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Background: The B-Raf proto-oncogene (BRAFV600E) gene mutation has been identified in a variety of malignancies, but no evidence of the efficacy of vemurafenib treatment in BRAFV600E mutant breast cancer (BC) has been reported. Case Presentation: We reported a 60-year-old woman with confirmed triple-negative BC with BRAFV600E mutation. Progression-free survival (PFS) for first-line chemotherapy was 7 months. The patient received vemurafenib and albumin-bound paclitaxel as second-line therapy, exhibiting regression of some pulmonary metastatic lesions with concomitant progression of other lesions, and achieved 4.4 months of PFS. Genetic testing of the progressed pulmonary lesion revealed the BRAFV600E mutation, and acquired new mutations and AR amplification. The patient ultimately died of multiple organ failure and achieved 12 months of overall survival. Conclusions: The BRAFV600E mutation may be a potential prognostic factor and therapeutic target for BC.

COX-2 fluorescent probes are promising tools for cancer diagnosis. Such probes have been conventionally designed by conjugating a fluorophore to COX-2 inhibitors through lengthy synthetic processes. Herein, a type of fluorescent probe for COX-2 imaging has been developed using a single-step process from rofecoxib. In total, six rofecoxib analogues were designed using this unique strategy. Several analogues retained comparative COX-2 targeting activity of rofecoxib and also exhibited attractive fluorescent properties, which were investigated using a combination of experimental and theoretical approaches. The most potent analogue

Background The introductions of anti‐ human epidermal growth factor receptor‐2 (HER2) agents have significantly improved the treatment outcome of patients with HER2‐positive breast cancer. BAT8001 is a novel antibody‐drug conjugate targeting human epidermal growth factor receptor‐2 (HER2)‐expressing cells composed of a trastuzumab biosimilar linked to the drug‐linker Batansine. This dose‐escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti‐tumor activity of BAT8001 in patients with HER2‐positive locally advanced or metastatic breast cancer. Methods This trial was conducted in subjects with histologically confirmed HER2‐positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21‐day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. Results Between March 2017 to May 2018, 29 HER2‐positive breast cancer patients were enrolled. The observed dose‐limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ‐glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%‐61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%‐94.2%) patients. Conclusions BAT8001 demonstrated favorable safety profiles, with promising anti‐tumor activity in patients with HER2‐positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2‐positive breast cancer., BAT8001 demonstrated favorable safety and tolerability profiles, with promising anti‐tumour activity in patients with HER2‐positive advanced or recurrent solid tumours. BAT8001 has the potential to provide a new therapeutic option in heavily pretreated patients with metastatic Her2‐positive breast cancer.

Background BAT8001 for injection is a novel antibody-drug conjugate (ADC) that targets HER2, which is composed of trastuzumab analogue (BAT0606) covalently linked to the drug-linker Batansine (a derivative of maytansine, which refers to the 3AA-MDC complex) by a stable thioether bond. Patients and methods In this open-label, phase 1 trial, we recruited 29 patients aged 18 years or older with HER2-positive advanced or recurrent breast cancer who had been previously treated with trastuzumab and/or lapatinib plus cytotoxic agents. Criteria for eligibility included HER2-positivity, having evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received BAT8001 intravenously once every 21 days, with dose escalation in five cohorts: 1.2mg/kg, 2.4mg/kg, 3.6mg/kg, 4.8mg/kg, and 6.0mg/kg. This study used a modified 3 + 3 dose escalation design to evaluate the dose-limiting toxicity (DLT) occurrence in the first cycle. Analyses included all patients who had received at least one dose of study treatment. The primary objective was to establish the safety, tolerability, pharmacokinetics (PKs), immunogenicity of BAT8001 in patients with HER2-positive metastatic breast cancer. The secondary objectives included evaluation of the metabolites and to make a preliminary assessment of the efficacy of BAT8001 for HER2 positive advanced solid tumors. Results Twenty-nine patients were enrolled in this study. The dose-limiting toxicity was grade 4 thrombocytopenia, which occurred in two patients administered of 6.0mg/kg, two patients administered of 4.8mg/kg and one patient administered of 3.6mg/kg BAT8001; thus, the maximum tolerated dose was 3.6mg/kg. The most common adverse event (AE) for any grade was increased aspartate aminotransferase, increased alanine aminotransferase, thrombocytopenia, increased alkaline phosphatase, increased uric acid, neutropenia, diarrhoea, nausea, vomiting, fatigue, and anemia. Grade 3 or greater AE occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhoea in 2 (6.9%) patients, and anemia in 1 (3.4%) patients. Objective responses (all partial responses) were observed in 11 (37.9%) and disease control rate in 24 (82.8%) of 29 patients who were evaluable for anti-tumor activity. The objective response rate and the disease control rate confirmed after 4 weeks was 27.6% and 65.5%, respectively. No pharmacokinetic interaction was observed. The total antibodies of BAT8001 were linearly correlated with the dose range of 1.2 to 6 mg/kg. Conclusions BAT8001 was safe, tolerable and the preliminary activity seems promising in patients with HER2-positive advanced or recurrent breast cancer. The results suggest that BAT8001 has the potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer. Citation Format: Shusen Wang, Ruoxi Hong, Liye Wang, Fei Xu, Wen Xia. The safety, tolerability, and pharmacokinetics of BAT8001 in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer: An open-label, dose-up, phase 1 study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-36.

