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Background Kawasaki Disease (KD), which is mainly characterized by systemic small and medium vasculitis in children, can lead to coronary artery lesions (CALs). Our previous study identified that STAT3 signaling plays essential roles during the acute phase of KD patients. However, whether its interacted protein MDM2 (Murine double minute 2), which functions as an E3 ligase is likewise involved in KD pathogenesis still unknown and remains to be investigated. Methods The role of MDM2 was investigated using the whole-blood samples from KD patients with CALs before and after IVIG treatment. The plasma and peripheral blood mononuclear cells were respectively isolated and collected. Meanwhile, a Candida albicans cell wall extracts (CAWS)‑induced KD mouse model was used to analyze the in vivo functions of MDM2. Real-time PCR, western blotting, and enzyme-linked immunosorbent methods were used respectively in the HCAECs or other cells to investigate the molecular mechanism of MDM2 involved in KD. Results MDM2 levels were downregulated, and STAT3 and VEGFA levels were upregulated in clinical blood samples from KD patients with CAL in the acute stage and in the mouse model. In the mouse model and HCAECs, MDM2 co-located with STAT3 . In vitro, the endogenous STAT3 protein level in HCAECs was upregulated after MDM2knockdown. Overexpression of MDM2 increased STAT3 ubiquitination and endogenous STAT3 and VEGFA levels decreased significantly. Additionally, the E3 ubiquitin ligase MDM2 can target its endogenous substrate STAT3 for ubiquitination. Conclusions Decreased MDM2 levels can reduce STAT3 ubiquitination, leading to STAT3 activation and the induction of VEGFA transcription, which is involved in the vascular endothelial inflammatory injury process of KD.

Constraints on mantle heterogeneity are important for understanding geochemical differentiation and recycling in Earth’s interior. Alkali basalts are of particular interest in this context due to the clear signatures of recycled components that they yield. Previous studies have focused more on oceanic basalts than on continental mafic rocks because the chemical and isotopic characteristics of the latter are often modified by crustal contamination; however, high-forsterite olivine crystals and olivine-hosted melt inclusions may record the compositions of primitive melts before extensive crustal contamination, providing valuable insights into mantle heterogeneity. Here we report the results of high-precision major-, minor-, and trace-element and Pb isotope analyses of olivine phenocrysts and melt inclusions from the Sailipu potassic alkali basalts from southern Tibet, which constrain the mantle source of continental potassic alkali basalts. The minor- and trace-element compositions of the olivine phenocrysts (e.g. Ni and Ca contents and 100 × Mn/Fe, 10 000 × Zn/Fe, and Ni/Co ratios) suggest that the primary magmas were derived from a phlogopite-bearing pyroxenite source in which peridotite residues were also present. The low- and high-Li contents of the olivine phenocrysts suggest the recycling of continental crustal material in their mantle source. Comparing the major-element compositions (e.g. SiO2, TiO2, Al2O3, MnO, CaO, and Na2O contents), FCMS and FCKANTMS parameters, and pseudo-ternary projections of the primary Sailipu magmas with experimental data suggests that the primary magmas were partial melts of olivine-poor or carbonated olivine-poor lithologies with a small amount of peridotite residue. The negative Nb and Ta and positive Pb anomalies seen in primitive mantle-normalized trace-element patterns and the extremely low Nb/U ratios of the melt inclusions suggest that recycling of continental crust was the main process involved in enriching the mantle source of the Sailipu magmas. The heterogeneous Pb isotopic compositions of the melt inclusions (208Pb/206Pb = 2.089 – 2.158; 207Pb/206Pb = 0.851 – 0.858) are consistent with the presence of peridotite residue in this source. The subduction of Indian continental crust introduced enriched material (including carbonatites) into the mantle.

This study aims to establish a method for the component content determination and fingerprint evaluation of Mori Cortex, fried Mori Cortex and its standard decoction, and to reveal the quality transfer law among the three based on transfer rate, extraction rate, and fingerprint similarity.Fifteen representative batches of Mori Cortex decoction pieces were collected to prepare fried Mori Cortex and its standard decoction.UPLC-PDA was employed to establish the content determination method and fingerprint.The established UPLC method and fingerprint could be applied to the detection of Mori Cortex, fried Mori Cortex and its standard decoction.The UPLC fingerprints of the 15 batches of Mori Cortex and fried Mori Cortex had good similarity(gt;0.9) and the same common peaks.However, only one characteristic peak(mulberroside A) could be observed in the fingerprint of fried Mori Cortex standard decoction, which indicated that the corresponding components of other common peaks in the fingerprint of Mori Cortex had low content in the water extract.The extraction rates of mulberroside A from Mori Cortex, fried Mori Cortex and its standard decoction were 1.49%-2.00%, 1.62%-2.27% and 0.75%-1.29%, respectively.Mulberroside A showed the transfer rate of 103.7%-116.3% from Mori Cortex to fried Mori Cortex and 45.7%-56.9% from fried Mori Cortex to its standard decoction.The extraction rates of the 15 batches of fried Mori Cortex standard decoctions were 14.7%-19.5%.All the above indicators were within±30% of the mean value.This study established a method for the determination of mulberroside A content and fingerprint of Mori Cortex, fried Mori Cortex and its standard decoction, and clarified the quality transfer law among the three.It established the method for quality evaluation of Mori Cortex and fried Mori Cortex and can provide reference for the whole-process quality control in the preparation of the agents containing fried Mori Cortex.

In this paper, a multifunctional terahertz (THz) absorber based on Dirac semimetal and vanadium dioxide ( V O 2 ) is proposed. By modulating the temperature of V O 2 , the absorber can be switched between the narrow band and wide band. When V O 2 is in the metallic state, the absorber has a broadband absorption effect with a bandwidth of approximately 4 THz. It has the advantages of insensitivity to polarization and wide-angle absorption. When V O 2 is in the insulating state, the absorber has two absorption peaks with absorptivity exceeding 90% and sensitivities of 297.7 and 402 GHz/RIU, and thus can be used as a highly sensitive sensor for cell detection. When the Fermi level of the Dirac semimetal is changed, the absorption characteristics can be modulated. The absorber has broad application prospects in multifunctional modulated devices.

