealed that 4F had lower cytotoxicity to normal breast cell line MCF-10A as compared with positive drug Doxorubicin. Although 4F had better cytotoxicity than Rhein, it had no influence on cells apoptosis in 4F-treated cells. Accumulation of autolysosomes and autophagosomes was observed in 4F-treated MDA-MB-231 cells, accompanied by increased level of Beclin-1 protein. Enhanced autophagic flux was verified by higher ratio of LC3-II/LC3-I, the degradation of p62 protein and alteration in red and green fluorescence puncta. These findings suggested that the process of MDA-MB-231 cell death induced by 4F seemed rely mainly on autophagy rather than apoptosis. 4F may be an alternative drug candidate against TNBC and merits more exploration.

The chemotherapy response score (CRS) is used to score histopathologic response to neoadjuvant chemotherapy (NACT) of patients with extrauterine high-grade serous carcinoma. This study was undertaken to determine if the CRS in the omentum, adnexa or when combined correlates with (1) progression-free survival (PFS) or overall survival (OS), (2) laparoscopic score of abdominal disease, (3) Cancer antigen 125 levels, (4) BRCA status, and (5) platinum-resistant disease. A total of 158 cases were retrospectively collected that received NACT between April 2013 and February 2018 at a single institution. The 3-tier Bohm CRS system was applied to the omentum and adnexa. Survival outcomes between scored subgroups were analyzed using Cox proportional hazards regression. Spearman rank correlation analyses were used to assess CRS and clinical data. A total of 119 cases were treated only with carboplatin/paclitaxel. Omental CRS was: 1 (23 cases, 19.3%), 2 (65 cases, 54.6%), and 3 (31 cases, 26.1%), whereas adnexal CRS was: 1 (50 cases, 42%), 2 (48 cases, 40.3%) and 3 (21 cases, 17.6%). The omental CRS was significantly associated with PFS as a 2-tier score (hazard ratio [HR]=0.612, 95% confidence interval [CI]: 0.378-0.989, P=0.045) but not associated with the PFS using the 3-tier score or with OS using either system. Adnexal CRS was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.49, 95% CI: 0.263-0.914, P=0.025) and 2-tier scores (HR=0.535, 95% CI: 0.297-0.963, P=0.037). The combined score was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.348, 95% CI: 0.137-0.88, P=0.026) and 2-tier scores (HR=0.364, 95% CI: 0.148-0.896, P=0.028). No CRS system used associated with laparoscopic assessment of disease. CRS in the omentum had no significant association with platinum resistance; however, the adnexal CRS 1/2 were 3 times as likely to develop platinum resistance compared with CRS 3 (relative risk=3.94, 95% CI: 1.03-15.09, P=0.046). The CRS, when used on the omentum, adnexa, and as a combined score, was significantly associated with PFS but not with OS. Adnexal CRS 1/2 are more likely to develop platinum-resistant disease. Therefore, the use of this pathology parameter may be useful for clinical management.

We used field observations (mapping and time-series observations) and satellite data to investigate the changes of environmental factors and plankton community structure during four pulsed upwelling events in the southern Taiwan Strait (STWS) during August 2004 and July 2005. Based on the surface temperature, salinity, and concentrations of nitrate, oxygen, and chlorophyll a (Chl a), we identified three stages of upwelling: recent, mature, and aged upwelled water. Diatoms and Synechococcus dominated during the first two and third stages of the upwelling, respectively. In recently upwelled water, phytoplankton grew rapidly, and nutrient concentrations were relatively high. Diatoms accounted for >69% of the total Chl a in recently upwelled and mature water. As the upwelled water aged, the phytoplankton community shifted to coexistence of diatoms and Synechococcus. The microzooplankton community was dominated by aloricate ciliates and tintinnids during upwelling, but the abundance of heterotrophic dinoflagellates increased as the upwelled water matured. Microzooplankton grazing reached a maximum during the mature stage and approximately balanced phytoplankton growth in aged, upwelled water. Overall, our study revealed rapid changes in the plankton community during the different stages of upwelling that reflected the complex and dynamic nature of upwelling systems.