IntroductionHR+/HER2− breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2− non-pCR populations, it is essential to accurate identification new prognostic markers.Materials and MethodsThe study retrospectively analyzed 105 stage II–III patients who were diagnosed with HR+/HER2− BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller–Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.ResultsAmong the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1–2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4–5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10–0.80; p = 0.018]. DFS was longer in the good response (MP grades 3–4) group than in the poor response (MP grades 1–2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05–0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9–75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.ConclusionThe study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

Cancers are highly heterogeneous and typically contain a small subset of drug-resisting cells called tumor initiating cells or cancer stem cells (CSCs). CSCs can self-renew, divide asymmetrically, and often cause tumor invasion and metastasis. Therefore, treatments specifically targeting CSCs are critical to improve patient survival. Recently, we identified a highly specific peptidomimetic (peptoid - PCS2) that selectively binds to the CSC subpopulation of lung cancer over the remaining cancer cells (non-CSCs). Subsequently, we identified plectin as the target of PCS2. Plectin is an intracellular structural protein, which is involved in tumor invasion and metastasis when it appears on cell surface. While PCS2 monomer did not display any anti-cancer activity, we designed a series of homo-dimeric versions of PCS2, and identified PCS2D1.2 optimized homo-dimer that displayed highly specific cytotoxicity towards CSCs over non-CSCs. PCS2D1.2 effectively blocked the in vitro colony formation and cell migration, hallmarks of CSCs. Furthermore, PCS2D1.2 reduced the in vivo tumor formation. In both in vitro and in vivo studies, PCS2D1.2 effectively reduced plectin expression and/or plectin-rich CSCs, but had no effect on non-CSCs. Therefore, PCS2D1.2 has the potential to be developed as a highly CSC specific drug candidate, which can be used in combination with current anti-cancer drugs.

Objective: Current evidence on the immunogenicity of influenza vaccination in patients with chronic obstructive pulmonary disease (COPD) is limited. To address this need for additional knowledge, we conducted a study on the immunogenicity of trivalent seasonal influenza vaccine (TIV) in COPD patients. Methods: We recruited patients from respiratory outpatient clinics of three hospitals in Tangshan, Hebei province who had stable confirmed COPD, were less than 80 y old, and reported not having had influenza or receiving TIV during the study season prior to enrollment. Patients who had a history of allergy to any TIV component or were classified as having very severe COPD were excluded from the study. Eligible and consenting participants were given one dose of TIV after obtaining a baseline blood sample. A second blood sample was obtained 5 weeks later. We used hemagglutination inhibition (HI) assays to measure antibody responses. We considered seropositive to be an HI titer ≥1:10. We considered seroprotection to be an HI titer ≥1:40 and seroconversion to be either a change from seronegative to a post-vaccination titer of ≥1:40 or a fourfold rise in antibody titer among baseline seropositive subjects. Each subject was followed for 1 month to assess the frequency and type of adverse events. Results: Eighty-eight subjects completed our study; the median age was 64 y; most (62.5%) had moderately severe COPD; 48.9% of the subjects had comorbid conditions in addition to COPD. Post–vaccination seropositive rates for influenza H1N1, H3N2, and B were all 100%; corresponding seroprotection rates were 96.6%, 93.2%, and 98.9%; seroconversion rates were 81.8%, 87.5%, and 75.0%. There were no statistical differences in seroconversion (P = .10) and seroprotection (P = .30) among the three types of influenza virus. Geometric mean titers (1:) of HI antibodies to H1N1, H3N2, and B were 18.8 (95% CI: 14.0–25.1), 12.2 (95% CI: 9.6–15.4), and 31.8 (95% CI: 26.1–38.8) at baseline, and 267.0 (95% CI: 213.8–333.4), 190.3 (95% CI: 151.7–238.6), and 201.1 (95% CI: 166.5-242.8) after vaccination. Conclusion: The immunogenicity of one dose of influenza vaccine was excellent in COPD patients. Our study supports recommending influenza vaccination for COPD patients to provide protection from influenza and its complications.