Background Atherosclerosis is a chronic inflammatory disease responsible for thrombosis, blood supply disorders, myocardial infarction and strokes, eventually leading to increased deaths and reduced quality of life. As inflammation plays a vital role in the development of this disease, the present study aims to investigate whether urinary trypsin inhibitor (UTI) with anti-inflammatory property can inhibit the proliferation, invasion and phenotypic switching of PDGF-BB-induced vascular smooth muscle cells (VSMCs) and probe its potential mechanism. Methods Western blot was used to detect the expressions of the proteins related to the Akt/eNOS/NO/cGMP signaling pathway, phenotypic switching and proliferation. CCK-8 assay and EdU staining were used to detect cell proliferation of VSMCs. Transwell and wound healing assays were respectively conducted to measure the invasion and migration of VSMCs. The concentration of NO was evaluated by NO detection kit. ELISA assay analyzed the expression of cyclic GMP (cGMP). Results The expressions of p-Akt and p-eNOS were elevated by UTI treatment. Furthermore, UTI inhibited the proliferation, migration and invasion of VSMCs. UTI also increased the expressions of proteins related to phenotypic switching. The amount of NO and expression of cGMP were both elevated under UTI treatment. Conclusion UTI inhibits the proliferation, invasion and phenotypic switching of PDGF-BB-induced VSMCs via Akt/eNOS/NO/cGMP signaling pathway, which might provide a theoretical basis for the UTI treatment of atherosclerosis.

In this study, the causes of the underestimated diurnal 2-m temperature range and the overestimated 2-m specific humidity in the winter of northern China in the Rapid-Refresh Multiscale Analysis and Prediction System–Short Term (RMAPS-ST) are investigated. Three simulations based on RMAPS-ST are conducted from 1 November 2016 to 28 February 2017. Further analyses show that the partitioning of surface upward sensible heat fluxes and downward ground heat fluxes might be the main contributing factor to the 2-m temperature forecast bias. In this study, two simulations are conducted to examine the effect of soil moisture initialization and soil hydraulic property on the 2-m temperature and 2-m specific humidity forecasts. First, the High-Resolution Land Data Assimilation System (HRLDAS) is used to provide an alternative soil moisture initialization. The results show that the drier soil moisture could lead to noticeable change in energy partitioning at the land surface, which in turn results in improved prediction of the diurnal 2-m temperature range, although it also enlarges the 2-m specific humidity bias in some parts of the domain. Second, a soil texture dataset developed by Beijing Normal University and the revised hydraulic parameters are applied to provide a more detailed description of soil properties, which could further improve the 2-m specific humidity bias. In summary, the combination of using optimized soil moisture initialization, an updated soil map, and revised soil hydraulic parameters can help improve the 2-m temperature and 2-m specific humidity prediction in RMAPS-ST.

To determine the prevalence and clinical features of olfactory and taste disorders among coronavirus disease 2019 (COVID-19) patients in China. A cross-sectional study was performed in Wuhan from April 3, 2020 to April 15, 2020. A total of 187 patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) completed face-to-face interviews or telephone follow-ups. We found that the prevalence of olfactory and taste disorders was significantly lower in the Chinese cohort than in foreign COVID-19 cohorts. Females were more prone to olfactory and taste disorders. In some patients, olfactory and taste disorders precede other symptoms and can be used as early screening and warning signs. Supplementary Information The online version contains supplementary material available at 10.1186/s40779-021-00339-y.

BackgroundThe Chinese Great Famine caused widespread starvation in 1959–1961. Its long-term association with depressive symptoms has not been studied.AimsTo estimate the burden of depressive symptoms and the association of famine exposure with depressive symptoms.MethodThe China Health and Retirement Longitudinal Study is a nationwide representative survey of 17 708 Chinese adults aged ≥45. Propensity score matching and modified Poisson regression were used to evaluate the association between self-reported famine exposure in early life and depressive symptoms among the overall participants. Such associations were also assessed by developmental stage using modified Poisson regression and logistic regression.ResultsThe prevalence of depressive symptoms was 26.2% (95% CI 25.1–27.3%) in 2011. As defined by loss of family members because of starvation, 11.6% (95% CI 10.1–13.1%) of this population experienced severe famine. When compared with participants who did not experience starvation, those who had experienced severe famine during fetal, mid-childhood, young-teenage and early-adulthood stages had 1.87 (95% CI 1.36–2.55), 1.54 (95% CI 1.23–1.94), 1.47 (95% CI 1.09–2.00) and 1.77 (95% CI 1.42–2.21) times higher odds of having depressive symptoms in late adulthood, respectively. The first two trimesters of pregnancy were a critical time window during the fetal stage when severe famine had a stronger association with depressive symptoms. Famine during infant, toddler, preschool or teenage stages was not associated with depressive symptoms. Overall, famine contributed to 13.6% of the depressive symptom burden in this population.ConclusionsThe Chinese Great Famine contributed substantially to the burden of depressive symptoms in China.Declaration of interestNone.