Background In view of the fact that peripheral blood parameters have been reported as predictors of immunotherapy to various cancers, this study aimed to determine the predictors of response to anti-programmed death-1 (anti-PD-1) therapy in patients with esophageal squamous cell carcinoma (ESCC) from peripheral blood parameters. Methods A retrospective analysis was conducted to investigate the predictive value of peripheral blood parameters including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) in the response to anti-PD-1 antibody treatment. 119 ESCC patients receiving combined treatment including anti-PD-1 antibody were enrolled in this study. Results The median progression-free survival (PFS) of all ESCC patients was 3.73 months. PFS rate in ESCC patients with low NLR at 6 weeks post treatment was higher than patients with high NLR (HR = 2.097, 95% CI 0.996–4.417, P = 0.027). However, PFS rate in ESCC patients with low NLR at baseline (HR = 1.060, 95% CI 0.524–2.146, P = 0.869) or 3 weeks post treatment (HR = 1.293, 95% CI 0.628–2.663, P = 0.459) was comparable with high NLR. And no statistically different was found in PFS rate between low PLR and high PLR at baseline (HR = 0.786, 95% CI 0.389–1.589, P = 0.469), 3 weeks post treatment (HR = 0.767, 95% CI 0.379–1.552, P = 0.452) or 6 weeks post treatment (HR = 1.272, 95% CI 0.624–2.594, P = 0.488) in ESCC patients. PFS rate was also comparable between low MLR and high MLR at baseline (HR = 0.826, 95% CI 0.408–1.670, P = 0.587), 3 weeks post treatment (HR = 1.209, 95% CI 0.590–2.475, P = 0.580) or 6 weeks post treatment (HR = 1.199, 95% CI 0.586–2.454, P = 0.596). PFS rate was similar between patients with low SII and high SII at baseline (HR = 1.120, 95% CI 0.554–2.264, P = 0.749), 3 weeks post treatment (HR = 1.022, 95% CI 0.500–2.089, P = 0.951) and 6 weeks post treatment (HR = 1.759, 95% CI 0.851–3.635, P = 0.097). Conclusions NLR at 6 weeks post treatment is a predictor of the response to anti-PD-1 treatment in patients with ESCC.

The construction of cascade reservoirs increases eutrophication and exacerbates algal blooms and thus threatens water quality. Previous studies on the microalgae in reservoir have mainly focused on the spatio-temporal patterns of surface microalgae communities at the horizontal scale, while few studies have simultaneously considered the successions of microalgae in vertical profiles including the sediments and the effects of the nutrients release and microalgae in sediments on microalgae in upper waters. In this study, we investigated the effects of microalgae and physico-chemical parameters in waters and sediments on the successions of vertical microalgae communities in Xipi Reservoir, Southeast China. The seasonal variations in microalgae compositions decreased gradually from the surface water (the dominance of Cryptophyta and Chlorophyta in spring, Chlorophyta and Cyanophyta in summer, and relatively uniform in autumn and winter) to the sediment (the dominance of Bacillariophyta throughout the year), which was influenced by the variations of physico-chemical factors in different layers. The spatio-temporal variations in microalgae communities in waters was attributing to not only the heterogeneities of the stratification, and the physico-chemical factors such as water temperature, pH, and nutrient concentrations, especially for phosphorus in the water column, but also the combinations of phosphorus release and microalgae composition in sediments. Environmental changes would be especially problematic for microalgae groups such as Cryptophyta, Dinophyta and Chlorophyta that were sensitive to the changes of temperature and nutrients. Our results are helpful for an extensive understanding of the dynamics of microalgae communities in reservoir, and contribute to reservoir management for ensuring the safety of drinking water.

