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Background: Growth differentiation factor 15 (GDF-15) is a homeostatic cytokine that regulates neural and cardio-metabolic functions, and its release is increased in response to stress, injury, and inflammation. In patients with coronary artery disease and heart failure (HF), three separate meta-analyses have found that elevated circulating GDF-15 was predictive of major adverse cardiovascular events (MACE), but none has evaluated its effects on incident MACE including HF and mortality hazard in type 2 diabetes. Methods: MEDLINE, EMBASE, and Scopus databases were queried. Articles that met the predefined eligibility criteria, including prospective studies that reported adjusted hazard ratios (aHRs), were selected according to the Cochrane Handbook and PRISMA guidelines. Study endpoints were (1) MACE including HF, and (2) all-cause mortality. Different GDF-15 concentration measurements were harmonized using a validated mathematical approach to express log2-transformed values in per standard deviation (SD). Study heterogeneity (I2), quality, and bias were assessed. Results: 19354 patients in 8 prospective studies were included. In 7 studies that reported 4247 MACE among 19200 participants, the incident rate was 22.1% during a median follow-up of 5.6 years. It was found that four of eight studies included HF decompensation or hospitalization as a component of MACE. In 5 studies that reported all-cause mortality, 1893 of 13223 patients died, at an incidence rate of 15.1% over 5.0 years. Of note, each 1 SD increase of log2[GDF-15] was associated with aHRs of 1.12 (1.09–1.15, I2 = 5%, p < 0.000001) and 1.27 (1.11–1.46, I2 = 86%, p = 0.00062) and for MACE and all-cause mortality, respectively. Conclusion: Elevated circulating level of GDF-15 was robustly predictive of MACE in patients with T2D but its prognostic significance in the prediction of mortality requires further studies.

Associative learning, a critical learning principle to improve an individual’s adaptability, has been emulated by few organic electrochemical devices. However, complicated bias schemes, high write voltages, as well as process irreversibility hinder the further development of associative learning circuits. Here, by adopting a poly(3,4-ethylenedioxythiophene):tosylate/Polytetrahydrofuran composite as the active channel, we present a non-volatile organic electrochemical transistor that shows a write bias less than 0.8 V and retention time longer than 200 min without decoupling the write and read operations. By incorporating a pressure sensor and a photoresistor, a neuromorphic circuit is demonstrated with the ability to associate two physical inputs (light and pressure) instead of normally demonstrated electrical inputs in other associative learning circuits. To unravel the non-volatility of this material, ultraviolet-visible-near-infrared spectroscopy, X-ray photoelectron spectroscopy and grazing-incidence wide-angle X-ray scattering are used to characterize the oxidation level variation, compositional change, and the structural modulation of the poly(3,4-ethylenedioxythiophene):tosylate/Polytetrahydrofuran films in various conductance states. The implementation of the associative learning circuit as well as the understanding of the non-volatile material represent critical advances for organic electrochemical devices in neuromorphic applications., Organic transistors that can simulate basic synaptic functions and act as biomimetic devices are advantageous for next generation bioelectronics. Here, the authors realize non-volatile organic electrochemical transistors with optimized performance required for associative learning circuits.

The development of organic thin-film transistors (OTFTs) with low power consumption and high gain will advance many flexible electronics. Here, by combining solution-processed monolayer organic crystal, ferroelectric HfZrOx gating and van der Waals fabrication, we realize flexible OTFTs that simultaneously deliver high transconductance and sub-60 mV/dec switching, under one-volt operating voltage. The overall optimization of transconductance, subthreshold swing and output resistance leads to transistor intrinsic gain and amplifier voltage gain over 5.3 × 104 and 1.1 × 104, respectively, which outperform existing technologies using organics, oxides and low-dimensional nanomaterials. We further demonstrate battery-powered, integrated wearable electrocardiogram (ECG) and pulse sensors that can amplify human physiological signal by 900 times with high fidelity. The sensors are capable of detecting weak ECG waves (undetectable even by clinical equipment) and diagnosing arrhythmia and atrial fibrillation. Our sub-thermionic OTFT is promising for battery/wireless powered yet performance demanding applications such as electronic skins and radio-frequency identification tags, among many others., Exploiting negative capacitance effects in organic thin-film transistors (OTFTs) is advantageous for enhancing device performance. Here, the authors report solution-processed sub-thermionic OTFTs and circuits with ferroelectric hafnium oxides that show ultra-low power and ultra-high gain.

Background: Evidence suggest periodontal bacterial infection can contribute to oral cancer initiation and progression. Aim: To investigate the effects of periodontal bacteria on oral cancer cell behavior using a cell-based system and a mouse carcinogenesis model. Methods: Oral cancer cell lines were polyinfected with four periodontal bacteria. Cytokine levels and relative changes in oncogene mRNA expression were determined post-infection. Oral tumours in mice induced by 4-nitroquinoline-1-oxide (4NQO) were compared with and without administrating periodontal bacteria. Results: Polyinfected oral cancer cells had upregulated MMP1, MMP9, and IL-8. The expression of cell survival markers MYC, JAK1, and STAT3 and epithelial-mesenchymal transition markers ZEB1 and TGF-β were also significantly elevated. Monoinfections showed F. nucleatum alone had comparable or greater effects than the four bacteria together. Fusobacterial culture supernatant, primarily LPS, was sufficient to induce IL-8 secretion, demonstrating that direct contact of live Fusobacteria with cancer cells might not be required to exert changes in cancer cell behaviour. In the 4NQO-induced oral tumour model, mice infected with bacteria developed significantly larger and more numerous lesions compared to those not infected. Conclusion: This study demonstrated that Fusobacteria could potentially enhance cancer cell invasiveness, survival, and EMT when presented in the oral tumour microenvironment. Abbreviations: 4NQO, 4-nitroquinoline-1-oxide; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial–mesenchymal transition; IL-8, interleukin-8; JAK1, Janus kinase 1; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; OSCCs, oral squamous cell carcinomas; PK, proteinase K; PMB, Polymyxin B; qRT-PCR, quantitative real-time polymerase chain reaction; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor beta; ZEB1, zinc finger E-Box binding homeobox 1

Detecting saliency in videos is a fundamental step in many computer vision systems. Saliency is the significant target(s) in the video. The object of interest is further analyzed for high-level applications. The segregation of saliency and the background can be made if they exhibit different visual cues. Therefore, saliency detection is often formulated as background subtraction. However, saliency detection is challenging. For instance, dynamic background can result in false positive errors. In another scenario, camouflage will result in false negative errors. With moving cameras, the captured scenes are even more complicated to handle. We propose a new framework, called saliency detection via background model completion (SD-BMC), that comprises a background modeler and a deep learning background/foreground segmentation network. The background modeler generates an initial clean background image from a short image sequence. Based on the idea of video completion, a good background frame can be synthesized with the co-existence of changing background and moving objects. We adopt the background/foreground segmenter, which was pre-trained with a specific video dataset. It can also detect saliency in unseen videos. The background modeler can adjust the background image dynamically when the background/foreground segmenter output deteriorates during processing a long video. To the best of our knowledge, our framework is the first one to adopt video completion for background modeling and saliency detection in videos captured by moving cameras. The F-measure results, obtained from the pan-tilt-zoom (PTZ) videos, show that our proposed framework outperforms some deep learning-based background subtraction models by 11% or more. With more challenging videos, our framework also outperforms many high-ranking background subtraction methods by more than 3%.

Autoantibodies are classically important in making an accurate diagnosis of systemic lupus erythematosus (SLE). Antihistone and antispliceosome autoantibodies were among the first antinuclear protein responses identified in SLE. Because antihistone antibodies have been described in many diseases, they are generally regarded as a nonspecific biomarker. However, autoantibody reactivity to higher ordered structures that are dependent on histones, such as chromatin or nucleosomes, has been consistently reported to be a highly sensitive and specific marker for SLE and drug-induced lupus. Antispliceosome antibodies primarily refer to anti–small nuclear ribonucleoproteins (snRNPs) directed against Sm and U1 ribonucleoproteins (RNP). Anti-Sm is a marker for SLE, whereas anti-U1 RNP is often associated with mixed connective tissue disease and a variety of other systemic autoimmune diseases. The early appearance of antinucleosome and anti-snRNPs antibodies suggests that loss of immune tolerance to chromatin and spliceosome is an early event in SLE.