Background: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population, and is characterized by early relapse and a complex molecular heterogeneity. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients, which are considered tumor recurrences within 24 months.Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx), a next-generation-sequencing-based diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB).Results: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging 6 alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%), and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least 1 CRGA, and 87% of patients had at least 1 actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected 1 patient with ERBB2 amplification and 1 patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before. Conclusions: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.

Purpose: We aimed to identify the relationship between the genomic characteristics and clinicopathological features of oligo-metastatic breast cancer.Methods: Oligo-metastatic breast cancer diagnosed by pathology from January 2001 and August 2019 were identified and we matched the poly-metastatic patients based on the clinicopathological features of the oligo-metastatic patients included. The database of all genomic alterations was shown according to the FoundationOne CDx reports. Clinicopathological characteristics were collected and the results of next-generation sequencing were analyzed.Results: A total of 26 breast cancer patients were enrolled in our study, including 14 patients with oligo-metastatic disease and 12 patients with poly-metastatic disease. There was no significant difference in number of gene alteration, tumor mutational burden, variants of unknown significance (VUS), and actional mutation in oligo- and poly-metastasis. PIK3CA, TP53 and ERBB2 were the most common shared alterations identified in patients included. Based on the median time of oligo-progression disease (oligo-PD), we divided the patients with oligo-metastasis into longer oligo-PD group (oligo-PD > 31.04 months) and shorter oligo-PD group (oligo-PD ≤ 31.04 months). The analysis of PIK3CA mutation sites showed that H1047R was associated with a good prognosis in patients with metastatic breast cancer. HER2 positive patients with oligo-metastasis was more likely to have a good prognosis. In addition, VUS might also be a potential prognostic biomarker in metastatic breast cancer. Conclusion: Through the genetic analysis of oligo-metastasis, we found PIK3CA H1047R, HER2 and VUS might predict the different clinical outcomes of breast cancer patients with oligo-metastasis for the individualized treatment.

In an increasingly diverse United States (US) population, racial disparities in preterm birth outcomes continue to widen.In this study, we examined temporal trends and risk of preterm birth among Asian American women over a quarter century (1992-2018).This is a retrospective cohort study using the 1992-2018 Natality data files. We conducted joinpoint regression analyses to examine trends in preterm birth among Asian Americans and non-Hispanic (NH) Whites. Bivariate and multivariable analyses were used to identify risk factors associated with preterm birth among Asian Americans and their ethnic sub-groups as compared to NH-Whites.There were a total of 251,278 preterm births among Asian American women, corresponding to a rate of 10.0%, which was relatively stable over time. The incidence of extremely, very and moderate-to-late preterm birth among Asian Americans was 0.4%, 0.9% and 8.7% respectively. Overall, Asian American women exhibited lower adjusted odds (OR = 0.92; 95% CI: 0.88-0.97) of preterm birth than their NH-White counterparts. Comparing Asian American subgroups to NH-Whites, Filipinas and Vietnamese mothers had increased adjusted odds, whereas Chinese, Korean, Japanese and Asian Indian women showed decreased adjusted odds for preterm birth.The risk of preterm birth varied among the ethnic subgroups of Asian Americans in the United States. Future studies should explore the socio-cultural and environmental nuances that might explain these differences.

A homogeneous fluorescence quenching immunoassay is described for simultaneous separation and detection of aflatoxin M1 (AFM1) in milk. The novel assay relies on monoclonal antibody (mAb) functionalized Fe3O4 decorated reduced-graphene oxide (rGO-Fe3O4-mAb) as both capture probe and energy acceptor, combined with tetramethylrhodamine cadaverine-labeled aflatoxin B1 (AFB1-TRCA) as the energy donor. In the assay, AFB1-TRCA binds to rGO-Fe3O4-mAb in the absence of AFM1, quenching the fluorescence of TRCA by resonance energy transfer. Significantly, the immunoassay integrates sample preparation and detection into a single step, by using magnetic graphene composites to avoid washing and centrifugation steps, and the assay can be completed within 10 min. Under optimized conditions, the visual and quantitative detection limits of the assay for AFM1 were 50 and 3.8 ng L−1, respectively, which were significantly lower than those obtained by fluorescence polarization immunoassay using the same immunoreagents. Owing to its operation and highly sensitivity, the proposed assay provides a powerful tool for the detection of AFM1.