In South China, both crustal reworking and crust–mantle interaction were important geological processes during the Paleozoic and Mesozoic eras. However, the relationships between these two processes and metal mineralization are still unknown. Here we report rhenium and osmium isotopic data for pyrite grains from a pyrite deposit associated with a granite intrusion in the Shangbao area, southeastern Hunan Province (South China). Two pyrite samples, both containing many euhedral pyrite grains, were collected from the same locality, but the samples yield distinct ages. Six euhedral pyrite grains from one sample yield an isochronal age of 279 ± 12 Ma, with an initial 187 Os/ 188 Os ratio of 0.39 ± 0.71, and Re and Os concentrations of 0.12–63.5 ppb and 2.14–185 ppt, respectively. This Early Permian age is in good agreement with the age of the strata that host the pyrite deposit. Five euhedral pyrite grains from the other sample yield an isochronal age of 75.2 ± 4.3 Ma, with an initial 187 Os/ 188 Os ratio of 0.141 ± 0.030 and Re and Os concentrations of 0.15–0.43 ppb and 1.0–39.9 ppt, respectively. If one pyrite grain with the highest 187 Re/ 188 Os and 187 Os/ 188 Os ratios is excluded, other four pyrite grains give an isochronal age of 85 ± 13 Ma. The Late Cretaceous age (75–85 Ma) is consistent with the zircon U–Pb age of the Shangbao granites (80.1 ± 0.3 Ma) to within uncertainties. Considering also the relatively lower radiogenic initial 187 Os/ 188 Os ratio of this sample, we suggest that the later stage pyrite ore was probably formed through crystallization from the magmatic hydrothermal fluids. Combined with other geological and associated magmatic data, we propose a skarn-related fluid–ore interaction process to explain the second stage of metallogenesis in the Shangbao pyrite deposit. The Early Permian pyrite ore was deposited in a brine basin with evaporites during the Early Permian. Later magmatic hydrothermal fluids originating from the Shangbao granites, which included mantle components, interacted with the strata and the Early Permian pyrite ore during the Late Cretaceous and precipitated a later stage pyrite ore. During the Late Mesozoic, the roll-back of subducted Paleo-Pacific plate caused lithospheric extension in South China, triggering the upwelling and partial melting of the asthenosphere. The resulting underplating of mantle-derived magmas provided a vast amount of heat and materials for the formation of the granites and polymetallic deposits in South China. Given that the multiple mineralization events were spatially and temporally associated with the Paleozoic–Mesozoic magmatism, the Re–Os isotopic dating of euhedral pyrite grains has been shown to be a viable method for unveiling the evolutionary history of ore-deposits. Skarn development caused by granite and mafic dike emplacement resulting from crust–mantle interaction explains the occurrence of two mineralization episodes at the same locality.

Aim The study was conducted to investigate the role of c-Myc in the regulation of ionizing radiation-induced cell cycle arrest and cell death in human cervical cancer cells. Methods Control and c-Myc-silenced Hela cells were collected at different time points after 60Co γ-ray radiation. Flow cytometry was used to measure cell cycle distribution and apoptosis. Immunofluorescence was applied to determine the percentage of cells in M phase. Transmission electron microscopy and immunoblotting were used to detect the induction of autophagy after radiation. Immunoblotting was also used to measure the expression levels of apoptosis-related proteins. Results In c-Myc-silenced cells, radiation induced delayed but long-lasting G2/M arrest and an abnormal M phase compared with the control. In addition, c-Myc knockdown significantly inhibited apoptotic cell death induced by radiation. Meanwhile, radiation-induced autophagy appeared stronger in c-Myc-silenced cells. Mechanically, we found that Caspase 8 and survivin expression was decreased in c-Myc-silenced Hela-630 cells. Conclusions These data showed that c-Myc serves as a co-regulator in radiation-induced G2/M cell cycle arrest and cell death in human cervical cancer cells.

To evaluate the efficiency of isoflurane-induced anesthetic preconditioning and the role of mitochondrial manganese superoxide dismutase (MnSOD) in hypertensive hypertrophied hearts.A prospective animal investigation.Medical center hospital research laboratory.Male spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto (WKY) rats.All pentobarbital-anesthetized open-chest rats were subjected to a 45-minute left coronary artery occlusion followed by a 120-minute reperfusion. Before ischemia, both SHR and WKY rats were assigned randomly to receive a 30-minute exposure to 0.9% saline or 1.0 minimum alveolar concentration isoflurane.The myocardial infarct size, assessed as a percentage of the area at risk, was significantly greater in the hypertrophied SHRs than in the WKY rats (65.3%±8.7% v 51.8%±7.2%, p0.05). Isoflurane preconditioning appreciably reduced the infarct size in the WKY hearts (30.9%±10.5%, p0.05) but not in the SHR hearts. MnSOD protein expression and enzymatic activity were increased drastically in response to isoflurane exposure in the hearts of the WKY rats (p0.05) but not in the SHRs.Isoflurane-induced anesthetic preconditioning is attenuated in hypertensive hypertrophied hearts. This impairment may be associated with the loss of MnSOD augmentation during ischemia and reperfusion.

Cenchrus spinifex is an invasive plant found in large areas of northern China. In this study, we focused on analysis of the effects of C. spinifex on soil nitrogen and plant nitrogen pools in Horqin sandy grassland. In addition, a pot experiment with以我国北方大面积发生的入侵植物少花蒺藜草为对象,研究了其对科尔沁沙质草地土壤氮库和地上植物氮库的影响,并在室内条件下,以自然生境中少花蒺藜草伴生牧草披碱草和扁穗冰草为对照,利用

Cholangiocarcinoma (CCA) is a devastating disease due to no effective treatments available. Since the non-mineral functions of vitamin D emerges, 1α,25(OH)2D3, the active form of vitamin D, has been applied in anti-cancer researches. In this study, we demonstrated that both the 1α,25(OH)2D3 analog, MART-10, and 1α,25(OH)2D3 possessed anti-growth effect on human CCA cells with MART-10 much more potent than 1α,25(OH)2D3. The growth inhibition of both drugs were mediated by induction of G0/G1 cell cycle arrest through upregulation of p27 and downregulation of CDK4, CDK6, and cyclin D3. Human neutrophil gelatinase associated lipocalin (NGAL) was found to be involved in 1α,25(OH)2D3 and MART-10 meditated growth inhibition for CCA as knockdown of NGAL decreased Ki-67 expression in SNU308 cells and rendered SNU308 cells less responsive to 1α,25(OH)2D3 and MART-10 treatment. Vitamin D receptor (VDR) knockdown partly abolished MART-10-induced inhibition of NGAL and cell growth in SNU308 cells. The xenograft animal study demonstrated MART-10 could effectively repressed CCA growth in vivo without inducing obvious side effects. The IHC examination of human CCA specimen for VDR revealed that higher VDR expression was linked with better prognosis. Collectively, our results suggest that MART-10 could be a promising regimen for CCA treatment.