33 pags., 23 figs., 5 tabs., The TROPOspheric Monitoring Instrument(TROPOMI), launched in October 2017 on board the Sentinel-5 Precursor (S5P) satellite, monitors the composition of the Earth's atmosphere at an unprecedented horizontal resolution as fine as 3.5×5.5 km2. This paper assesses the performances of the TROPOMI formaldehyde(HCHO) operational product compared to its predecessor, the OMI (Ozone Monitoring Instrument) HCHO QA4ECV product, at different spatial and temporal scales. The parallel development of the two algorithms favoured the consistency of the products, which facilitates the production of long-term combined time series. The main difference between the two satellite products is related to the use of different cloud algorithms, leading to a positive bias of OMI compared to TROPOMI of up to 30% in tropical regions. We show that after switching off the explicit correction for cloud effects, the two datasets come into an excellent agreement. For medium to large HCHO vertical columns(larger than 5×1015 molec. cm-2) the median bias between OMI and TROPOMI HCHO columns is not larger than 10% (, Part of the reported work was carried out in the framework of the Copernicus Sentinel-5 Precursor Mission Performance Centre (S5p MPC), contracted by the European Space Agency (ESA/ESRIN, contract no. 4000117151/16/I-LG) and supported by the Belgian Federal Science Policy Office (BELSPO), the Royal Belgian Institute for Space Aeronomy (BIRA-IASB) and the German Aerospace Centre (DLR). BIRA-IASB acknowledges national funding from BELSPO and ESA through the ProDEx projects TRACE-S5P (TRACE-S5P project) and TROVA. Part of this work was also carried out in the framework of the S5p Validation Team (S5PVT) AO projects NIDFORVAL (ID no. 28607, PI Gaia Pinardi, Corinne Vigouroux, BIRA-IASB). Multi-sensor HCHO developments have been funded by the EU FP7 QA4ECV project (grant no. 607405), in close cooperation with KNMI, University of Bremen, MPIC-Mainz and WUR. Work by Hitoshi Irie was supported by the Environment Research and Technology Development Fund (JPMEERF20192001 and JPMEERF20215005) of the Environmental Restoration and Conservation Agency of Japan, JSPS KAKENHI (grant numbers JP19H04235 and JP20H04320) and the JAXA 2nd Research Announcement on the Earth Observations (grant number 19RT000351).

Crystallized p-type small-molecule semiconductors have great potential as efficient and stable hole transporting materials (HTMs) for perovskite solar cells (PSCs) due to their relatively high hole mobility, good stability and tunable HOMOs depending on the molecular orientation. Here, a thienoacene-based organic semiconductor, 2,9- diphenyldinaphtho[2,3-b:2’,3’-f]thieno[3,2-b]thiophene (DPh-DNTT), was thermally evaporated and employed as the dopant-free HTM that can be scaled up for large-area fabrication. By controlling the deposition temperature, the molecular orientation was modulated into a dominated face-on orientation possessing π-π stacking direction towards the surface normal to maximize the out-of-plane carrier mobility. With an engineered face-on orientation, the DPh-DNTT film shows an improved out-of-plane mobility of 3.3 ×10-2 cm2V-1s-1, outperforming the HTMs reported so far. Such orientation-reinforced mobility contributes to a remarkable efficiency of 20.2% for CH3NH3PbI3 inverted PSCs with enhanced stability. The results reported here provide insights into engineering the orientation of molecules for the dopant-free organic HTMs for PSCs.

BackgroundThe goal of this study was to investigate treatment outcome and related intervention processes of mindfulness-based cognitive therapy versus health qigong-based cognitive therapy versus waitlist control among individuals with mood disorders.MethodsA total of 187 individuals with mood disorders were randomized and allocated into mindfulness-based cognitive therapy, health qigong-based cognitive therapy, or waitlist control groups. All participants were assessed at three time points with regard to depressive and anxiety symptoms, physical and mental health status, perceived stress, sleep quality, and self-efficacy. Linear mixed models analysis was used to test the individual growth model by studying the longitudinal data.ResultsMindfulness-based cognitive therapy and health qigong-based cognitive therapy both produced greater improvements on all outcome measures as compared with waitlist control. Relatively, more reductions of mood symptoms were observed in the health qigong-based cognitive therapy group as compared with the mindfulness-based cognitive therapy group. Health qigong-based cognitive therapy is more conducive to physical health status whereas mindfulness-based cognitive therapy has more favorable mental health outcomes. Individual growth curve models indicated that alterations in perceived stress was the common predictor of mood changes in both intervention groups.ConclusionsThe predominant emphasis on physical health in health qigong-based cognitive therapy makes it more acceptable and effective than mindfulness-based cognitive therapy as applied in Chinese individuals with mood disorders. The influence of Chinese culture is discussed.Trial registrationHKU Clinical Trials Registry. Identifier:HKUCTR-2558. Registered 21st Nov 2018.

ObjectivesTo study the prevalence and risk factors of fragility fractures in a longitudinal cohort of patients with systemic lupus erythematosus (SLE).MethodsAll patients who fulfilled ≥4 1997 ACR criteria for SLE and have been registered in our cohort database since 1990 were included. Symptomatic fragility fractures, defined as those that occurred with no preceding injury or after a low-energy impact, were identified from the SLE organ damage index (SDI) data and verified by record review. A longitudinal cohort of 383 SLE patients who participated in a cross-sectional study in 2011 and had a baseline dual energy x-ray absorptiometry (DEXA) scan performed was further analyzed for factors predicting new fragility fractures over time. These patients were stratified into 2 groups according to the presence of previous fragility fracture or osteoporosis at baseline, defined as a DEXA T score Results1140 SLE patients were included (age of onset 34.7±14.4 years; 91.5% women). 102 fractures (hip [n=15]; vertebral [n=54]; limbs (non-hip) [n=14]; digital/rib [n=19]) developed in 91(8.0%) patients over a mean of 13.1 years. The prevalence of major osteoporotic and hip fractures was 0.56 and 0.10 per 100 patient-years, respectively. A cohort of 383 SLE patients were further analyzed (age at DEXA scan 40.5±13 years; 94% women). Osteoporosis was present in 105 patients (13 with past fractures) at baseline and 8 other patients had osteopenia but a history of fragility fractures. Patients with osteoporosis/previous fractures (N=113), compared to those without (N=270), were more likely to have SLE onset during childhood (ConclusionIn a longitudinal cohort of SLE followed for over 12 years, new fragility fracture developed in 8.9% of patients. Increasing age, osteoporosis, a personal or family history of fractures were major risk factors.Disclosure of InterestsNone declared

ObjectivesTo study the effect of serum PCSK9 on major cardiovascular adverse events (MACEs) in Chinese patients with systemic lupus erythematosus (SLE).MethodsConsecutive patients who fulfilled ≥4 1997 ACR criteria for SLE and consented for a biomarker study between 2009 and 2012 were included. Stored serum samples from these patients were assayed for the levels of PCSK9 using a commercial ELISA kit (OKBB00903, Lot# 1344, Aviva Systems Biology, San Diego, US). New MACEs (acute coronary syndrome, ischemic stroke, peripheral vascular disease) documented by imaging and angiographic studies over time was evaluated. Patients were stratified into high/low PCSK9 groups according to the best cut-off level by ROC analysis for the prediction of these events. The cumulative incidence of new MACEs and mortality over time was studied by Kaplan-Meier’s analysis and compared between the high and low PCSK9 subgroups. Cox regression was performed to study the effect of the PCSK9 subgroups on new MACEs and mortality, adjusted for other confounding factors.Results539 SLE patients were studied (93% women, age 41.9±14.0 years; disease duration 106±90.4 months at entry). The mean PCSK level at baseline was 265±158ng/ml and a cut-off of 243.25ng/ml best predicted a new vascular event by the maximum Youden’s index (ROC analysis: AUC 0.63[0.51-0.74]; sensitivity 69%; specificity 61%). 220 SLE patients had baseline PCSK9 level of ≥243.25ng/ml (high PCSK9) and 319 patients had level below 243.25ng/ml (low PCSK9). Patients with high PCSK9 (n=220) had more active SLE than those with low PCSK9 (n=319) (pConclusionHigh circulating levels of PCSK9 increase the risk of MACEs and vascular mortality in patients with SLE.Disclosure of InterestsNone declared