OBJECTIVE: To examine trends in rates of preterm birth by race and plurality; to evaluate the association between race, plurality, and phenotypes of preterm birth. STUDY DESIGN: Temporal trends analyses for preterm birth by race and plurality were performed for the years 1971–2018. Adjusted logistic regression models were utilized to evaluate the association between race, plurality, and phenotypes of preterm birth. RESULTS: We observed that 1105,266 (0.7%), 1901,604 (1.2%), and 14,769,746 (9.3%) births belonged to extreme preterm, very preterm, and moderate-to-late preterm categories, respectively. We also observed that the risk of extreme preterm (RR: 2.69, 95% CI: 2.642–2.75) was highest for Black mothers as compared to White mothers. CONCLUSION: Over the study period, preterm births disproportionately impacted Black mothers as well as pregnancies of higher plurality. With the persistence of racial disparities and growing trend of delayed childbearing and multiple pregnancies, targeted intervention is necessitated toward these vulnerable subgroups.

Electroencephalograph (EEG) plays a significant role in the diagnostics process of epilepsy, but the detection rate is unsatisfactory when the length of interictal EEG signals is relatively short. Although the deliberate attacking theories for undirected brain network based on node removal method can extract potential network features, the node removal method fails to sufficiently consider the directionality of brain electrical activities. To solve the problems above, this study proposes a feature tensor-based epileptic detection method of directed brain networks. First, a directed functional brain network is constructed by calculating the transfer entropy of EEG signals between different electrodes. Second, the edge removal method is used to imitate the disruptions of brain connectivity, which may be related to the disorder of brain diseases, to obtain a sequence of residual networks. After that, topological features of these residual networks are extracted based on graph theory for constructing a five-way feature tensor. To exploit the inherent interactions among multiple modes of the feature tensor, this study uses the Tucker decomposition method to get a core tensor which is finally reshaped into a vector and input into the support vectors machine (SVM) classifier. Experiment results suggest that the proposed method has better epileptic screening performance for short-term interictal EEG data.

Objective To examine temporal trends of eclampsia by plurality in the US spanning three decades (1989–2018); and to investigate risk factors for eclampsia among singleton and multiple pregnancies in the US during the study period. Study design: We conducted a retrospective cohort study using the Natality data files, including information on all births within the gestational age of 20–42 weeks from 1989 through 2018. We used joinpoint regression analysis to evaluate trends in rates of eclampsia over the study period. We employed logistic regression models to examine the association between plurality and eclampsia after adjusting for socio-demographic and gestational factors. Main outcome measures: The primary outcome was eclampsia among singleton and multiple pregnancies. Findings: There was a 2.8% (95% CI: −5.4, −0.1) average annual reduction in eclampsia rates among singletons, whereas among multiples there was a decline of about 3.7% (95% CI: −6.4, −1.0) annually. Mothers with multiple pregnancies had three-fold increased adjusted odds (OR = 95% CI: 2.95–3.21) of experiencing eclampsia when compared to those with singleton gestations. Non-Hispanic (NH) Black mothers with singletons had 37% greater adjusted odds of developing eclampsia than their NH-White peers (95%CI: 1.33–1.42). Conclusion There was an overall decreasing trend in eclampsia incidence in the US from 1989 to 2018, regardless of plurality. The occurrence of eclampsia was associated with plurality, race/ethnicity, maternal age and maternal BMI. Given the heterogeneity in clinical presentations of eclampsia, personalized/standardized risk prediction models are needed to enable consistent diagnosis and timely intervention.

We analysed Natality data obtained from the National Vital Statistics System from 1971 through 2018. Overall, the rates of singletons declined among all racial groups over the five decades of the study. However, the rates of twins and higher-order multiples increased over the same period although for the past two decades, the rates of higher-order multiples had substantially plummeted. The global health implication of these findings is that policy changes in the US in the form of professional practice guidelines have succeeded in reducing the birth of vulnerable populations (i.e., higher-order multiples) who are predominantly created using assisted reproductive technology. Key words: • Trends in Multiple Gestations • US • Black • White • Singletons • Twins • Higher-order multiples Copyright © 2020 Wang et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