A modified Gleason grading system as proposed in the 2005 International Society of Urological Pathology (ISUP) consensus meeting is the current grading system for prostate cancer. With this modified ISUP Gleason grading system, many Gleason score (GS) 6 cancers by the old grading system are upgraded to GS7 cancers on biopsy diagnosis even with minimal quantity (≤5%) of Gleason pattern 4 (GP4) component (GS7miniGP4). However, grade concordance between the core needle biopsy of GS7miniGP4 and the corresponding radical prostatectomy (RP) specimens has not been studied. In this study, we analyzed the pathologic features of 256 consecutive needle biopsies and their corresponding RP specimens. The quantity of GP4 was calculated as the percentage of total cancer for GS7 cancer in the biopsy. Of 256 biopsies, 88 (34.4%), 107 (41.8%), and 61 (23.8%) had a GS of 6, 3+4=7, and 4+3=7, respectively. Of 107 biopsies with GS 3+4=7, 22 (20.6%) are GS7miniGP4. Ten of 22 cases of G7miniGP4 in the biopsies (45%) had pathologically insignificant tumor in the RP. The quantity of GP4 in the GS7 biopsy significantly correlated with GS, pathologic stage, and total tumor volume in the corresponding RP. The GS, pathologic stages, total tumor volume, and insignificant tumor rate in RP were not significantly different between the biopsy groups of GS 3+3=6 and GS7miniGP4, whereas those parameters were significantly different between biopsy groups of GS 3+3=6 and GS 3+4=7 with GP4 6% to 50% and between biopsy groups of GS7miniGP4 and GS7 with GP4 6% to 50%. Our data demonstrate that pathologic parameters in the RP are similar between the biopsy groups of GS7miniGP4 and GS6, and the grading of cases with biopsy GS7miniGP4 is often downgraded in RP specimens. The clinical significance of minimal quantity (≤5%) of GP4 in biopsies with GS7 prostate cancer needs to be further evaluated, particularly because of its potential impact on clinical decisions between active surveillance versus surgery.

For the head and neck squamous cell carcinoma (HNSCC), surgery in combination with radiation therapy is the current standard treatment. However, the complex anatomy and important functions over the head and neck region often make HNSCC patients with severe comorbidities. Even after aggressive treatment, the 5 year survival for HNSCC patients is only around 61%. Thus, new therapeutic regimens against HNSCC are urgently needed. 1α,25-Dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] is a potent anti-tumor agent in a variety of pre-clinical studies, but its clinical application is impeded by hypercalcemic side effect. A new class of less-calcemic 1α,25(OH) 2 D 3 analog, MART-10 (19-nor-2α-(3-hydroxypropyl)- 1α,25-Dihydroxyvitamin D 3 ), has been shown to be much more potent than 1α,25(OH) 2 D 3 in inhibiting cancer cell growth in vitro and in vivo without inducing hypercalcemia. In this study, we compared the antiproliferative activity of MART-10 with 1α,25(OH) 2 D 3 and the mechanism responsible for the inhibition in FaDu and SCC-25 squamous carcinoma cells. Our results demonstrate that MART-10 is more potent than 1α,25(OH) 2 D 3 in suppressing FaDu and SCC-25 cell growth through greater cell cycle arrest at G 0 /G 1 , accompanied by a greater downregulation of ki-67 expression and upregulation of p21 and p27. We also showed that telomerase expression in SCC-25 was suppressed to a greater extent by MART-10 than by 1α,25(OH) 2 D 3. Thus, given the previously-proven in vivo antitumor effect and safety of MART-10 and bleak background of HNSCC, based on our current result, we concluded that MART-10 has a potential as a chemo-preventive and – therapeutic agent to treat HNSCC.

An algorithm of spatio-temporal combining video denoising based on structural similarity is proposed for the video surveillance system. By motion detection to multi-frame images with block structural similarity, this algorithm can adaptively distinguish the still regions and motion regions of video image. Temporal weighted average filter to the still regions and spatial ANL filter to the motion regions are used separately. Experimental results show that the proposed algorithm can improve the image quality and greatly reuduce the computation time.

Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3+) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P=0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P=0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.

Pulmonary neuroendocrine tumors (PNET) are histologically subclassified into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). The criteria for subclassification in cytological specimens are not well defined. In this study, we reviewed histologically confirmed 18 TC, 8 AC, 10 LCNEC, and 10 SCLC cytologic specimens from 45 patients. The following features were reviewed: small clusters, geographic sheets, trabecular structures, pseudo-rosettes, single cells, doublets, triplets or short cords, papillary-like structures, capillary vasculatures, necrosis, smear background, cell size, cell pleomorphism, amount of cytoplasm, plasmacytoid cells, spindle cells, nuclear atypia, molding, palisading and smearing, chromatin textures, nucleoli, and mitotic figure count. Based on our results, geographic clusters and necrosis were often seen in LCNEC and SCLC; while AC only showed scattered single cell necrosis. TC and AC commonly exhibited trabecular structures. Papillary-like structures and capillary vasculature were only present in TC, AC, and LCNEC. Cells forming doublets, triplets, and short cords were more commonly seen in SCLC and rarely seen in other entities. Plasmacytoid and spindle cells were only seen in TC and AC. Nuclear smearing was not identified in TC, rare in AC, focally present in LCNEC and obvious in SCLC. Mitotic figures were nearly absent in TC, ≤5/10 HPF in AT, and ≥10/10 HPF in SCLC. LCNEC showed a wide span of mitotic count ranging between 2 and 16/10 HPF. In this study, we propose a set of cytological features that are essential for subclassification of PNETs in cytologic specimens. Diagn. Cytopathol. 2013;41:689–696. © 2013 Wiley Periodicals, Inc.

Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality. The virus is spread through the aerosolization of host rodent excreta and endemic to the humid pampas of Argentina. Recently, significant progress has been achieved with the development of new technologies (e.g. reverse genetics) that have expanded knowledge about the pathogenesis and viral replication of Junín virus. We will review the pathogenesis of Junín virus in various animal models and the role of innate and adaptive immunity during infection. We will highlight current research regarding the role of molecular biology of Junín virus in elucidating virus attenuation. We will also summarize current knowledge on Junín virus pathogenesis focusing on the recent development of vaccines and potential therapeutics.

Green, practical, and efficient hydrothiolation of 2,2′-dithiosalicylic acid to terminal alkynes was found to proceed smoothly in water under mild reaction conditions with moderate to good yields. The use of metal catalysts and toxic solvents was avoided, and good to excellent stereoselectivity and regioselectivity were obtained. Herein, the reaction conditions and regioselectivity are discussed, and a preliminary reaction mechanism is proposed. Hydrothiolation of 2,2′-dithiosalicylic acid to terminal alkynes proceeded in water under mild reaction conditions with moderate to good yields.

The cytologic diagnosis of synovial sarcoma (SS) can be difficult when it occurs in unusual locations, atypical age groups, and/or have unusual morphology. We report a case of primary mediastinal SS in a 65-year-old male with a long smoking history who presented with increasing shortness of breath and was found to have a 14.2 cm mediastinal mass. Smears from the endobronchial ultrasound guided fine needle aspiration of the mass were moderately cellular consisting of loosely cohesive clusters, some of which demonstrated nuclear molding, and dispersed single cells. The relatively uniform tumor cells had a high nuclear-to-cytoplasmic ratio, finely granular chromatin, and inconspicuous nucleoli. Some of the single cells had spindled morphology with unipolar wispy tails and naked nuclei. Based on the clinical presentation and the cytomorphologic features, our initial differential diagnoses included atypical carcinoid, small cell carcinoma, basaloid squamous cell carcinoma, sarcoma, and lymphoma. Immunohistochemical studies on the cell block sections revealed that the tumor cells were focally positive for cytokeratin and diffusely positive for CD56, while negative for CD45, synaptophysin and chromogranin. Ultimately, an immunohistochemical stain for TLE-1 demonstrated diffusely strong nuclear positivity and molecular studies showed the presence of the t(X; 18) SYT/SSX1 translocation confirming the diagnosis of SS. In this report, we describe the cytomorphologic features of SS, its diagnostic pitfalls, and potential mimics in the mediastinum.

Metastatic urothelial carcinoma (UC) to serous effusion (SE) is extremely rare and its cytomorphological features have only been described in case reports. In this study, we searched the pathology database at University of Michigan for SEs due to metastatic UC in the last 20 years. A total of 25 cases from 20 patients with clinically and pathologically confirmed metastatic UC in SEs were retrieved. The specimens consisted of 15 pleural, 8 peritoneal, and 2 pericardial effusions. Smears were reviewed and evaluated for the following features: cellularity, single cells, cell clusters or short cords, cell wrapping, "windows" between the cells, two-tone cytoplasm, cytoplasmic vacuoles, signet ring cells, nuclear to cytoplasmic (N/C) ratio, nuclear hyperchromasia, irregular nuclear membrane, nuclear centricity, double or multiple nuclei, nucleoli, anaplastic cells and mitosis. Our results showed that UC manifested in SEs predominantly as a single cell population with or without clusters or short cords, and frequently exhibited the "cell wrapping" of two or more cells. Individual UC cell in SEs exhibited nuclear enlargement with increased N/C ratio, irregular nuclear membranes, hyperchromatic coarse chromatin and frequently prominent nucleoli. Double or multinucleated cells, cells with vacuolated cytoplasm or signet ring appearance were also frequently present. Our results demonstrated that while certain features could suggest the diagnosis of UC, the cytomorphological features are not specific and often overlap with those of reactive mesothelium, mesothelioma, metastatic adenocarcinoma, or squamous cell carcinoma in SEs. Accurate diagnosis of UC rests on the combination of clinical history, cytomorphologic features and appropriate immunohistochemical panel.

The present study aimed to explore the mechanisms by which c-Myc is involved in mitotic catastrophe. HeLa-630 is a cell line stably silenced for c-Myc expression that was established in the laboratory of the School of Radiation Medicine and Protection. Multinucleated cells were observed in this line, and gene expression analysis was utilized to examine differences in gene expression in these cells compared with in the control cells transfected with the control plasmid. Gene ontology analysis was performed for differentially expressed genes. Expression profile analyses revealed that cells with silenced c-Myc exhibited abnormal expression patterns of genes involved in various functions, including the regulation of microtubule nucleation, centrosome duplication, the formation of pericentriolar material, DNA synthesis and metabolism, protein metabolism and the regulation of ion concentrations. Pathway analyses of differentially expressed genes demonstrated that these genes were primarily involved in diverse signal transduction pathways, including not only the adherens junction pathway, the transforming growth factor-β signaling pathway and the Wnt signaling pathway, among others, but also signaling pathways with roles in cytokine and immune regulation. The proportion of multinucleated cells with multipolar spindles was significantly higher in silenced c-Myc cells as compared with the control cells, and this discrepancy became more pronounced following cell irradiation. The inhibition of c-Myc in tumors may account for the radiosensitization of certain tumor cell types.

The in situ synthesized TiB–TiB2 ceramic–matrix composite is prepared by spark plasma sintering using Ti and TiB2 powders. The microstructures, mechanical properties and the sintering mechanism of the composites are investigated. The composite sintered at 1700 °C has a relative density of 99.4%, average Vickers hardness of 26.5 GPa, flexural strength of 661 MPa and fracture toughness of 6.95 MPa m1/2. According to the microstructure evolution of the composites, the description of the sintering process can be divided into four stages: activation and melt of the metal powder, reaction of Ti with TiB2, coarsening of TiB, and rapid densification. Only if the above mentioned sintering stages proceed in turn and are all fully completed, the high quality composite can be obtained.