ObjectivesTo study the effect of osteoporosis on major adverse cardiovascular events (MACEs) and mortality in a longitudinal cohort of patients with systemic lupus erythematosus (SLE).MethodsPatients who fulfilled ≥4 1997 ACR criteria for SLE and participated in a cross-sectional study on osteoporosis in the year 2011 were studied. All patients had a dual energy x-ray absorptiometry (DXA) scan (Delphi densitometer; Hologic, Bedford, USA) performed between the years 2004-2008 and were followed in the rheumatology clinics by the same team of physicians. The incidence of new MACEs, which were defined as ischemic vascular events (acute coronary syndrome, stroke, peripheral vascular disease) documented by imaging and angiographic studies, was evaluated. Patients were stratified into 2 groups according to the presence of osteoporosis at baseline, which was defined as a DXA T score of Results383 SLE patients were studied (age at DXA scan 40.5±13 years; 94% women; SLE duration 8.0±7.4 years). Osteoporosis at the hip, femoral neck or spine at baseline was present in 105 patients (13 with old fragility fractures) and 8 patients had osteopenia and past fragility fractures. The demographic characteristics, prevalence of traditional atherosclerotic risk factors and antiphospholipid (aPL) antibodies (lupus anticoagulant or moderate/high titers of IgG-anticardiolipin antibodies) were not significantly different between those with osteoporosis/fracture (N=113) and without (N=270). Patients with osteoporosis/fracture were more likely to be using glucocorticoids (79% vs 62%; p=0.002) and mycophenolate mofetil/azathioprine/calcineurin inhibitors (58% vs 48%; p=0.08) but less likely to be treated with hydroxychloroquine (40% vs 51%; p=0.051) at baseline. Over a follow-up of 153±41 months, 44 new MACEs (acute coronary syndrome [n=19]; ischemic stroke [n=19]; peripheral vascular disease with digital gangrene/amputation [n=6]) developed in 42 patients. The incidence of MACEs was significantly higher in patients with osteoporosis/fracture than those without (1.59 vs 0.63/100 patient-years; p=0.001). The cumulative risk of MACEs at 3, 5 and 10 years was 6.3%, 11.7%, 14.7%, and 0.4%, 1.9%, 4.7%, respectively, in the osteoporosis and non-osteoporosis groups (log rank test; p=0.002; univariate hazard ratio 2.58[1.40-4.74]; p=0.002). In a Cox regression model, osteoporosis/fracture remained an independent risk factor for the development of MACEs after adjustment for age, sex, LDL level, atherogenic index, diabetes mellitus, hypertension, past MACE, aPL antibodies, smoking, obesity and the use medications that included immunosuppressive drugs, aspirin/warfarin, statins, vitamin D and bisphosphonates (HR 2.41[1.25-4.67]; p=0.009). At last follow-up, 62(16%) patients succumbed (MACEs in 8 patients [vascular mortality], infective complications in 27 patients, cancer in 10 patients). Osteoporosis/fracture was associated with vascular mortality (HR 11.1[1.02-120]; p=0.048) but not with all-cause mortality (HR 1.55[0.89-2.68]; p=0.12) after adjustment for the same covariates in separate multivariate models.ConclusionOsteoporosis increases the risk of MACEs and vascular mortality in patients with SLE, which is not accounted by traditional vascular risk factors. Elevation of inflammatory cytokines in SLE that are common to bone metabolism and atherosclerotic vascular disease may be responsible.Disclosure of InterestsNone declared

BackgroundThe SIMPLE (SIMple Disease Assessment for People with Lupus Erythematosus) index is a composite numeric tool that captures disease activity from patients’ self-assessment with minimal physicians’ input. The SIMPLE index consists of 2 components: patient self-reported survey questionnaire (3 items from the lupus symptoms domain from the validated LupusPRO, 10 items from Lupus Impact Tracker [LIT], change in the health status and current glucocorticoids use [and dose]) and two laboratory tests (low complements [C3/C4] and urine protein-creatinine ratio >0.5). The values are put in an equation to derive a number, which is transformed to a 0- to 100-point scale by a formula using weighted scores of the above parameters. The SIMPLE index has been validated in US with good correlation with physicians’ assessment of disease activity.ObjectivesTo validate the SIMPLE index for systemic lupus erythematosus (SLE) disease activity assessment in a longitudinal cohort of Chinese patients.MethodsAdult patients (age ≥18 years) who fulfilled the 2012 SLICC criteria for SLE and were followed in the Rheumatology clinics of Tuen Mun Hospital, Hong Kong were recruited. Patients were followed for a total of 3 consecutive visits, including hospitalization. Participants were invited to complete the SIMPLE questionnaire before seeing doctors on the same day of clinic visit or hospital stay. The two laboratory results were supplemented by research nurses. Physicians, who were blinded to the SIMPLE results, were asked to complete disease activity assessment by the SELENA-SLEDAI and physicians’ global assessment (PGA) after consultation. Correlation was made between the SIMPLE score and the SLEDAI/PGA scores by Spearman’s rank correlation test. Correlation was also performed for the changes in total/clinical SLEDAI, PGA with the change in SIMPLE index during subsequent visits relative to baseline.Results399 SLE patients were studied (93.7% women; age 45.3±13.4 years; disease duration 13.3±8.0 years). The proportion of patients having a history of neuropsychiatric and renal disease that required immunosuppressive therapies was 9.8% and 55.6%, respectively. At visit 1, 18 (4.5%) patients had clinical SLEDAI ≥5 and 98 (24.6%) had clinical SLEDAI 1-4. The mean total SLEDAI was 3.02±2.87 and PGA score was 0.60±0.53. A total of 178 patients (44.6%) had SDI score ≥1. The mean SIMPLE index was 25.6±12.8. SIMPLE index correlated significantly with clinical SLEDAI (ρ=0.56; p24 points best predicted a clinical SLEDAI score of 1-4 (area under the curve [AUC] 0.72[0.68-0.75]; sensitivity 0.65; specificity 0.64), and >31 points best predicted a clinical SLEDAI score of ≥5 (AUC 0.84[0.77-0.91]; sensitivity 0.76, specificity 0.81).ConclusionThe SIMPLE index shows a good correlation with SELENA-SLEDAI and PGA. It is also sensitive to change in SLEDAI and PGA score during subsequent visits. The SIMPLE index is a simple tool that enables patients to self-report disease activity and communicate with the health care team more efficiently.Disclosure of InterestsNone declared

Tumor heterogeneity plays a key role in cancer relapse and metastasis, however, the distinct cellular behaviors and kinetics of interactions among different cancer cell subclones and the tumor microenvironment are poorly understood. By profiling an isogenic model that resembles spontaneous human ovarian cancer metastasis with an highly metastatic (HM) and non-metastatic (NM) tumor cell pair, one finds an upregulation of Wnt/β-catenin signaling uniquely in HM. Using humanized immunocompetent mice, one shows for the first time that activated β-catenin acts nonautonomously to modulate the immune microenvironment by enhancing infiltrating tumor-associated macrophages (TAM) at the metastatic site. Single-cell time-lapse microscopy further reveals that upon contact with macrophages, a significant subset of HM, but not NM, becomes polyploid, a phenotype pivotal for tumor aggressiveness and therapy resistance. Moreover, HM, but not NM, polarizes macrophages to a TAM phenotype. Mechanistically, β-catenin upregulates cancer cell surface metadherin, which communicates through CEACAM1 expressed on macrophages to produce CCL3. Tumor xenografts in humanized mice and clinical patient samples both corroborate the relevance of enhanced metastasis, TAM activation, and polyploidy in vivo. The results thus suggest that targeting the β-catenin-metadherin/CEACAM1-CCL3 positive feedback cascade holds great therapeutic potential to disrupt polyploidization of the cancer subclones that drive metastasis.