To delineate the characteristics of a novel HLA-DQB1 allele identified during routine HLA matching in a leukemia family.The mother and brother of the patient were subjected to PCR sequence-specific oligonucleotide probe (SSOP), PCR sequence-based typ1ing (SBT), as well as next-generation sequencing (NGS).PCR-SBT revealed that the patient's mother and brother's HLA-DQB1 sequences did not fully match with any known allele combination. NGS revealed that the novel allele has differed from the closest matched DQB1*03:02 with a TG substitution at position 233 in exon 2, which resulted in substitution of Valine at codon 46 by Glycine. Pedigree analysis confirmed that the novel HLA-DQB1 allele was inherited from his mother.A novel HLA-DQB1 allele has been identified through next generation sequencing and was officially named as HLA-DQB1*03:362 by the World Health Organization HLA Factor Nomenclature Committee.

Summary High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7–H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7–H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7–H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7–H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7–H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.

At present, effective therapeutic drugs for triple‑negative breast cancer (TNBC) are lacking due to the absence of identified or available targets. Therefore, the present study aimed to identify key molecular targets and a specific targeted therapeutic drug to aid with the development of novel therapeutic strategies for TNBC. Based on the high expression of EGFR and Rac1 in TNBC and inspired by a novel antitumor strategy termed combi‑targeting, novel anthraquinone‑quinazoline hybrid 7B was synthesized to simultaneously target EGFR and Rac1. It was hypothesized that hybrid 7B may possess enhanced potency compared with its parent compounds. Breast cancer cell viability was detected by performing MTT assays. Flow cytometry was conducted to detect the effects of hybrid 7B on the cell cycle, apoptosis and the mitochondrial outer membrane potential. Ultrastructural alterations were observed by transmission electron microscopy. Cell invasion and migration were assessed by performing Transwell and wound‑healing assays, respectively. The expression levels of epithelial‑mesenchymal transition (EMT) markers and metastasis‑related proteins were detected by western blotting. Compared with Rhein and gefitinib, hybrid 7B displayed superior antiproliferative activity in MDA‑MB‑231 cells with an IC50 value of 2.31 µM, which was 14‑fold higher compared with the EGFR tyrosine kinase inhibitor gefitinib. Further experiments demonstrated that hybrid 7B significantly reduced the mitochondrial membrane potential, enhanced MDA‑MB‑231 cell apoptosis and induced cell cycle arrest at the G2/M phase compared with the control group. Typical morphological alterations of apoptotic cells were observed in hybrid 7B‑treated MDA‑MB‑231 and MCF‑7 cells. Compared with the control group, hybrid 7B significantly inhibited MDA‑MB‑231 cell invasion and migration by downregulating Rac1, EGFR, matrix metalloproteinases, snail family transcriptional repressor 1, Vimentin and β‑catenin protein expression levels, and upregulating E‑cadherin protein expression levels. The present study demonstrated that hybrid 7B inhibited TNBC cell migration and invasion by reversing EMT and targeting EGFR and Rac1; therefore, hybrid 7B may serve as a promising therapeutic agent for TNBC.

The hydromedusa Blackfordia virginica is an invasive species that has disrupted coastal marine food webs throughout the world. Here, we report the response of plankton community to B. virginica blooms in a subtropical lagoon in China. Chlorophyll-a concentrations increased after the peak of B. virginica abundance, which was coincident with high concentrations of ammonium. An increase of the biomass and composition of pico- and nano-phytoplankton during the bloom resulted from bottom-up effects due to the nutrients excreted by B. virginica. The average size and grazing rates of microzooplankton concurrently decreased. The negative correlation between the abundances of B. virginica and microzooplankton was accurately simulated by a generalized linear model and redundancy analysis. This study provided empirical evidence of the impacts of the B. virginica bloom on the food web and the mechanisms responsible for those effects. These impacts may lead to serious ecological and environmental consequences for the lagoonal ecosystem.

To verify a HLA-DQB1*03:90N allele and method to improve the accuracy of HLA typing.A total of 2265 hematopoietic stem cell donors from Shenzhen Branch of China Marrow Donor Program in 2018 were initially detected by a PCR sequence-specific oligonucleotide probe (SSOP) method. Among these, a rare HLA-DQB1 allele was identified by sequence-based tying (SBT) and Ion Torrent S5 next generation sequencing (NGS).The SSOP typing result suggested the HLA-DQB1 to be a rare allele, while an insertion and a deletion was suspected in its exon 2 by SBT, which were confirmed by NGS as DQB1*03:90N and DQB1*06:01, respectively.Rare alleles suspected by the SSOP method should be verified by other methods to ensure the accuracy of HLA genotyping. Rare alleles formed by deletions can be detected by NGS with accuracy.