CEBS (Chemical Effects in Biological Systems) is an integrated public repository for toxicogenomics data, including the study design and timeline, clinical chemistry and histopathology findings and microarray and proteomics data. CEBS contains data derived from studies of chemicals and of genetic alterations, and is compatible with clinical and environmental studies. CEBS is designed to permit the user to query the data using the study conditions, the subject responses and then, having identified an appropriate set of subjects, to move to the microarray module of CEBS to carry out gene signature and pathway analysis. Scope of CEBS: CEBS currently holds 22 studies of rats, four studies of mice and one study of Caenorhabditis elegans. CEBS can also accommodate data from studies of human subjects. Toxicogenomics studies currently in CEBS comprise over 4000 microarray hybridizations, and 75 2D gel images annotated with protein identification performed by MALDI and MS/MS. CEBS contains raw microarray data collected in accordance with MIAME guidelines and provides tools for data selection, pre-processing and analysis resulting in annotated lists of genes of interest. Additionally, clinical chemistry and histopathology findings from over 1500 animals are included in CEBS. CEBS/BID: The BID (Biomedical Investigation Database) is another component of the CEBS system. BID is a relational database used to load and curate study data prior to export to CEBS, in addition to capturing and displaying novel data types such as PCR data, or additional fields of interest, including those defined by the HESI Toxicogenomics Committee (in preparation). BID has been shared with Health Canada and the US Environmental Protection Agency. CEBS is available at http://cebs.niehs.nih.gov. BID can be accessed via the user interface from https://dir-apps.niehs.nih.gov/arc/. Requests for a copy of BID and for depositing data into CEBS or BID are available at http://www.niehs.nih.gov/cebs-df/.

A long-standing goal in genetic therapy for cancer is a systemic gene delivery system that selectively targets tumor cells, including metastases. Here we describe a novel cationic immunolipoplex system that shows high in vivo gene transfer efficiency and antitumor efficacy when used for systemic p53 gene therapy of cancer. A cationic immunolipoplex incorporating a biosynthetically lipid-tagged, anti-transferrin receptor single-chain antibody (TfRscFv), was designed to target tumor cells both in vitro and in vivo. A human breast cancer metastasis model was employed to evaluate the in vivo efficacy of systemically administered, TfRscFv-immunolipoplex-mediated, p53 gene therapy in combination with docetaxel. The TfRscFv-targeting cationic immunolipoplex had a size of 60–100 nm, showed enhanced tumor cell binding, and improved targeted gene delivery and transfection efficiencies, both in vitro and in vivo. The p53 tumor suppressor gene was not only systemically delivered by the immunolipoplex to human tumor xenografts in nude mice but also functionally expressed. In the nude mouse breast cancer metastasis model, the combination of the p53 gene delivered by the systemic administration of the TfRscFv-immunolipoplex and docetaxel resulted in significantly improved efficacy with prolonged survival. This is the first report using scFv-targeting immunolipoplexes for systemic gene therapy. The TfRscFv has a number of advantages over the transferrin (Tf) molecule itself: (1) scFv has a much smaller size than Tf producing a smaller immunolipoplex giving better penetration into solid tumors; (2) unlike Tf, the scFv is a recombinant protein, not a blood product; (3) large scale production and strict quality control of the recombinant scFv, as well as scFv-immunolipoplex, are feasible. The sensitization of tumors to chemotherapy by this tumor-targeted and efficient p53 gene delivery method could lower the effective dose of the drug, correspondingly lessening the severe side effects, while decreasing the possibility of recurrence. Moreover, this approach is applicable to both primary and recurrent tumors, and more significantly, metastatic disease. The TfRscFv-targeting of cationic immunolipoplexes is a promising method of tumor targeted gene delivery that can be used for systemic gene therapy of cancer with the potential to critically impact the clinical management of cancer.

Prostate cancer (PCa) often presents as a multifocal disease with heterogeneity in Gleason score (GS) and genetic alterations. Dominant/index tumor nodule (DN), the largest nodule in a multifocal disease, is presumed to harbor the most aggressive biological behavior and therefore dictate the overall clinical behavior of PCa. In this study, we examined the pathological features of DN and re-evaluated the validity of the "DN" concept in multifocal PCa. A total of 201 consecutive radical prostatectomy specimens were totally submitted and examined. All independent cancer foci were recorded with prognostically important pathological parameters. Unifocal and multifocal disease was present in 25 (12.4 %) and 176 (87.6 %) cases, respectively. In 20 (11.3 %) multifocal cases, the highest GS, the largest tumor volume (TV), and extraprostatic extension (EPE) did not concur in the same tumor nodules. Non-DNs had a higher GS and EPE in 13 cases each and had both the highest GS and EPE in 5 cases. In the majority of multifocal prostate cancer (88.7 %), DNs have the highest GS and EPE. In these cases, DN is still a valid concept and can be used for assigning overall GS and procuring tissue for research. However, in a significant number of cases (11.3 %), the largest TV, the highest GS, and EPE did not concur in the same tumor nodules. In these cases, pathologists should de-emphasize the concept of DN. Instead, they should place the emphasis on the multifocal nature of the disease and document the pathological features of all independent tumor foci that have the largest TV, the highest GS, and EPE.

Caveolin-1, an indispensable component of caveolae serving as a transformation suppressor protein, is highly expressed in poorly metastatic mouse osteosarcoma FBJ-S1 cells while highly metastatic FBJ-LL cells express low levels of caveolin-1. Calcium concentration is higher in FBJ-S1 cells than in FBJ-LL cells; therefore, we investigated the possibility that calcium signaling positively regulates caveolin-1 in mouse FBJ-S1 cells. When cells were treated with the calcium channel blocker nifedipine, cyclosporin A (a calcineurin inhibitor), or INCA-6 (a nuclear factor of activated T-cells [NFAT] inhibitor), caveolin-1 expression at the mRNA and protein levels decreased. RNA silencing of voltage-dependent L-type calcium channel subunit alpha-1C resulted in suppression of caveolin-1 expression. This novel caveolin-1 regulation pathway was also identified in mouse NIH 3T3 cells and Lewis lung carcinoma cells. These results indicate that caveolin-1 is positively regulated at the transcriptional level through a novel calcium signaling pathway mediated by L-type calcium channel/Ca(2+)/calcineurin/NFAT.