Background The International Consensus on Antinuclear Antibody (ANA) Patterns (ICAP) has recently proposed nomenclature in order to harmonize ANA indirect immunofluorescence (IIF) pattern reporting. ICAP distinguishes competent-level from expert-level patterns. A survey was organized to evaluate reporting, familiarity, and considered clinical value of ANA IIF patterns. Methods Two surveys were distributed by European Autoimmunity Standardization Initiative (EASI) working groups, the International Consensus on ANA Patterns (ICAP) and UK NEQAS to laboratory professionals and clinicians. Results 438 laboratory professionals and 248 clinicians from 67 countries responded. Except for dense fine speckled (DFS), the nuclear competent patterns were reported by > 85% of the laboratories. Except for rods and rings, the cytoplasmic competent patterns were reported by > 72% of laboratories. Cytoplasmic IIF staining was considered ANA positive by 55% of clinicians and 62% of laboratory professionals, with geographical and expertise-related differences. Quantification of fluorescence intensity was considered clinically relevant for nuclear patterns, but less so for cytoplasmic and mitotic patterns. Combining IIF with specific extractable nuclear antigens (ENA)/dsDNA antibody testing was considered most informative. Of the nuclear competent patterns, the centromere and homogeneous pattern obtained the highest scores for clinical relevance and the DFS pattern the lowest. Of the cytoplasmic patterns, the reticular/mitochondria-like pattern obtained the highest scores for clinical relevance and the polar/Golgi-like and rods and rings patterns the lowest. Conclusion This survey confirms that the major nuclear and cytoplasmic ANA IIF patterns are considered clinically important. There is no unanimity on classifying DFS, rods and rings and polar/Golgi-like as a competent pattern and on reporting cytoplasmic patterns as ANA IIF positive.

Aim To review the clinical use and the effectiveness of tamoxifen in patients with advanced or recurrent ovarian cancer. Methods A retrospective review of clinical records was conducted in patients who received tamoxifen for the treatment of ovarian cancer between 2002 and 2016. We reviewed the clinical setting that it was given, duration of use, patients' tolerability, clinical benefit and progression‐free survival. We also attempted to identify predictive markers for response. Results A total of 92 patients received tamoxifen during this 15‐year period. The patients received a median of 2.5 lines of chemotherapy before switching to tamoxifen, and they remained on tamoxifen for a median of 5.6 months (range 0–85 months), with 24 patients receiving it for more than 12 months. Seventy‐six patients continued on tamoxifen for more than 2 months. In this group, 75 patients had an evaluable response, either by CA 125 or clinically and clinical benefit rate (defined as complete, partial response and static disease) was seen in 42 patients (56%), with majority of patients having static disease. The median progression‐free survival was 5.3 months (95% confidence interval, 2.6–8.1). Tamoxifen was well tolerated. Hormone receptor status was not demonstrated to predict response. Conclusion Patients with advanced ovarian cancer who have failed previous lines of chemotherapy may achieve static disease with tamoxifen with minimal side effects. Tamoxifen may still have a role in the era of molecular target therapy., Patients with advanced ovarian cancer who have failed previous lines of chemotherapy may achieve static disease with tamoxifen with minimal side effects. Tamoxifen may still have a role in the era of molecular target therapy.

Background: To evaluate the interpretation and reporting of antinuclear antibodies (ANA) by indirect immunofluorescence assay (IFA) using HEp-2 substrate based on common practice and guidance by the International Consensus on ANA patterns (ICAP).Method: Participants included two groups [16 clinical laboratories (CL) and 8 in vitro diagnostic manufacturers (IVD)] recruited via an email sent to the Association of Medical Laboratory Immunologists (AMLI) membership. Twelve (n=12) pre-qualified specimens were distributed to participants for testing, interpretation and reporting HEp-2 IFA. Results obtained were analyzed for accuracy with the intended and consensus response for three main categorical patterns (nuclear, cytoplasmic and mitotic), common patterns and ICAP report nomenclatures. The distributions of antibody titers of specimens were also compared. Results: Laboratories differed in the categorical patterns reported; 8 reporting all patterns, 3 reporting only nuclear patterns and 5 reporting nuclear patterns with various combinations of other patterns. For all participants, accuracy with the intended response for the categorical nuclear pattern was excellent at 99% [95% confidence interval (CI): 97-100%] compared to 78% [95% CI: 67-88%] for the cytoplasmic, and 93% [95% CI: 86%-100%] for mitotic patterns. The accuracy was 13% greater for the common nomenclature [87%, 95% CI: 82-90%] compared to the ICAP nomenclature [74%, 95% CI: 68-79%] for all participants. Participants reporting all three main categories demonstrated better performances compared to those reporting 2 or less categorical patterns. The average accuracies varied between participant groups, however, with the lowest and most variable performances for cytoplasmic pattern specimens. The reported titers for all specimens varied, with the least variability for nuclear patterns and most titer variability associated with cytoplasmic patterns. Conclusions: Our study demonstrates significant accuracy for all participants in identifying the categorical nuclear staining as well as traditional pattern assignments for nuclear patterns. However, there was less consistency in reporting cytoplasmic and mitotic patterns, with implications for assigning competencies and training for clinical laboratory personnel.

Background To evaluate the interpretation and reporting of antinuclear antibodies (ANA) by indirect immunofluorescence assay (IFA) using HEp-2 substrates based on common practice and guidance by the International Consensus on ANA patterns (ICAP). Method Participants included two groups [16 clinical laboratories (CL) and 8 in vitro diagnostic manufacturers (IVD)] recruited via an email sent to the Association of Medical Laboratory Immunologists (AMLI) membership. Twelve (n = 12) pre-qualified specimens were distributed to participants for testing, interpretation and reporting HEp-2 IFA. Results obtained were analyzed for accuracy with the intended and consensus response for three main categorical patterns (nuclear, cytoplasmic and mitotic), common patterns and ICAP report nomenclatures. The distributions of antibody titers of specimens were also compared. Results Laboratories differed in the categorical patterns reported; 8 reporting all patterns, 3 reporting only nuclear patterns and 5 reporting nuclear patterns with various combinations of other patterns. For all participants, accuracy with the intended response for the categorical nuclear pattern was excellent at 99% [95% confidence interval (CI): 97–100%] compared to 78% [95% CI 67–88%] for the cytoplasmic, and 93% [95% CI 86%–100%] for mitotic patterns. The accuracy was 13% greater for the common nomenclature [87%, 95% CI 82–90%] compared to the ICAP nomenclature [74%, 95% CI 68–79%] for all participants. Participants reporting all three main categories demonstrated better performances compared to those reporting 2 or less categorical patterns. The average accuracies varied between participant groups, however, with the lowest and most variable performances for cytoplasmic pattern specimens. The reported titers for all specimens varied, with the least variability for nuclear patterns and most titer variability associated with cytoplasmic patterns. Conclusions Our study demonstrated significant accuracy for all participants in identifying the categorical nuclear staining as well as traditional pattern assignments for nuclear patterns. However, there was less consistency in reporting cytoplasmic and mitotic patterns, with implications for assigning competencies and training for clinical laboratory personnel.