Eutrophication and undesired algal blooms in surface water are common and have been linked to increasing nutrient loading. Effects of extreme events such as storms on reservoir nutrient and phytoplankton remain unclear. Here we carried out continuous high-frequency measurements in a long and narrow dam reservoir in southeast China during a storm period in June-July 2015. Our results show a strong nutrient-phytoplankton relationship as well as a very rapid response to storm runoff. We observed an increase in total suspended matter (TSM), ammonium (NH4-N), and dissolved reactive phosphate (DRP), with a sharp decline in chlorophyll-a (Chl-a) in the high flow periods. Afterward, Chl-a, total phytoplankton abundance and Cyanophyta fraction elevated gradually. Nitrate was diluted at first with increasing discharge before concentration increased, likely following a delayed input of groundwater. Physiochemical parameters and Chl-a were evenly distributed in the water column during the flooding period. However, 10% of NH4-N and 25% of DRP were removed in surface water (0-1m) when an algal bloom (Chl-a>30μgL-1) occurred 10days after peak discharge. Conversely, total particulate P (TPP) of surface water was 58% higher than in the deeper water. Dynamic factor analysis (DFA) revealed that TSM, NH4-N, DRP, total P and discharge significantly explain Chl-a variations following storms (Ceff=0.89). These findings highlight that the reservoir ecosystem was vulnerable to pulse input from storm runoff and the Cyanophyta bloom was likely fueled by phosphate and ammonium rather than nitrate.

To assess the association of KIR/HLA alleles with hepatocellular carcinoma (HCC) and hepatitis B virus (HBV) infection among ethnic Han Chinese patients from southern China.For 95 patients with HCC and 171 healthy controls, the genotype of HLA-C alleles was determined with a PCR sequence-specific oligonucleotides typing method on an Illumina GenDx NGSgo platform. Genotypes comprised of HLA-C and KIR gene alleles were also subjected to statistical analysis.In total 16 KIR genes (2DL2, 2DS2, 2DS3, 2DS5, 3DS1, 2DS1, 2DL5, 2DS4, 3DL1, 3DP1, 2DL3, 2DP1, 3DL3, 2DL1, 3DL2 and 2DL4) were discovered in the two groups. The frequencies of KIR2DL3 alleles and combinational genotypes of KIR2DL3/HLA-C1C2 were significantly lower in the patient group compared with the controls (0.9368 vs. 0.9883, χ²3.84; P0.05, OR = 0.1; 0.0112 vs. 0.2663, χ²3.84; P0.05, RR = 0.03). The frequency of HLA-C2C2 genotype of the patient group was significantly lower than that of the controls (0.0316 vs. 0.2690, P0.05, RR = 0.09), while the frequency of HLA-C1C2 genotype was significantly higher than that of the controls (0.2316 vs. 0.0058, P0.05, RR = 51.23).Above results suggested that the KIR2DL3 allele is associated with lower risk for HCC. There may be individual difference in patients with HCC and HBV infection but various combinations of KIR/HLA alleles.

Extra-gastrointestinal stromal tumors (EGISTs) predominantly occur outside of the gastrointestinal tract, and their biological and histological characteristics are similar to those of GISTs. Primary EGIST occurrence in the liver is extremely rare. The present study reports a case of primary EGIST in the caudate lobe of the liver in a 61-year-old Chinese man. Contrast-enhanced computed tomography revealed a 7.3×5.1-cm heterogeneously enhanced neoplasm with solid and cystic components located in the caudate lobe of the liver. The patient underwent caudate lobe (specifically, Spiegel lobe) resection. Immunohistochemical analysis of the resected tumor revealed a strong positivity for cluster of differentiation (CD)117, discovered on GIST-1 and CD34. Thus, based on the histological and immunohistochemical findings, the final diagnosis was primary hepatic EGIST. Follow up was conducted at 3-month intervals for the first year and 6-months thereafter. The patient was asymptomatic without any sign of recurrence during the follow-up period. Lab tests were in normal range, and no mass was found in CT scan.