Ovarian cancer is the most deadly gynecologic cancer among women worldwide. Poor response to current treatment makes it necessary to discover new diagnostic biomarkers to detect the cancer early and develop new and effective prevention strategies. Calcitriol, the active metabolite of vitamin D, protects against multiple cancers through unelucidated mechanisms. The oncogenic long non-coding RNA (lncRNA) CCAT2 (colon cancer associated transcript 2) is overexpressed in ovarian cancer. Here, we foundd that calcitriol inhibited CCAT2 expression in ovarian cancer cell lines. Treatment with calcitriol inhibited ovarian cancer cell proliferation, migration, and invasion. As a result of CCAT2 inhibition, calcitriol decreased the binding of transcription factor TCF7L2 (TCF4) to the MYC promoter, resulting in the repression of c-Myc protein expression. Our results suggest a novel anti-cancer mechanism of vitamin D by targeting CCAT2 in ovarian cancer. The findings may help develop vitamin D as a practical and inexpensive nutraceutical for ovarian cancer prevention.

Power battery is the core component of electric vehicles, and its characteristics determine the performance of electric vehicles. Lithium-ion power battery is a kind of time-varying nonlinear system, which has different external features under different application conditions and aging state. In order to implement the optimized charging method under changeable application conditions, the estimation of the internal states is extremely necessary. For this purpose, this paper studies the multiple states joint estimation based on the accurate and reliable battery modeling method. First, the modeling of lithium-ion battery and the parameter identification of the models are studied. A parameter identification method is proposed based on forgetting factor recursive extended least square. The battery model’s order is based on Bayesian information criterions. Second, multiple states joint estimation algorithm for power battery under charging mode is studied. For the estimated accuracy of the battery’s state of charge is associated with the battery usable capacity, state of charge and usable capacity joint estimation algorithm, based on several different order battery models is proposed. State of power estimation algorithm of the battery under multiple factors constraints is proposed based on the solution discrete analysis of the continuous time traction battery differential state equation. Finally, multiple states joint estimation algorithm is achieved. Validation results show that the proposed estimation algorithm can achieve high accuracy.

Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy.

Adlay oil (AO) is an important component of adlay seeds that has many beneficial functions to human health. In this study, the variations in the chemical composition and antioxidant activity of AOs extracted from adlay samples obtained from four main producing areas of China were first investigated. Results revealed that the AO of the adlay samples varied from 7.398 ± 0.486% to 8.464 ± 0.725%. The highest contents of total fatty acid, triolein, total phenolic, and total flavonoid were observed in Xingren AO, whereas coixol content was found to be highest in Pucheng AO. The AO samples were grouped successfully in accordance with the origins by partial least squares-discriminant analysis and hierarchical cluster analysis based on the contents of the chemical components. Furthermore, AOs exhibited considerable levels of 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity (IC50 , 0.924 ± 0.113 to 1.116 ± 0.109 mg/mL) radical scavenging activity, ferric-reducing antioxidant power (FRAP) activity (EC50 , 0.019 ± 0.002 to 0.028 ± 0.002 mg/mL) activity, and β-carotene-linoleic acid bleaching activity (IC50, 0.233 ± 0.008 to 0.414 ± 0.012 mg/mL) activity. Total phenolic and total flavonoid both demonstrated highest correlation with ABTS values (r = -0.952 and r = -0.960, respectively). The results derived from above studies suggest that geographic origin has a certain influence on the phytochemical profiles and antioxidant activity of the AOs. PRACTICAL APPLICATION: The chemical composition and antioxidant activity of adlay oils extracted from the adlay samples obtained from four main producing areas of China were evaluated, including total fatty acid, triolein, total phenolic, and total flavonoid, and ABTS radical scavenging activity, FRAP activity, and β-carotene-linoleic acid bleaching activity.

The residue kinetics of bacitracin in animals has rarely been quantitatively described due to inadequate sensitivity of analytical methods. A sensitive and selective quantitative liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-MS/MS) method was developed to determine the residue depletion kinetics of zinc bacitracin in pigs. The tissues samples were extracted with acidified methanol/water solution (v/v, 1:1, 1 % formic acid) and followed by liquid-liquid extraction with saturated solution of 0.1 mmol dithizone in chloroform. The extracts were subjected to Phenomenex Strata-X cartridges for further cleanup with 0.1 % formic acid in methanol. Analysis was performed on a C18 column with positive-ion electrospray mass spectrometry and multiple-reaction monitoring mode. The product ions at m/z 199 and 227 were selected for bacitracin A confirmation and at 199 for quantification. The developed method was linear in the concentration ranges of 150–4000 μg/L for bacitracin with limit of detection (LOD) and limit of quantification (LOQ) of 25 and 50 μg/kg for kidney and 20 and 50 μg/kg for skin with fat, liver, and muscle. The recoveries from different tissues were higher than 82.1 % at three different spiking levels with relative standard deviations (RSDs) less than 8.8 %. The residue depletion study showed that higher concentration and longer residue time were detected in kidney than in other three tissues. The elimination half-life in kidney was 0.45 days, and the recommended withdrawal period was zero. These results suggest that the established method satisfactorily enables a closer study of residue depletion kinetics of bacitracin in swine.