Achieving gigahertz transit frequencies in low-voltage organic thin-film transistors (TFTs) will require a contact resistance below about 1 Ohm-cm [1,2]. A general approach to reduce the contact resistance in organic devices is to modify the surface of the metal contacts with a chemisorbed interface layer, ostensibly by reducing the nominal injection barrier. Combined with a thin gate dielectric, this approach can enable contact resistances below 30 Ohm-cm and transit frequencies above 10 MHz at low voltages in coplanar organic TFTs [3,4]. However, further reduction of the contact resistance depends strongly on non-idealities of the interface other than the nominal barrier height according to the Schottky-Mott limit. We show a detailed study on the efficacy of interface layers based on various thiols to improve the contact resistance in coplanar dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene (DNTT) TFTs. We compare the contact resistance of multiple sets of TFTs to results from ultraviolet photoelectron spectroscopy measurements and find strong evidence that Fermi-level pinning prevents a significant reduction of the contact resistance below about 100 Ohm-cm in DNTT TFTs. Therefore, we conclude that this approach may not be a generally sufficient method by itself to eliminate the contact resistance in organic TFTs.

A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed.Consensus was reached in 26 statements. At an individual level, eradication ofEvidence supports the proposal that eradication therapy should be offered to all individuals infected with

The correspondence of Lee et al 1 questions why the recent paper2 of the international consensus on ANA patterns (ICAP) consortium about the clinical relevance of HEp-2 indirect immunofluorescent assay (IIFA) patterns does not include the HEp-2000 substrate (Immunoconcepts, Sacramento, California, USA). The decision not to include the HEp-2000 substrate origins from the initial conception of ICAP: it was decided not to include manipulated cellular substrates.3 Since the HEp-2000 cells are transfected with the SS-A/Ro60 cDNA, this substrate was not incorporated in the consensus. Obviously, this decision is disputable and perhaps should be reconsidered in the near future. Indeed, it is to be taken into account that also the ‘non-manipulated’ substrates may be different. First, characteristics of the subcultures may have gradually deviated from the original HEp-2 cells. It is even argued that in time the HEp-2 cells have been contaminated with HeLa-cells.4 Second, diagnostic companies use distinct fixation procedures that eventually also may affect the HEp-2 IIFA patterns. Cell cycle progression can also be manipulated in order …

Objective Anti-DFS70 antibodies correlating with the nuclear dense fine speckled (DFS) pattern in the HEp-2 indirect immunofluorescence assay (IFA) are less common in patients with systemic autoimmune rheumatic disease (SARD) than in healthy subjects and their clinical associations remain elusive. We hosted a multi-center HEp-2 IFA training program to improve the ability of clinical laboratories to recognize the DFS pattern and to investigate the prevalence and relevance of anti-DFS70 antibodies. Methods DFS pattern sera identified by HEp-2 IFA in 29 centers in China were redirected to a central laboratory for anti-DFS70 testing by line immunoblot assay (LIA), enzyme-linked immunosorbent assay (ELISA), and IFA with HEp-2 ELITE/DFS70-KO substrate. Anti-extractable nuclear antigen antibodies were measured by LIA and the clinical relevance was examined in adult and pediatric patients. Results HEp-2 IFA positive rate and DFS pattern in positive sera were 36.2% (34,417/95,131) and 1.7% (582/34,417) in the patient cohort, and 10.0% (423/4,234) and 7.8% (33/423) in a healthy population, respectively. Anti-DFS70 prevalence among sera presenting the DFS pattern was 96.0, 93.7, and 49.6% by ELISA, LIA, and HEp-2 ELITE, respectively. 15.5% (52/336) of adult and 50.0% (20/40) of pediatric anti-DFS70 positive patients were diagnosed with SARD. Diseases most common in anti-DFS70 positive patients were spontaneous abortion (28.0%) in adults and juvenile idiopathic arthritis (22.5%) in pediatric patients. Conclusion Accurate DFS pattern identification increased the detection rate of anti-DFS70 antibodies by ELISA and LIA. Anti-DFS70 antibodies are remarkably high in cases of spontaneous abortion and in pediatric SARD patients, but not prevalent in adult SARD patients.

Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment.

The contact resistance limits the downscaling and operating range of organic field-effect transistors (OFETs). Access resistance through multilayers of molecules and the nonideal metal/semiconductor interface are two major bottlenecks preventing the lowering of the contact resistance. In this work, monolayer (1L) organic crystals and nondestructive electrodes are utilized to overcome the abovementioned challenges. High intrinsic mobility of 12.5 cm2 V-1 s-1 and Ohmic contact resistance of 40 Ω cm are achieved. Unlike the thermionic emission in common Schottky contacts, the carriers are predominantly injected by field emission. The 1L-OFETs can operate linearly from VDS = -1 V to VDS as small as -0.1 mV. Thanks to the good pinch-off behavior brought by the monolayer semiconductor, the 1L-OFETs show high intrinsic gain at the saturation regime. At a high bias load, a maximum current density of 4.2 µA µm-1 is achieved by the only molecular layer as the active channel, with a current saturation effect being observed. In addition to the low contact resistance and high-resolution lithography, it is suggested that the thermal management of high-mobility OFETs will be the next major challenge in achieving high-speed densely integrated flexible electronics.

Background Despite the wide use of the Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF34), the measurement invariance of the SCNS-SF34 across the main groups—gender and age—which might be of interest in the application of the instrument has never been confirmed. To provide an accurate assessment tool to evaluate the unmet needs of Chinese cancer patients, the present study aimed to assess the measurement invariance of the SCNS-SF34 across gender and age groups and to assess the validity and reliability of the Chinese version of the SCNS-SF34. Methods The SCNS-SF34 was administrated to 1106 Chinese cancer patients. Other instruments included the Memorial Symptom Assessment Scale-Short Form (MSAS-SF), the Short-Form-12 Health Survey version 2 (SF-12 v2) and the Hospital Anxiety and Depression Scale (HADS). Factor structure, internal construct validity, convergent validity, known-group validity and internal consistency were assessed. Results Our data fit the original five-factor model. Multi-group confirmatory factor analysis indicated measurement invariance across age and gender groups. The domains of the SCNS-SF34 had moderate correlations with the corresponding domains of the MSAS-SF, the SF-12 v2 and the HADS, which supported convergent validity. Of the 34 items, 33 had an item-total correlation that was corrected for an overlap of > 0.4 to support the internal construct validity. The SCNS-SF34 aptly differentiated patients by age and gender. The Cronbach’s alpha coefficient ranged from 0.64 to 0.87. Conclusions We confirm the measurement invariance of the Chinese version of the SCNS-SF34 across gender and age group. It is a valid and reliable tool for evaluating the needs of Chinese patients with cancer.

This chapter offers a reading of Pei Wei’s “On the Pride of Place of Being”, or in David Knechtges’ translation, “Disquisition on Esteeming the Existent.” In this work, Pei sets out the reasons why the concept of “being” should be privileged in philosophical and ethical reflection. This was an audacious project, for in so doing Pei Wei took on almost the entire intellectual establishment, which during the early years of the Jin dynasty was enamored of the view that “being” is derivative, that all beings ultimately arise from a deeply profound and mysterious source, which though subject to different interpretation can only be described as “non-being” or “nothingness” in view of its radical “transcendence.” The “chongyou lun” in its entirety has not been made available in English translation; it merits a full presentation, with special attention to bringing out the logical flow of its argument. In my concluding remarks, I will briefly comment on its place and reception in Xuanxue learning, and raise a couple of hermeneutical questions for discussion.

The indirect immunofluorescence assay (IFA) on HEp-2 cells is the reference method for autoantibody screening. The HEp-2 IFA pattern provides useful information on the possible autoantibodies in the sample. The International Consensus on Antinuclear Antibody Patterns (ICAP) initiative seeks to define and harmonize the nomenclature of HEp-2 IFA patterns. The most relevant and usual patterns have been assigned an alphanumeric code from anti-cell (AC)-1 to AC-28 and were organized into a classification algorithm (www.ANApatterns.org). The systemic sclerosis-associated autoantibodies to DNA topoisomerase I (Topo I) produce a peculiar composite 5-element HEp-2 IFA pattern (Topo I-like pattern) comprising the staining of the nucleus, metaphase chromatin plate, nucleolar organizing region, cytoplasm and nucleolus. In a recent assessment of the European Consensus Finding Study Group on autoantibodies, a well-defined anti-Topo I sample was blindly analyzed and classified according to ICAP AC patterns by 43 participant laboratories across Europe. There were wide variations among these laboratories in reporting nuclear, nucleolar and cytoplasmic patterns, indicating the inadequacy of the existing AC patterns to report the Topo I-like pattern. Several ICAP member laboratories independently demonstrated the overall consistency of the HEp-2 IFA Topo I-like pattern using HEp-2 slides from different manufacturers. The ICAP committee reviewed 24 candidate images and selected the four most representative images to be available on the ICAP website. The proper recognition of the AC-29 pattern should trigger suspicion of the presence of anti-Topo I antibodies, which may engender appropriate analyte-specific reflex tests to confirm the autoantibody specificity.