Pancreatic cancer is a lethal disease without effective treatments at present. It ranks as s as 4th and 5th in cancer-related mortality in the western countries and worldwide. Locally advanced pancreatic duct carcinoma (PDAC) and metastatic PDAC, usually found the metastases over liver, peritoneum, or lung, have been shown to be with dismal prognosis. Brain metastasis is a rare entity and most cases reported before were found post-mortem. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) has been deemed as a precursor of PDAC with very slow progression rate. Here we reported a case diagnosed with IPMN-derived PDAC with brain metastasis. After surgeries for PDAC and brain metastasis, subsequent chemotherapy and radiotherapy were also given. One and half year after surgery, this patient is still living with good performance status, which may warrant individualization of therapeutic strategy for PDAC with only brain metastasis.

Pulmonary neuroendocrine tumors (PNET) are histologically subclassified into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). The criteria for subclassification in cytological specimens are not well defined. In this study, we reviewed histologically confirmed 18 TC, 8 AC, 10 LCNEC, and 10 SCLC cytologic specimens from 45 patients. The following features were reviewed: small clusters, geographic sheets, trabecular structures, pseudo-rosettes, single cells, doublets, triplets or short cords, papillary-like structures, capillary vasculatures, necrosis, smear background, cell size, cell pleomorphism, amount of cytoplasm, plasmacytoid cells, spindle cells, nuclear atypia, molding, palisading and smearing, chromatin textures, nucleoli, and mitotic figure count. Based on our results, geographic clusters and necrosis were often seen in LCNEC and SCLC; while AC only showed scattered single cell necrosis. TC and AC commonly exhibited trabecular structures. Papillary-like structures and capillary vasculature were only present in TC, AC, and LCNEC. Cells forming doublets, triplets, and short cords were more commonly seen in SCLC and rarely seen in other entities. Plasmacytoid and spindle cells were only seen in TC and AC. Nuclear smearing was not identified in TC, rare in AC, focally present in LCNEC and obvious in SCLC. Mitotic figures were nearly absent in TC, ≤5/10 HPF in AT, and ≥10/10 HPF in SCLC. LCNEC showed a wide span of mitotic count ranging between 2 and 16/10 HPF. In this study, we propose a set of cytological features that are essential for subclassification of PNETs in cytologic specimens.

The cytologic diagnosis of synovial sarcoma (SS) can be difficult when it occurs in unusual locations, atypical age groups, and/or have unusual morphology. We report a case of primary mediastinal SS in a 65-year-old male with a long smoking history who presented with increasing shortness of breath and was found to have a 14.2 cm mediastinal mass. Smears from the endobronchial ultrasound guided fine needle aspiration of the mass were moderately cellular consisting of loosely cohesive clusters, some of which demonstrated nuclear molding, and dispersed single cells. The relatively uniform tumor cells had a high nuclear-to-cytoplasmic ratio, finely granular chromatin, and inconspicuous nucleoli. Some of the single cells had spindled morphology with unipolar wispy tails and naked nuclei. Based on the clinical presentation and the cytomorphologic features, our initial differential diagnoses included atypical carcinoid, small cell carcinoma, basaloid squamous cell carcinoma, sarcoma, and lymphoma. Immunohistochemical studies on the cell block sections revealed that the tumor cells were focally positive for cytokeratin and diffusely positive for CD56, while negative for CD45, synaptophysin and chromogranin. Ultimately, an immunohistochemical stain for TLE-1 demonstrated diffusely strong nuclear positivity and molecular studies showed the presence of the t(X; 18) SYT/SSX1 translocation confirming the diagnosis of SS. In this report, we describe the cytomorphologic features of SS, its diagnostic pitfalls, and potential mimics in the mediastinum.

We report two cases of malignant deciduoid mesothelioma (MDM), a very rare variant of malignant mesothelioma (MM). Case 1: An 18-year-old male with no history of asbestos exposure presented with worsening abdominal pain, anorexia, and vomiting after a motor vehicle accident. A CT scan showed small amount of ascites and abdominal mass. An exploratory laparotomy revealed multiple yellow tan, firm nodules on the peritoneum and omentum. He received palliative treatment and died 5 months after the diagnosis. Case 2: A 64-year-old female with history of asbestos exposure initially presented with abdominal distension. CT scan showed abdominal mass with a large amount of ascites. A diagnostic laparoscopy revealed multiple peritoneal nodules. She underwent several regimens of chemotherapy over a period of 69 months and is still alive to date. In both cases, features of mesothelial origin were subtle and the smears showed predominantly single cells with marked nuclear atypia. The second case also contained few two-dimensional loose cell clusters with scalloped or hobnail borders. The clusters often exhibited a pseudoacinar structure surrounding a globular extracellular material. Groups of three to four cells often formed doublets and triplets with cell-to-cell windows. Our results show that MDM may not present with the traditional cytological features described in MM and can manifest with more nuclear pleomorphism resulting in erroneous diagnosis. Recognition of the subtle mesothelial features along with the appropriate ancillary tests is essential for accurate diagnosis.

The differential diagnosis of rectal serrated polyps is challenging due to its unique anatomic location, the evolving concept of serrated polyps over the past several years, and to histologic changes seen in rectal mucosal prolapse. We reclassified 95 rectal polyps diagnosed originally as "sessile serrated adenoma" (SSA), "serrated polyp," or "hyperplastic polyp (HP) with features of SSA" in a 5-year period based on World Health Organization classification criteria for colorectal serrated polyps. BRAF (V600E) mutation assay was performed to explore its value in the differential diagnosis for serrated polyps. Twenty-six originally diagnosed SSAs were reclassified as SSA (15/26, 57.7%), HP with mucosal prolapse (HP-P; 7/26, 26.9%), and HP (4/26, 15.4%). Fifty-two polyps originally diagnosed "HP with features of SSA" were reclassified as HP-P (24/52, 46.2%), HP (10/52, 19.2%), inflammatory-type polyp (5/52, 9.6%), and serrated polyp unclassifiable (13/52, 25.0%). Thirty-one of the 78 originally diagnosed SSA or HP with features of SSA were reclassified as HP-P, which accounted for 32.6% of the rectal polyps in this study. Mucosal prolapse along with chronic inflammation and tissue embedding artifact were the most common features that led to misdiagnosis in rectal serrated polyps. BRAF mutation was identified in 8 of 11 HP, 4 of 4 SSA, and 8 of 11 unclassifiable serrated polyp of the rectum, and was absent in control tissue. Thus, histopathologic changes suggesting prolapsed rectal mucosa should take precedence over BRAF results.