Background: The impact of chemotherapy response score (CRS) on prognosis has varied among studies. We addressed the prognostic significance of CRS and the prognostic value of previously undescribed histologic features using a cohort of 245 patients. Methods: Retrospective study in patients with advanced extrauterine high-grade serous carcinomas treated with neoadjuvant chemotherapy followed by interval tumor reductive surgery from 1990 to 2018 in our hospital. Gynecologic pathologists assessed tumor CRS and other histologic features. Clinical information was collected, and multivariate analyses were conducted. Results: A modified 2 tier CRS (CRS 1/2 versus CRS 3) was significantly associated, independent of scoring site (omental versus adnexal), with overall survival (OS) (omentum, p = 0.018, adnexa, p = 0.042, entire cohort, p = 0.002) and progression-free survival (PFS) (p = 0.021, p = 0.035, and p = 0.001, respectively). On multivariate survival analysis, 2 tier CRS, oncocytic change, inflammation, and desmoplasia were significant for OS (p = 0.034, p = 0.020, p = 0.007, and p = 0.010, respectively). Likewise, 2 tier CRS, inflammation, and desmoplasia were significant for PFS (p = 0.012, p = 0.003, p = 0.011, respectively). Conclusions: The modified 2 tier CRS was significantly associated with survival, independent of scoring site. Additional histologic features including oncocytic change, inflammation, and desmoplasia can also predict patient outcomes.

Long-wave photoconductive infrared detector (wavelength over 10 μm) is important to the fields of low-temperature target detection, over-the-horizon detection, and anti-jamming target recognition. The readout integrated circuit of long-wave infrared photoconductive detector cannot adapt because of its low resistance and high non-uniformity. A self-adaptive readout integrated circuit for correction of long-wave infrared photoconductive detector is designed. The circuit adopts a bridge input structure with feedback comparison type ADC and DAC, and then outputs through RTIA amplifier. It can not only effectively readout the signal of the long-wave photoconductive detector with non-uniformity, but also increase the dynamic range of the output signal of the readout integrated circuit. The simulation and test show that the non-uniformity has been improved evidently. The non-uniformity of resistance is reduced to less than 0.5 % equivalently, and the non-uniformity of output signal is reduced from more than 50 % to less than 10 %. The circuit can work properly at normal temperature and low temperature. It has the advantages of low power consumption and low noise. This correction circuit can not only solve the key problems in current projects but also lay an important theoretical foundation for the design and development of the readout integrated circuit of high-performance and large array of long-wave photoconductive infrared detector in the future.

Rationale: DICER1 syndrome is an autosomal-dominant tumor predisposition syndrome associated with numerous cancerous and noncancerous conditions. The most common sex cord-stromal tumor associated with DICER1 syndrome is Sertoli-Leydig cell tumor of the ovary (SLCT), which is extremely unusual and accounts for

The Taiwan Strait (TWS), connecting the South China Sea and the East China Sea, is affected by complex land-sea interactions as well as by human activities on both sides of the Strait. In such a subtropical strait ecosystem, phytoplankton communities exhibit spatiotemporal variations that are complex and dynamic compared with those of classical coastal-oceanic systems. Long-term measurements and reliable analytical methods are required to clarify the processes and mechanisms associated with these complex changes. Here, we use decadal-scale field observations in the TWS (25 cruises during 2004–2018) to show that the realized niches of phytoplankton groups enable to explain the spatiotemporal variations of the phytoplankton communities in response to the different water masses in the TWS during the Northeast (NE) and Southwest (SW) monsoons. Diatoms, prasinophytes, and chlorophytes are characterized by the wide breadths of their temperature, salinity, and nutrient niches in both monsoons. They not only dominate in coastal water during the NE monsoon, but also flourish in upwelled water and plume water during the SW monsoon. Synechococcus and haptophytes were characterized by relatively high temperature, high salinity, and intermediate nutrient concentrations, and dominated in mesotrophic offshore water. Cryptophytes and dinoflagellates performed well in the coastal water influenced by the China Coastal Current during the NE monsoon due to their low-temperature, low-salinity, and high-nutrient niches. Prochlorococcus, a specialist with high-temperature, high-salinity, low-nutrient niches, is high in water affected by the Kuroshio intrusion in both monsoons. These results facilitate prediction of the responses of a subtropical strait ecosystem influenced by human activities and climate change. Multiple stresses would be especially problematic for phytoplankton such as cryptophytes and Prochlorococcus that are sensitive to changes of temperature and nutrient concentrations.