Objective: We examined adulthood diagnostic, functioning, and social outcomes of childhood ADHD in a Hong Kong Chinese clinical sample. Method: We identified from the central registry 499 Chinese adults clinically diagnosed with ADHD aged 6 to 12 in 2002-2005 in four Hong Kong child psychiatric centers. Assessments included ADHD Clinical Diagnostic Scale (ACDS), Structured Clinical Interview for DSM Disorders (SCID), and World Health Organization Disability Assessment Schedule (WHO-DAS). Results: Eligible participants = 499. One hundred forty-five completed assessments, two deceased, six incarcerated, 100 had invalid contact, 83 declined, 34 emigrated, and 129 unable to attend. Mean follow-up duration = 14.9 years. Nonrespondents were slightly younger (19.78 vs. 20.53, p < .001). In all, 83.1% of all participants currently met Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) ADHD criteria (36.8% inattentive subtype (IA), 43% combined, 3.3% hyperactive/impulsive subtype (H/I) ). One third of persistent ADHD participants currently received care. ADHD persistence was associated with significantly increased psychiatric comorbidity (49.5% vs. 22.7%, p = .02) and poor academic and social outcomes. ADHD persistence and comorbidity independently predicted impairment. Conclusion: Adulthood-persistence of clinically presented childhood ADHD is common and impairing in Hong Kong Chinese.

Crystals of organic semiconductors are excellent candidates for flexible and array-based electronics. Large-scale synthesis of organic crystals in a controllable way while maintaining homogeneous single-crystal property has been a great challenge. The existence of grain boundaries and small crystal domains, however, restrict the device performance and limit the access to commercially viable organic electronics in the industry. Herein, we report the inch-scale synthesis of highly oriented 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) organic single crystal by nucleation seed-controlled shearing method. The organic field-effect transistors developed from such single crystal have excellent carrier mobility as high as 14.9 cm2 V–1 s–1 and uniformity (standard deviation is 1.3 cm2 V–1 s–1) of 225 devices. We also found that the rotation of the principal axis in the crystal is governed by the orientations of seeds and the possible mechanism behind this phenomenon is proposed based on the density f...

Cervical cancer is one of the leading causes of cancer death in women globally, despite the widespread use of cytology/human papillomavirus (HPV) screening. In the present study, we aimed to identify the potential role of microRNA (miRNA) as a diagnostic biomarker in the detection of cervical pre-malignant lesions and cancer. In total, we recruited 582 patients with cervical diseases and 145 control individuals. The expression levels of six miRNAs (miR-20a, miR-92a, miR-141, miR-183*, miR-210 and miR-944) were found to be significantly up-regulated in cervical cancer and pre-malignant lesions compared to normal cervical samples, indicating that they are oncogenic miRNAs. Receiver operating characteristic curve analysis showed that these six miRNAs can be used to distinguish patients with cervical pre-malignant lesions or cancer from normal individuals and they also had a good predictive performance, particularly in cervical lesions. Combined use of these six miRNAs further enhanced the diagnostic accuracy over any single miRNA marker, with an area under the curve of 0.998, 0.996 and 0.959, a diagnostic sensitivity of 97.9%, 97.2% and 91.4%, and a specificity of 98.6%, 96.6% and 87.6% for low-grade lesions, high-grade lesions and cancer, respectively. This six oncogenic miRNA signature may be suitable for use as diagnostic marker for cervical pre-malignant lesions and cancer in the near future.

Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival. The growth of OCCC cell lines, OVTOKO and KK, were inhibited after iASPP silencing. Such effect was related to senescence triggering as evidenced by increased SA-β-Gal staining and p21WAF1/Cip1 expression. Moreover, knockdown of iASPP induced PLK1 downregulation, whereas either genes' silencing sensitized the cells in response to cisplatin treatment. More prominent apoptosis was induced by cisplatin in OCCC cells after the knockdown of either iASPP or PLK1 as evidenced by the formation of more cleaved caspase 3. Heightened chemosensitivity to cisplatin after iASPP knockdown was further demonstrated in in vivo xenograft model. Additionally, both iASPP and PLK1 were shown to regulate autophagic flux as the induction of LC3B-II and LC3 puncta were much less in OCCC cells with either knockdown. Importantly, inhibition of autophagy also enhanced chemosensitivity to cisplatin in OCCC cells. These findings strongly imply that iASPP and PLK1 affect the chemoresistance of OCCC via the regulation of autophagy and apoptosis. Both iASPP and PLK1 can be potential therapeutic targets for treating OCCC in combination with conventional chemotherapy.

Objectives In accordance with the Precision Medicine Initiative, new treatment strategies for head and neck squamous cell carcinoma (HNSCC) are needed to yield better therapeutic outcomes. The purpose of this study was to establish and validate chimeric antigen receptor (CAR)-T cells targets in HNSCC. Methods Putative CAR-T antigens were identified in The Cancer Genome Atlas database. To validate antigen suitability, quantitative RT-PCR, flow cytometry, and immunofluorescent staining were performed. A retroviral human CD70 CAR construct, using truncated CD27 conjugated with 4-1BB and CD3-zeta costimulatory molecules, was used to transduce activated human T cells to generate CD70 CAR-T cells. Cell-based cytotoxicity and cytokine ELISAs were used to measure efficacy of killing. Results Nine potential CAR-T targets (CD276, EGFR, MICA, MICB, MAGE-A4, FAP, EPCAM, CD70, B4GALNT1) were identified based on their high expression in tumors compared to flanking control tissues. CD70 was selected for further proof-of-principle analysis based on its differential expression in several tumor subtypes, and showed substantial heterogeneity in individual tumors analyzed. Cell surface CD70 protein and CD70 mRNA were detected from low to high levels in established HNSCC cancer cell lines. CD70 was highly expressed in 4 of 21 tumor biopsies (19%), and 3 of 4 specimens showed strong CD70 expression on the tumor cell surface. CD70-specific CAR-T cells were generated and further demonstrated to recognize and kill CD70-positive HNSCC cells efficiently, but not CD70-negative cancer cells. Conclusion CD70-specific CAR-T cells specifically recognized and efficiently eliminated CD70-positive HNSCC cells. This study provides the basis for further investigation into CD70 and other CAR-T targets.

Background: Anti-mitochondrial antibodies (AMA) are found in >90% of primary biliary cholangitis patients. Anti-rods/rings antibodies (anti-RR) are most commonly associated with interferon-α and ribavirin treatment in hepatitis C patients. Clinical laboratories routinely screen for AMA and anti-RR using indirect immunofluorescence on HEp-2 cells (HEp-2-IFA). Therefore, we sought to establish reference materials for use in AMA and anti-RR testing. Methods: AMA-positive and anti-RR-positive human plasma samples (AMA-REF and RR-REF), identified as potential reference materials based on preliminary data, were further validated by multiple laboratories using HEp-2-IFA, immunoprecipitation (IP), western blotting, IP-western, line immunoassay (LIA), addressable laser bead immunoassay (ALBIA) and enzyme-linked immunosorbent assay (ELISA). Results: AMA-REF showed a strong positive cytoplasmic reticular/AMA staining pattern by HEp-2-IFA to ≥1:1280 dilution and positive signal on rodent kidney/stomach/liver tissue. AMA-REF reacted with E2/E3, E3BP, E1α and E1β subunits of the pyruvate dehydrogenase complex by IP and western blotting and was positive for AMA antigens by LIA, ALBIA and ELISA. RR-REF showed a strong positive rods and rings staining pattern by HEp-2-IFA to ≥1:1280 dilution. RR-REF reacted with inosine monophosphate dehydrogenase by IP, IP-western and ALBIA. RR-REF also produced a nuclear homogenous staining pattern by HEp-2-IFA, immunoprecipitated proteins associated with anti-U1RNP antibody and reacted weakly with histones, nucleosomes, Sm and nRNP/Sm by LIA. Conclusions: AMA-REF and RR-REF are useful reference materials for academic or commercial clinical laboratories to calibrate and establish internal reference standards for immunodiagnostic assays. AMA-REF and RR-REF are now available for free distribution to qualified laboratories through Plasma Services Group.