The adverse effects of diclofenac (DCF) on ecosystems and human health have induced increasing interest in its elimination in environment. DCF can be removed to some extent by nitrifying and heterotrophic microbes during wastewater treatment process. However, the actual roles of nitrifying and heterotrophic microbes in the transformation of DCF remain unclear. In this study, batch experiments were conducted to explore the biological transformation of DCF in enriched nitrifying sludge (NS), heterotrophic sludge (HS) and activated sludge (AS) systems. DCF was removed three times faster in enriched NS than in HS. Three transformation pathways of DCF in enriched NS, HS, and AS were proposed and compared. Hydroxylation was the crucial transformation step in the three transformation pathways. A faster hydroxylation reaction contributed to the faster removal of DCF in enriched NS. More transformation products (TPs) and reaction types (i.e. reductive dechlorination, sulphidation and methylation reactions) were observed in HS. Furthermore, some TPs that were resistant to degrade in enriched NS, such as DCF-benzoic acid, could be further transformed in HS. Accordingly, enriched NS could remove DCF more rapidly while HS could further transform some TPs resistant to degrade in enriched NS. Nitrifying and heterotrophic microbes may cooperatively and rapidly eliminate not only DCF, but also its TPs.

This study aimed to improve the sensitivity of lateral flow immunoassay (LFIA) using two strategies, including using a high sensitivity label and an indirect-labeling format, which were simultaneously applied to develop a highly sensitive LFIA to detect 22 β-lactams. In the new format, β-lactam receptors were used without any labeling, and anti-receptor monoclonal antibodies (mAbs) were labeled with amorphous carbon nanoparticles (ACNs). The new LFIA is based on the following steps: 1) screening mAbs against the receptors for antigen-antibody binding sites away from the active site of the receptors; and 2) detecting immune complexes using receptor-mAb-ACNs. The cut-off values against ampicillin, amoxicillin, benzylpenicillin, dicloxacillin, cloxacillin, oxacillin, nafcillin, cefquinome, cefoperazone, cefapirin, ceftazidime, cephalothin, cefepime, cefoxitin, cefazolin, ceftriaxone, ceftiofur, cefotaxime, cefalexin, imipenem, meropenem, and ertapenem were 1, 2, 2, 10, 10, 10, 10, 3, 3, 3, 5, 10, 10, 20, 20, 20, 30, 30, 100, 10, 15, and 15 ng/mL, respectively, which is significantly lower than that of receptor-mAb-colloidal gold-LFIA using the same immune reagents.

Cyclooxygenase-2 (COX-2) imaging agents are potent tools for early cancer diagnosis. Almost all of the COX2 imaging agents using celecoxib as backbone were chemically modified in the position of N-atom in the sulfonamide group. Herein, a novel COX-2 probe (CCY-5) with high targeting ability and a near-infrared wavelength (achieved by attaching a CY-5 dye on the pyrazole ring of celecoxib using a migration strategy) was evaluated for its ability to probe COX-2 in human cancer cells. CCY-5 is expected to have high binding affinity for COX-2 based on molecular docking and enzyme inhibition assay. Meanwhile, CCY-5 caused stronger fluorescence imaging of COX-2 overexpressing cancer cells (Hela and SCC-9 cells) than that of normal cell lines (RAW 264.7 cells). Lipopolysaccharide (LPS) treated RAW264.7 cells revealed an enhanced fluorescence as LPS was known to induce COX-2 in these cells. In inhibitory studies, a markedly reduced fluorescence intensity was observed in cancer cells, when they were co-treated with a COX-2 inhibitor celecoxib. Therefore, CCY-5 may be a selective bioimaging agent for cancer cells overexpressing COX-2 and could be useful as a good monitoring candidate for effective diagnosis and therapy in cancer treatment.

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)—a free-radical gas—plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.