The microenvironment of a tumour is an important factor in ovarian cancer metastasis. The present study aimed to simulate the in vivo microenvironment of an ovarian carcinoma using a co-culture system consisting of human lymphatic endothelial cells (HLECs) and human ovarian carcinoma cells with directional high lymphatic metastasis (SKOV3-PM4s) in order to investigate the role of both cell types in ovarian carcinoma metastasis. The SKOV3-PM4s cultured in the HLEC-conditioned medium exhibited increased numbers of pseudopodia and mitotic figures, proliferated at a faster rate and exhibited enhanced invasion and migratory abilities. Furthermore, the HLECs cultured in SKOV3-PM4-conditioned medium exhibited significant morphological alterations and vacuolisation of the cytoplasm, as well as increased invasion, migratory and tube forming abilities. In addition, spontaneous fusion of the SKOV3-PM4s and HLECs was observed in the co-culture system using laser confocal microscopy. The gelatin zymography assay demonstrated that matrix metalloproteinase-2, which was downregulated in the SKOV3-PM4s, was upregulated in the co-culture system. The results of the present study suggested that the invasion ability of the SKOV3-PM4s was increased in the in vitro co-culture system of SKOV3-PM4 and HLECs. Therefore, alterations in the cell microenvironment may represent a novel strategy for ovarian cancer therapy.

A novel single sideband (SSB) radio-over-fiber (ROF) system based on a dual-electrode dual-parallel Mach–Zehnder modulator (DE-DPMZM) is proposed, in which the Mach–Zehnder modulator (MZM) is used to produce a single sideband signal and the dual-parallel structure is used to suppress the third-order intermodulation distortion (IMD3) to improve the spurious-free dynamic range (SFDR) of the ROF system. A theoretical analysis is given and simulation experiment is carried out. The results show that the proposed scheme can improve 25 dB in SFDR which is up to 127.854 dB Hz 2 / 3 compared with the conventional SSB ROF system. In addition, the single sideband modulation can extend the transmission distance of optic signal.

Lymph node metastasis is one of the most valuable determinants for the prognosis of ovarian cancer. However, the molecular mechanisms underlying lymphangiogenesis in ovarian cancer is still poorly understood. Secreted protein acidic and rich in cysteine (SPARC), a Ca2+-binding matricellular glycoprotein that modulates cell adhesion, migration and differentiation, is thought to play a decisive role in tumor metastasis. Vascular endothelial growth factor (VEGF)-C and VEGF-D contributes to tumor-associated lymphatic vessel growth, enhancing the metastatic spread of tumor cells to lymph nodes. The aim of the present study was to investigate the relationship among SPARC, VEGFs and lymph node metastasis in ovarian cancer. We found that SKOV3 cells expressed high-level SPARC, much more than SKOV3-PM4 cells (a subline with high directional lymphatic metastatic potentials established from the metastatic lymph node generated by human ovarian carcinoma cell line SKOV3 in nude mice) did at both mRNA and protein levels. A SPARC-overexpressed SKOV3-PM4 cell line was constructed and it was found that upregulation of SPARC expression suppressed the growth, migration and invasion of SKOV3-PM4 cells as well as markedly reduced the expression of VEGF-D at both mRNA and protein level by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay. In 47 of ovarian malignant tissues, the expression of SPARC, VEGF-C and VEGF-D were determined by immunohistochemistry. Lymphatic microvessel density (LVD) and microvessel density (MVD) were evaluated by immunostaining with CD34 and D2-40 antibodies, respectively. We found that SPARC expression was significantly lower in tissues with lymph node metastasis as compared to tissues without lymph node metastasis. SPARC expression was inversely associated with the degree of malignancy and it had a negative correlation with VEGF-C expression, VEGF-D expression, LVD and MVD which were actually higher for advanced tumors than for non-advanced tumors. These results suggest SPARC might function as a tumor suppressor inhibiting angiogenesis and lymphangiogenesis in ovarian cancer by reducing the expression of VEGF-C and VEGF-D.