Apolipoprotein A-I (apoA-I) shares with other exchangeable apolipoproteins a high level of structural plasticity. In the lipid-free state, the apolipoprotein amphipathic α-helices interact intra- and intermolecularly, providing structural stabilization by self-association. We have reported that lipid-free apoA-I becomes amyloidogenic upon physiologically relevant (myeloperoxidase-mediated) Met oxidation. In this study, we established that Met oxidation promotes amyloidogenesis by reducing the stability of apoA-I monomers and irreversibly disrupting self-association. The oxidized apoA-I monomers also exhibited increased cellular cholesterol release capacity and stronger association with macrophages, compared to nonoxidized apoA-I. Of physiologic relevance, preformed oxidized apoA-I amyloid fibrils induced amyloid formation in nonoxidized apoA-I. This process was enhanced when self-association of nonoxidized apoA-I was disrupted by thermal treatment. Solid state NMR analysis revealed that aggregates formed by seeded nonoxidized apoA-I were structurally similar to those formed by the oxidized protein, featuring a β-structure-rich amyloid fold alongside α-helices retained from the native state. In atherosclerotic lesions, the conditions that promote apoA-I amyloid formation are readily available: myeloperoxidase, active oxygen species, low pH, and high concentration of lipid-free apoA-I. Our results suggest that even partial Met oxidation of apoA-I can nucleate amyloidogenesis, thus sequestering and inactivating otherwise antiatherogenic and HDL-forming apoA-I.—Witkowski, A., Chan, G. K. L., Boatz, J. C., Li, N. J., Inoue, A. P., Wong, J. C., van der Wel, P. C. A., Cavigiolio, G. Methionine oxidized apolipoprotein A-I at the crossroads of HDL biogenesis and amyloid formation.

Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness. Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models. Results: Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity. Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.

Background: Postoperative pain is a major complaint following abdominal surgery for gynecological diseases. Effective postoperative pain control after abdominal surgery is particularly important for patient recovery, mobility, and satisfaction. Acupuncture has been commonly used for pain management. However, its efficacy in postoperative pain control is inconclusive and health economic evaluation is limited. Methods: A randomized, sham-controlled, patient- and- assessor-blind trial is designed to evaluate the efficacy and safety of acupuncture in managing postoperative pain following abdominal surgery of gynecological diseases. Patients who are eligible for laparotomy with a midline incision for gynecological neoplasia, including ovarian mass, uterine mass, and cervical lesions, will be recruited. Seventy-two participants will be randomly allocated to an acupuncture or non-invasive sham control in a 1:1 ratio. Treatment will be done within 2 h before operation, upon arrival to the ward and once daily for 5 days. The Pain Numerical Rating Scale (NRS) on the first 5 days during hospitalization will be the primary outcome and will be analyzed using the area-under-the-curve (AUC) method. The secondary outcome measures include frequency of rescue analgesic use during hospital stay, cumulative morphine consumption; quality of recovery as measured by time to recovery variables and the Quality of Recovery-9 (QoR-9); quality of life as measured by the Short Form-6 dimension (SF-6D) and EuroQol-5 Dimension-5 Level (EQ-5D-5 L). The incremental cost-effectiveness ratio of acupuncture vs sham acupuncture will be calculated. Discussion: This study protocol provides an example of integrative medicine practice in a hospital setting for the management of postoperative pain using acupuncture treatment. The acupuncture treatment protocol, if proven to be effective, can be implemented in routine settings to play a role in postoperative pain management for patients who have undergone abdominal surgery for gynecological diseases., published_or_final_version

Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. Methods: The upstream miRNA regulators were predicted by in silico analysis. Expression of GRB7 was examined by qPCR, immunoblotting and immunohistochemical analyses, while miR-193a-3p levels were evaluated by qPCR and in situ hybridization in ovarian cancer cell lines and clinical tissue arrays. MS-PCR and pyrosequencing analyses were used to assess the methylation status of miR-193a-3p. Stable overexpression or gene knockdown and Tet-on inducible approaches, in combination with in vitro and in vivo tumorigenic assays, were employed to investigate the functions of GRB7 and miR-193a-3p in ovarian cancer cells. Results: Both miR-193a-3p and its isoform, miR-193b-3p, directly targeted the 3' UTR of GRB7. However, only miR-193a-3p showed a significantly inverse correlation with GRB7-upregulated ovarian cancers. Epigenetic studies revealed that methylation-mediated silencing of miR-193a-3p led to a stepwise decrease in miR-193a-3p expression from low to high-grade ovarian cancers. Intriguingly, miR-193a-3p not only modulated GRB7 but also ERBB4, SOS2 and KRAS in the MAPK/ERK signaling pathway to enhance the oncogenic properties of ovarian cancer cells in vitro and in vivo. Conclusion: These findings suggest that epigenetic silencing of miR-193a-3p by DNA hypermethylation is a dynamic process in ovarian cancer progression, and miR-193a-3p may be explored as a promising miRNA replacement therapy in this disease.

In the development of flexible organic field-effect transistors (OFET), downsizing and reduction of the operating voltage are essential for achieving a high current density with a low operating power. Although the bias voltage of the OFETs can be reduced by a high-k dielectric, achieving a threshold voltage close to zero remains a challenge. Moreover, the scaling down of OFETs demands the use of photolithography, and may lead to compatibility issues in organic semiconductors. Herein, a new strategy based on the ductile properties of organic semiconductors is developed to control the threshold voltage at close to zero while concurrently downsizing the OFETs. The OFETs are fabricated on prestressed polystyrene shrink film substrates at room temperature, then thermal energy (160 °C) is used to release the strain. The OFETs conformally attached to the wrinkled structure are shown to locally amplify the electric field. After shrinking, the horizontal device area is reduced by 75%, and the threshold voltage is decreased from -1.44 to -0.18 V, with a subthreshold swing of 74 mV dec

Accumulating evidence indicates that the human papillomavirus (HPV) E6 protein plays a crucial role in the development of cervical cancer. Subpopulations of cells that reside within tumours are responsible for tumour resistance to cancer therapy and recurrence. However, the identity of such cells residing in cervical cancer and their relationship with the HPV-E6 protein have not been identified. Here, we isolated sphere-forming cells, which showed self-renewal ability, from primary cervical tumours. Gene expression profiling revealed that cluster of differentiation (CD) 55 was upregulated in primary cervical cancer sphere cells. Flow-cytometric analysis detected abundant CD55(+) populations among a panel of HPV-positive cervical cancer cell lines, whereas few CD55(+) cells were found in HPV-negative cervical cancer and normal cervical epithelial cell lines. The CD55(+) subpopulation isolated from the C33A cell line showed significant sphere-forming ability and enhanced tumourigenicity, cell migration, and radioresistance. In contrast, the suppression of CD55 in HPV-positive CaSki cells inhibited tumourigenicity both in vitro and in vivo, and sensitized cells to radiation treatment. In addition, ectopic expression of the HPV-E6 protein in HPV-negative cervical cancer cells dramatically enriched the CD55(+) subpopulation. CRISPR/Cas9 knockout of CD55 in an HPV-E6-overexpressing stable clone abolished the tumourigenic effects of the HPV-E6 protein. Taken together, our data suggest that HPV-E6 protein expression enriches the CD55(+) population, which contributes to tumourigenicity and radioresistance in cervical cancer cells. Targeting CD55 via CRISPR/Cas9 may represent a novel avenue for developing new strategies and effective therapies for the treatment of cervical cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Simple Summary Hexokinase II (HKII) is a key glycolysis enzyme associated with tumorigenesis, but its molecular mechanism and pathophysiological role in chemoresistant ovarian cancer remain elusive. In this study, we delineate the novel mechanism showing that activated phosphorylated-p53 (P-p53 Ser15) is required for the regulation of HKII intracellular trafficking and metabolic regulation in chemosensitive ovarian cancer, but not in chemoresistant ovarian cancer harboring p53 mutation. We have observed that increased nuclear HKII-P-p53 (Ser15) interaction is likely associated with chemosensitivity and better survival outcomes in epithelial ovarian cell lines, human primary epithelial ovarian cancer cells, and tumor sections. Nuclear HKII-P-p53 (Ser15) interaction may function as a promising prognostic biomarker, enabling prediction of patients with poor prognosis for deciding better clinical strategies. Abstract In epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII-P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII-P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.