Motivation: The CEBS data repository is being developed to promote a systems biology approach to understand the biological effects of environmental stressors. CEBS will house data from multiple gene expression platforms (transcriptomics), protein expression and protein–protein interaction (proteomics), and changes in low molecular weight metabolite levels (metabolomics) aligned by their detailed toxicological context. The system will accommodate extensive complex querying in a user-friendly manner. CEBS will store toxicological contexts including the study design details, treatment protocols, animal characteristics and conventional toxicological endpoints such as histopathology findings and clinical chemistry measures. All of these data types can be integrated in a seamless fashion to enable data query and analysis in a biologically meaningful manner. Results: An object model, the SysBio-OM (Xirasagar et al., 2004) has been designed to facilitate the integration of microarray gene expression, proteomics and metabolomics data in the CEBS database system. We now report SysTox-OM as an open source systems toxicology model designed to integrate toxicological context into gene expression experiments. The SysTox-OM model is comprehensive and leverages other open source efforts, namely, the Standard for Exchange of Nonclinical Data () which is a data standard for capturing toxicological information for animal studies and Clinical Data Interchange Standards Consortium () that serves as a standard for the exchange of clinical data. Such standardization increases the accuracy of data mining, interpretation and exchange. The open source SysTox-OM model, which can be implemented on various software platforms, is presented here. Availability: A universal modeling language (UML) depiction of the entire SysTox-OM is available at and the Rational Rose object model package is distributed under an open source license that permits unrestricted academic and commercial use and is available at . Currently, the public toxicological data in CEBS can be queried via a web application based on the SysTox-OM at Contact: xirasagars@saic.com Supplementary information: Supplementary data are available at Bioinformatics online.

An ideal therapeutic for cancer would be one that selectively targets to tumor cells, is nontoxic to normal cells, and that could be systemically delivered, thereby reaching metastases as well as primary tumor. Immunoliposomes directed by monoclonal antibody or its fragments are promising vehicles for tumor-targeted drug delivery. However, there is currently very limited data on gene delivery using these vehicles. We have recently described a cationic immunoliposome system directed by a lipid-tagged, single-chain antibody Fv fragment (scFv) against the human transferrin receptor (TfR) that shows promising efficacy for systemic p53 tumor suppressor gene therapy in a human breast cancer metastasis model. However, the extremely low yield of this lipid-tagged scFv limited further downstream development and studies. Here we report a different expression strategy for the anti-TfR scFv, which produces high levels of protein without any tags, and a different approach for complexing the targeting scFv to the liposomes. This approach entails covalently conjugating the scFv to the liposome via a cysteine at the 3'-end of the protein and a maleimide group on the liposome. Our results show that this conjugation does not impair the immunological activity or targeting ability of the scFv. The scFv-cys targets the cationic liposome-DNA complex (lipoplex) to tumor cells and enhances the transfection efficiencies both in vitro and in vivo in a variety of human tumor models. This scFv-immunoliposome can deliver the complexed gene systemically to tumors in vivo, where it is efficiently expressed. In comparison with the whole antibody or transferrin molecule itself, the scFv has a much smaller size for better penetration into solid tumors. It is also a recombinant protein rather than a blood product; thus, large scale production and strict quality control are feasible. This new approach provides a promising system for tumor-targeted gene delivery that may have potential for systemic gene therapy of various human cancers.

Background Although lobectomy is considered the standard surgical treatment for the majority of patients with non-small-cell lung cancer (NSCLC), the operation project for patients with stage IA NSCLC (T1a, tumor diameter ≤2 cm) remains controversial. Sublobectomy is appropriate only in certain patients as many doctors consider it to be overtreatment. We evaluated the five-year overall survival rate of sublobectomy and lobectomy for stage IA NSCLC (T1a, tumor diameter ≤2 cm) through a meta-analysis. Methods The five-year overall survival rate (OS) of stage IA (T1a) NSCLC after sublobectomy (including wedge resection and segmentectomy) and lobectomy were compared. We also compared the OS of stage IA (T1a) NSCLC after segmentectomy and lobectomy. The log (hazard ratio, ln (HR)) and its standard error (SE) were used as the outcome measure for data combining. Results There were 12 eligible studies published between 1994 and 2013 in which the total number of participants was 18,720. When compared to lobectomy, there was a statistically significant difference of sublobectomy on OS of stage IA (T1a) NSCLC patients (HR 1.38; 95% confidence interval (95% CI), 1.19 to 1.61; P

We have previously shown that the human ETS1 protein (p51-ETS1), when ectopically expressed in colon cancer cell lines, is able to reduce its tumorigenicity without affecting its growth properties. To understand the mechanism of tumor reduction, we have expressed two different forms of ETS1 in colon cancer cell lines. Data presented in this paper indicate that the naturally occurring spliced variant protein, p42-ETS1, lacking the region encoded by ETS1 exon VII, represses the tumorigenicity, while p51-ETS1 reduces the tumorigenicity. Repression of tumorigenicity mediated by p42-ETS1 appears to be caused by its ability to induce apoptosis in epithelial cancer cells. This work can have profound medical significance in that it may open up new insights into the potential role of the p42-ETS1 in the induction of apoptosis in epithelial cell cancers and may provide a rationale for its use for potential gene therapy experiments to initiate cell death in cancer cells.