This paper presents an experimental study about the effects of UV irradiation on polyether polyurethane (PU) fibers investigated by FTIR, SAXS and AFM, and the multiple mechanism is finally proposed.The results show that, at low UV irradiation (0.6W/m2, 0.9W/m2), the mechanism responsible for UV degradation of polyether PU fibers could be described as a primary reaction causing the break up of chemical bonds and forming the new quinone structure, along with a secondary reaction to explain hydrogen peroxide formed in the presence of UV irradiation, water and oxygen environment which promotes QUV aging by providing loose structure of polyether PU fibers. Moreover, the micro phase separation is promoted for a parallel reaction occurred to produce new polyether PUs and more compact micro domains by the residual isocyanate in pre-polymerization stage and alcohols formed under QUV aging. Under higher UV irradiation (1.2W/m2, 1.5W/m2), in addition to the primary reaction, a tertiary reaction showing the re-polymerization occurred under accumulation of aging products (carboxylic acids and alcohols) is also considered as the mechanism, while the secondary reaction would be inhibited for the peak assigned to H2O2 is not observed. Also, this decreases micro phase separation of polyether PU fibers for the primary reaction is dominant.

Autologous chondrocyte implantation (ACI) has emerged as a novel approach to cartilage repair through the use of harvested chondrocytes. However, the expansion of the chondrocytes from the donor tissue in vitro is restricted by the limited cell numbers and the dedifferentiation of the chondrocytes. The present study investigated the effect of collagen-based films, including collagen, hydroxyapatite (HA)/collagen (HC) and in situ synthesis of nano-HC (nHC), on monolayer cultures of chondrocytes. As a substrate for the chondrocytes monolayer culture in vitro, nHC was able to restrain the dedifferentiation of chondrocytes and facilitate cell expansion, which was detected by methyl thiazolyl tetrazolium assay, scanning electron microscopy, calcein-acetoxymethyl/propidium iodide staining, hematoxylin and eosin staining, Safranin O staining, immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction. Furthermore, the nHC films significantly facilitated cell growth and enhanced the expression of cartilage-specific extracellular matrix (ECM) components, including aggrecan and type II collagen. In addition, nHC films markedly downregulated the expression of collagen type I, an indicator of dedifferentiation. The results indicated that nHC, a collagen-based substrate optimized by nanoparticles, was able to better support cell growth and preserve cell phenotype compared with collagen alone or HC. The nHC film, which favors cell growth and prevents the dedifferentiation of chondrocytes, may therefore serve as a useful cartilage-like ECM for chondrocytes. In conclusion, nHC film is a promising substrate for the culture of chondrocytes in cell-based therapy.

Matrix metalloproteinases (MMPs) are a family of calcium-dependent zinc-containing endopeptidases, which play an integral role in migration and invasion of ovarian cancer. Rac1 proteins might mostly influence cell migration and invasion by generating endogenous reactive oxygen species. Therefore, inhibiting MMPs and regulating the Rac1/ROS/MAPK/AP-1 pathway may be a new therapeutic strategy for ovarian cancer. In this study, we found that rhein could suppress the invasion and migration of SKOV3-PM4 cells with characteristics of directional highly lymphatic metastasis. Phorbol 12-myristate 13-acetate (PMA), which is a Rac1 activator, significantly enhanced the expression levels of MMP-2, -3, -9 and -19 proteins, whereas the results of rhein and Rac1 inhibitor NSC23766 were just the opposite. The inhibitory effects of rhein were associated with the upregulation of tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2 and NM23-H1. Subsequent mechanism studies revealed that rhein reduce the production of reactive oxygen species (ROS) and lower NADPH oxidase activity. Furthermore, rhein significantly inhibited JNK, AP-1 phosphorylation in the cells treated with PMA. The results obtained from the cells treated with NSC23766 alone or NSC23766 combined with rhein, were consistent with rhein treatment alone. Taken together, these results indicate that rhein may be a potential inhibitor of Rac1 and can inhibit the migration and invasion of SKOV3-PM4 cells through modulating matrix metalloproteinases and RAC1/ROS/MAPK/AP-1 signaling pathway-associated proteins.

Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a microtubule-associated protein that regulates spindle assembly in human cells and is overexpressed in various malignancies. However, the role of NEK2 in hepatocellular carcinoma (HCC) remains undetermined. We performed RNA-seq of the HCC cell line SMMC-7721 and the normal liver cell line HL-7702 using the Ion Proton System. NEK2 expression was detected using quantitative reverse transcription polymerase chain reaction in two cell lines and 5 matched HCC and adjacent non-tumorous liver tissues. The correlation between survival and NEK2 expression was analyzed in 359 patients with HCC using RNASeqV2 data available from The Cancer Genome Atlas (TCGA) website (https://tcga-data.nci.nih.gov/tcga/). The expression of NEK2, phospho-AKT and MMP-2 was evaluated by immunohistochemistry in 63 cases of HCC and matched adjacent non-tumorous liver tissues. Relationships between protein expression and clinicopathological parameters were assessed, and the correlations between NEK2 with phospho-AKT and MMP-2 expressions were evaluated. A total of 610 differentially expressed genes (DEGs) were revealed in the transcriptome comparison, 297 of which were upregulated and 313 were downregulated in HCC. NEK2, as the most obviously different DEG in cells and tissues from the RNA-seq data, was listed as an HCC candidate biomarker for further verification. NEK2 was overexpressed in HCC cells and tissues (P=0.002, P=0.013) and HCC patients with a high expression of NEK2 had a poor prognosis (P=0.0145). Clinical analysis indicated that the overexpression of NEK2 in HCC was significantly correlated with diolame complete (P

Intracranial mature teratoma is a rare lesion in adults. Despite several intracranial mature teratomas had been reported not to be located at the midline region, no one was found to be within cerebral falx. Herein, we reported a 37-year-old female patient with an intracranial mature teratoma confined within frontal cerebral falx. Her main complaint was intermitted headache, which could not be relieved recently by taking painkiller. Excepting for mild papilledema, we did not find positive neurological signs on physical examination. CT scanning showed it was a round homogenously hypodense lesion with hyperdense signal at its rim. MRI revealed the lesion was 3.5 cm×3.6 cm×4.5 cm in volume, with uniformed hypointensity on T1WI, hyperintensity on T2WI and enhancement in the capsule. It was totally removed via inter-hemispheric approach, and we found the lesion was confined within the frontal cerebral falx. Postoperatively, it was proved histologically to be a mature teratoma. At three years of fellow up, neither neurological deficits nor recurrent sings on MRI was found. To our best knowledge, this is the first case of intracranial mature teratoma within cerebral falx.

Metastatic dissemination is a feature of most cancers including prostate cancer (PCa), and is the main cause of treatment failure and mortality. The aim of the study is to explore the mechanisms of PCa metastasis and to search for potential prognostic markers using proteomics. Two-dimensional fluorescent differential gel electrophoresis (2D-DIGE) was used to quantify proteins in normal prostate epithelial cells, bone metastasis-derived PC-3 cells, and visceral metastasis-derived PC-3M cells. Metastatic potential was confirmed by flow cytometry, electron microscopy, proliferating cell nuclear antigen assay, and wound healing assay. Differential protein expression was compared between PCa cells with different metastatic potentials (LNcap, DU145, PC-3 and PC-3M) and normal prostate epithelial cells (RWPE-1). Selected candidate proteins in human prostate tissues were analyzed using GOA, UniProt and GeneCards analyses. Eighty-six proteins were differentially expressed between cell lines (>1.5-fold, P