The rapidly declining prevalence of Helicobacter pylori infection and widespread use of potent anti-secretory drugs means peptic ulcer disease has become substantially less prevalent than it was two decades ago. Management has, however, become more challenging than ever because of the threat of increasing antimicrobial resistance worldwide and widespread use of complex anti-thrombotic therapy in the ageing population. Peptic ulcers not associated with H pylori infection or the use of non-steroidal anti-inflammatory drugs are now also imposing substantial diagnostic and therapeutic challenges. This Seminar aims to provide a balanced overview of the latest advances in the pathogenetic mechanisms of peptic ulcers, guidelines on therapies targeting H pylori infection, approaches to treatment of peptic ulcer complications associated with anti-inflammatory analgesics and anti-thrombotic agents, and the unmet needs in terms of our knowledge and management of this increasingly challenging condition.

Some HCV patients using ribavirin and interferon alpha (IFN-α) develop anti-rods and rings (RR) autoantibodies, the main target of which is inosine monophosphate dehydrogenase (IMPDH), the rate-determining enzyme in de novo GTP biosynthesis. In vitro inhibition of IMPDH by ribavirin induces RR formation. Here we investigate whether other commonly used drugs that interfere with GTP biosynthesis can induce RR structures in vitro and vivo and elicit generation of autoantibodies. HEp-2 cells treated for 24h with ribavirin, mycophenolic acid (MPA), azathioprine, methotrexate or acyclovir were positive for RR structures. However, adefovir, entecavir, tenofovir and lamivudine did not induce RR structures in these cells. Structures induced by ribavirin in HEp-2 cells are stable after 24h drug-washout, while structures induced by other drugs are relatively labile, disappearing within 2h. Looking at patients treated with these drugs, HCV patients treated with ribavirin (n=17) showed higher average percentage of RR-positive peripheral mononuclear cells than autoimmune patients treated with RR-inducing immunosuppressant drugs (n=21). Serum from 173 autoimmune patients who had been treated with MPA, azathioprine or methotrexate was tested for presence of anti-RR autoantibodies, and only one sample was found to be positive. Conversely, of 48 anti-RR autoantibody positive samples identified at Fleury Laboratories over 30months, 94% were from HCV patients treated with ribavirin plus IFN-α. These data indicate that RR structures can be induced by a variety of drugs in vitro and in vivo, but anti-RR autoantibody production is mostly restricted to HCV patients under ribavirin+IFN-α treatment.

The n-channel behavior has been occasionally reported in the organic field-effect transistors (OFETs) that usually exhibit p-channel transport only. Reconfirmation and further examination of these unusual device performances should deepen the understanding on the electron transport in organic semiconductors. 6,13-bis(triisopropyl-silylethynyl) pentacene (TIPS-pentacene), a widely examined p-channel material as Au is used for source-drain electrodes, has recently been reported to exhibit electron transport when grown from non-polar solvent on divinyltetramethyldisiloxanebis (benzocyclobutene) (BCB) dielectric, spurring the study on this unusual electron transport. This paper describes FET characteristics of solution-grown TIPS-pentacene single crystals on five polymer gate dielectrics including polystyrene (PS), poly(methyl methacrylate) (PMMA), poly(4-vinyl phenol) (PVP), poly(vinyl alcohol) (PVA) and poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) (P(VDF-TrFE-CFE)). In addition to the p-channel behavior, electron transport occurs in the crystals on PMMA, PS, thick PVA (40 nm) and a bilayer dielectric of PMMA on P(VDF-TrFE-CFE), while does not on PVP and thin PVA (2 nm). The two distinct FET characteristics are consistent with the previous reported trap effect of hydroxyl groups (in PVP and PVA) and reduced injection barrier by Na+ ions (as impurity in PVA). The highest electron mobility of 0.48 cm2 V−1 s−1 has been achieved in the crystals on PMMA. Furthermore, the electron transport is greatly attenuated after the crystals are exposed to the vapor of a variety of polar solvents and the attenuated electron transport partially recovers if the crystals are heated, indicating the adverse effect of polar impurities on electron transport. By reconfirming the n-channel behavior in the OFETs based on TIPS-pentacene, this work has implications for the design of n-channel and ambipolar OFETs.

Purpose Environment is an independent factor affecting quality of life. Studies suggest that health practices consider having an impact on quality of life. The purpose of the present paper was to examine the association between environmental conditions and quality of life, and how individual health practices affected this association. Methods Participants aged 20 or above were recruited from 11 tertiary planning units in the centre of Kowloon. These tertiary planning units were selected as they represent the overall living environment in Hong Kong, with older poorer urban areas alongside relatively affluent districts. A mediation analysis was implemented using multiple linear regressions to examine the effects of environmental conditions on quality of life. The predictor variables included sociodemographic and environmental conditions, health practices and health service utilisation. Results Of the eligible 607 participants, 390 females and 217 males with a mean age of 47.4 were included for analysis. Physical, psychological and environmental factors were conducive and connected to quality of life. After adjusting for fruit and vegetable intake, gender, education level and chronic illness, perceived stress and sleep quality had significant mediating effects. Conclusion Environment is an important factor that affects the overall well-being of individuals. The interaction of environmental quality with individual variables, specifically stress and sleep is extremely important when assessing its impact on the quality of life. The findings of this study support the importance of individual stress and sleep in mediating the relationship between the environment and quality of life.

Ovarian cancer is the most lethal gynecological malignancies owing to the lack of definitive symptoms until development of widespread metastases. Identification of novel prognostic and therapeutic targets is therefore an urgent need to improve survival. Here, we demonstrated high expression of the mitochondrial gatekeeping enzyme, pyruvate dehydrogenase kinase 1 (PDK1), in both clinical samples and cell lines of ovarian cancer. PDK1 expression was significantly associated with metastasis, reduced chemosensitivity, and poor overall and disease-free survival, and further highlighted as an independent prognostic factor. Silencing of PDK1 retarded lactate production, ovarian cancer cell adhesion, migration, invasion, and angiogenesis, and consequently metastasis, concomitant with decreased α5β1 integrin expression. Phospho-kinase array profiling and RNA sequencing analyses further revealed reduction of JNK activation and IL-8 expression in PDK1-depleted cells. Conversely, PDK1 overexpression promoted cell adhesion via modulation of α5β1 integrins, along with cell migration, invasion, and angiogenesis through activation of JNK/IL-8 signaling. PDK1 depletion additionally hindered tumor growth and dissemination in nude mice in vivo. Importantly, PDK1 levels were upregulated upon treatment with conditioned medium from omental tissues, which in turn promoted metastasis. Our findings suggest that PDK1, which is regulated by the tumor microenvironment, controls lactate production and promotes ovarian cancer cell metastasis via modulation of α5β1 integrin and JNK/IL-8 signaling. To our knowledge, this is the first report to demonstrate an association between PDK1 and survival in patients with ovarian cancer, supporting its efficacy as a valuable prognostic marker and therapeutic molecular target for the disease.