Background: Diabetic retinopathy, nephropathy and neuropathy in patients with type 1 diabetes (T1D) are microvascular complications that can adversely impact disease prognosis and incur greater healthcare costs. Early identification of patients at risk of these microvascular complications using predictive models through machine learning (ML) can be helpful in T1D management. The objective of current review was to systematically identify and summarize published predictive models that used ML to assess the risk of diabetic nephropathy, retinopathy and neuropathy in T1D patients. Methods: A targeted review of English literature was undertaken in PubMed (http://www.ncbi.nlm.nih. gov/pubmed) and Google Scholar (http://scholar.google.com/) from January 1, 2016 to May 31, 2019. Eligible articles were also identified from cross-references. Following concepts were used in combination to conduct the search queries: diabetes, retinopathy, nephropathy, neuropathy, microvascular complication, risk/predictive model, and ML/artificial intelligence/data mining. Results: A total of 3,769 hits were found from all sources combined, duplicates were removed, titles and abstracts were screened, 61 studies underwent full-text review and a total of six studies met the eligibility criteria. Among them, four studies had developed risk models using data obtained from T1D patients alone, whereas two used data from both T1D and type 2 diabetes (T2D) patients. There was only one study that evaluated all three types of microvascular complications while the other five focused on one individual complication, i.e., either diabetic retinopathy, nephropathy or neuropathy. Only two studies evaluated time to developing a complication. The other four studies assessed complications as either binary (yes/no) or categorical (multiple levels). Prediction models were built using cross-sectional data from survey questionnaire (n=1, Iran) and longitudinal data (n=5) which were further classified as sources of electronic medical records (EMR) (n=3, US: 1, Europe: 2), clinical trial (n=1, US) and prospective study (n=1, Europe). Common predictors across studies as well as across types of microvascular complications included age, gender, diabetes duration, BMI, blood pressure, lipid level, and mean or a single HbA1C value. Commonly used ML algorithms included classification and regression tree (CART) and random forest (RF) (CART/RF, n=3), support vector machines (SVMs, n=2), logistic regression (LR, n=2) and neural networks (NNs, n=1). Model performance was evaluated using area under curve (AUC, n=4) and accuracy (n=2). Only half (n=3) of the included studies tested their developed models in an external dataset of patients with T1D. Conclusions: Overall, very few studies reported predictive models for diabetic retinopathy, nephropathy and neuropathy using ML specifically for T1D patients. Future research that utilizes contemporary clinical data from T1D patients to predict the three types of microvascular complications is needed.

Xinnao shutong (XNST) capsules have been clinically used in China to treat cerebrovascular diseases. Previous studies have demonstrated that XNST has significant neuroprotective effects against acute cerebral ischemic stroke. The present study investigated the effects and mechanisms of XNST treatment following chronic cerebral hypoperfusion. Thirty-six adult male Sprague-Dawley rats were treated with XNST or vehicle following permanent bilateral common carotid artery (BCCA) ligation. Body weight was recorded on days 0, 3, 7, 14, 28, and 42 post-surgery. The Morris water maze (MWM) test was used to assess cognitive function in rats. Immunofluorescent staining and western blot were used to assess the severity of neuronal plasticity, white matter injury, and the numbers and/or phenotypic changes incurred to microglia. Protein levels of p-AKT (Thr308) and p-ERK (Thr202/Tyr204) were detected 42 days after BCCA ligation was performed. The results indicate that XNST treatment significantly reduced escape latency, decreased the frequency of platform crossing compared to the vehicle group. Synaptophysin, protein levels improved and white matter injury ameliorated following XNST treatment. Meanwhile, XNST reduced the number of M1 microglia and increased the number of M2 microglia. Furthermore, p-AKT (Thr308) and p-ERK (Thr202/Tyr204) levels were increased 42 days following BCCA ligation. In summary, our results suggest that XNST mitigates memory impairments by restoration of neuronal plasticity and by modulation of microglial polarization following chronic cerebral hypoperfusion in rats.

Aditoprim (ADP) has potential use as an antimicrobial agent in animals. However, its pharmacodynamic properties have not been systematically studied yet. In this study, the in vitro antibacterial activities of ADP and its main metabolites were assayed, and the in vivo antibacterial efficacy of ADP for the treatment of swine streptococcosis was evaluated. It was shown that Salmonella and Streptococcus from swine, Escherichia coli and Salmonella from chickens, E. coli, Streptococcus, Mannheimia, Pasteurella from calves, Streptococcus and Mannheimia from sheep, and E. coli, Flavobacterium columnare, Acinetobacter baumannii and Yersinia ruckeri from fishes were highly susceptible to ADP. Haemophilus parasuis from swine, Staphylococcus aureus, Aeromonas punctate, Mycobacterium tuberculosis, Streptococcus agalactiae from fishes, and Klebsiella from calves and sheep showed moderate susceptibility to ADP, whereas E. coli, Actinobacillus pleuropneumonia, Pasteurella, S. aureus, Clostridium perfringens from swine, S. aureus, C. perfringens from chickens, and S. aureus from calves were resistant to ADP. The main metabolites of ADP showed equal activity to that of their parent compound, and the prevention and therapeutic dosages of ADP recommended for swine streptococcosis were 10 and 20~40 mg/kg b.w., respectively. This study firstly showed that ADP had strong antibacterial activity and had potential to be used as a single drug in the treatment of bacterial infectious diseases.

Aditoprim (ADP) is a newly developed antibacterial agent in veterinary medicine. The metabolism and disposition of ADP in swine, broilers, carp and rats were investigated by using a radio tracer method combined with a radioactivity detector and a liquid chromatography/ion trap/time-of-flight mass spectrometry. After a single oral administration, more than 94% of the dose was recovered within 14 d in the four species. The urine excretion was dominant in swine and rats, making up 78% of the dose. N-monodesmethyl-ADP, N-didesmethyl-ADP and 10 new metabolites were characterized. These metabolites were biotransformed from the process of demethylation, α-hydroxylation, N-oxidation and NH2-glucuronidation. After an oral dose for 7 d, ADP-derived radioactivity was widely distributed in tissues and high concentrations were especially observed in bile, liver, kidney, lung and spleen. The radioactivity in the liver was eliminated much more slowly than in other tissues, with a half-life of 4.26, 3.38, 6.69 and 5.21 d in swine, broilers, carp and rats, respectively. ADP, N-monodesmethyl-ADP and N-didesmethyl-ADP were the major metabolites in edible tissues. Notably, ADP was detected with the highest concentration and the longest duration in these tissues. These findings indicated that ADP is the marker residue and the liver is the residue target tissue.

Aditoprim (ADP) is a recently developed dihydrofolate reductase inhibitor that has shown promise for therapeutic use in veterinary medicine because of its excellent pharmacokinetic properties. In this study, a sensitive and reliable multi-residue chromatography-ultraviolet (HPLC-UV) method for the quantitative analysis of ADP and its three major metabolites was developed, and the tissue distribution and depletion profiles of ADP and its major metabolites in pigs, broilers and carp were investigated. Edible and additional tissues (heart, lung, stomach, intestine and swim bladder) were collected for analysis at six different withdrawal periods after ADP administration for 7 days. ADP, N-monomethyl-ADP and N-didesmethyl-ADP were detected in almost all tissues in the three species. The liver, kidney and lung showed higher residue concentrations, and the liver showed a longer residue half-life (t1/2) than other tissues. In the liver, ADP was the most abundant component with the longest persistence. The results suggest that the liver was the residual target tissue and ADP was the marker residue, and the conclusive withdrawal time (WDT) of 20 days in pigs, 16 days in broilers and 25 days in carp was estimated using the assessment methodologies approved by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

In this paper, we propose a novel framework for ASD diagnosis using structural magnetic resonance imaging (MRI). Our method deals explicitly with the distributional differences of gray matter (GM) and white matter (WM) features extracted from MR images. We project linearly the GM and WM features onto a canonical space where their correlations are mutually maximized. In this canonical space, features that are highly correlated with the class labels are selected for ASD diagnosis. In addition, graph matching is employed to preserve the geometrical relationships between samples when projected onto the canonical space. Our evaluations based on a public ASD dataset show that the proposed method outperforms all competing methods on all clinically important measures in differentiating ASD patients from healthy individuals.

A series of quinoxaline 1,4-di-N-oxide derivatives variously substituted at C-2 position were synthesized and evaluated for in vitro antimycobacterial activity. Seventeen compounds exhibited potential activity (MIC ⩽6.25 μg/mL) against Mycobacterium tuberculosis (H37Rv), in particular the compounds 3d and 3j having an MIC value of 0.39 μg/mL. None of the compounds exhibited cytotoxicity when using an MTT assay in VERO cells. To further investigate the structure–activity relationship, CoMFA (q2 = 0.507, r2 = 0.923) and CoMSIA (q2 = 0.665, r2 = 0.977) models were performed on the basis of antimycobacterial activity data. The 3D-QSAR study of these compounds can provide useful information for further rational design of novel quinoxaline 1,4-di-N-oxides for treatment of tuberculosis.