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In this study, a methodology utilizing peptide conformational imprints (PCIs) as a tool to specifically immobilize porcine pancreatic alpha-trypsin (PPT) at a targeted position is demonstrated. Owing to the fabrication of segment-mediated PCIs on the magnetic particles (PCIMPs), elegant cavities complementary to the PPT structure are constructed. Based on the sequence on targeted PPT, the individual region of the enzyme is trapped with different template-derived PCIMPs to show certain types of inhibition. Upon hydrolysis, N -benzoyl-L-arginine ethyl ester (BAEE) is employed to assess the hydrolytic activity of PCIMPs bound to the trypsin using high-performance liquid chromatography (HPLC) analysis. Further, the kinetic data of four different PCIMPs are compared. As a result, the PCIMPs presented non-competitive inhibition toward trypsin, according to the Lineweaver-Burk plot. Further, the kinetic analysis confirmed that the best parameters of PPT/PCIMPs 233-245+G were V max = 1.47 × 10 -3 mM s -1 , K m = 0.42 mM, k cat = 1.16 s -1 , and k cat / K m = 2.79 mM -1 s -1 . As PPT is bound tightly to the correct position, its catalytic activities could be sustained. Additionally, our findings stated that the immobilized PPT could maintain stable activity even after four successive cycles.

Coke powders in the coking wastewater generated by petroleum refining industry needs to be removed to achieve water reuse for lack of water resources. This study developed a decoking hydrocyclone in the closed coking wastewater circulation treatment system to remove coke powders, which was highly efficient and environmentally friendly. Computational Fluid Dynamics (CFD) method was carried out to study the tangential velocity distribution index n-value to guide design of decoking hydrocyclone and experiment was conducted to verify the coke powders removal effect. It was found that the increase of n-value is conducive to the improvement of coke powders separation efficiency. A decoking hydrocyclone with a cone angle of 15° and an inlet size of 4 × 6 mm is the optimum hydrocyclone and the recovery efficiency of coke powders is stable at more than 90%. It is the first time for hydrocyclone successfully applied to the removal of coke powders in coking wastewater in the decoking process of petroleum refining industry, in which the separation efficiency of coke powders is considerably improved., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Removal of coke powders in coking wastewater using a hydrocyclone optimized by n-value”., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Decreased awareness of memory declines in mild cognitive impairment (MCI) has been linked to structural or functional changes in a wide gray matter network; however, the underlying white matter pathway correlations for the memory awareness deficits remain unknown. Moreover, consistent findings have not been obtained regarding the cognitive basis of disturbed awareness of memory declines in MCI. Due to the methodological drawbacks (e.g., correlational analysis without controlling confounders related to clinical status, a problem related to the representativeness of the control group) of previous studies on the aforementioned topic, further investigation is required. To addressed the research gaps, this study investigated white matter microstructural integrity and the cognitive correlates of memory awareness in 87 older adults with or without mild cognitive impairment (MCI). The patients with MCI and healthy controls (HCs) were divided into two subgroups, namely those with normal awareness (NA) and poor awareness (PA) for memory deficit, according to the discrepancy scores calculated from the differences between subjective and objective memory evaluations. Only the results for HCs with NA (HC-NA) were compared with those for the two MCI groups (i.e., MCI-NA and MCI-PA). The three groups were matched on demographic and clinical variables. An advanced diffusion imaging technique-diffusion spectrum imaging-was used to investigate the integrity of the white matter tract. The results revealed that although the HC-NA group outperformed the two MCI groups on several cognitive tests, the two MCI groups exhibited comparable performance across different neuropsychological tests, except for the test on reasoning ability. Compared with the other two groups, the MCI-PA group exhibited lower integrity in bilateral frontal-striatal fibers, left anterior thalamocortical radiations, and callosal fibers connecting bilateral inferior parietal regions. These results could not be explained by gray matter morphometric differences. Overall, the results indicated that mnemonic anosognosia was not sufficient to explain the memory awareness deficits observed in the patients with MCI. Our brain imaging findings also support the concept of anosognosia for memory deficit as a disconnection syndrome in MCI., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Studies have reported that apolipoprotein E epsilon 4 (APOE ɛ4) has adverse effects on executive functions (EFs) in late adulthood. However, the results have been inconsistent. Insufficient measurements of executive functioning, uncontrolled clinical and demographic confounders, and moderation effects from other environmental factors are suspected to account for the inconsistency., Objective: This study used aggregate measures to examine the effects of APOE ɛ4 on four components of EFs, namely switching, working memory, inhibition, and reasoning. We further investigated whether high educational attainment, a proxy measure for cognitive reserve, moderates the adverse effects of ɛ4 on EFs., Methods: Cognitively unimpaired older participants were divided into groups based on APOE genotype and into subgroups based on educational attainment level. The demographic and clinical variables were matched between the groups. Four core components of the EFs were measured using a relatively comprehensive battery., Results: The results revealed that although no main effect of the APOE genotype was observed across the four EF components, the potentially adverse effects of ɛ4 on inhibition were alleviated by high educational attainment. A main effect of education on the reasoning component was also observed. The moderation analysis revealed that for older adults with 12 years of education or fewer, the relationship between the APOE ɛ4 genotype and inhibition performance became increasingly negative., Conclusion: This study highlights the distinctive role of response inhibition in the gene-environment interaction and underlines the importance of considering factors of both nature and nurture to understand the complex process of cognitive aging.

Background: Although evidence suggests that subjective memory complaints (SMCs) could be a risk factor for dementia, the relationship between SMCs and objective memory performance remains controversial. Old adults with or without mild cognitive impairment (MCI) may represent a highly heterogeneous group, based partly on the demonstrated variability in the level of executive function among those individuals. It is reasonable to speculate that the accuracy of the memory-monitoring ability could be affected by the level of executive function in old adults., Objective: This study investigated the effects of executive function level on the consistency between SMCs and objective memory performance while simultaneously considering demographic and clinical variables in nondemented older adults., Setting: Participants were recruited from both the memory clinics and local communities., Participants: Participants comprised 65 cognitively normal (CN) older adults and 54 patients with MCI., Measurements: Discrepancy scores between subjective memory evaluation and objective memory performance were calculated to determine the degree and directionality of the concordance between subjective and objective measures. Demographic, emotional, genetic, and clinical information as well as several executive function measurements were collected., Results: The CN and MCI groups exhibited similar degrees of SMC; however, the patients with MCI were more likely to overestimate their objective memory ability, whereas the CN adults were more likely to underestimate their objective memory ability. The results also revealed that symptoms of depression, group membership, and the executive function level together predicted the discrepancy between the subjective and objective measures of memory function; however, the executive function level retained its unique predictive ability even after the symptoms of depression, group membership, and other factors were controlled for., Conclusion: Although both noncognitive and cognitive factors were necessary for consideration, the level of executive function may play a unique role in understanding the equivocal relationship of the concurrence between subjective complaints and objective function measures. Through a comprehensive evaluation, high-risk individuals (i.e., CN individuals heightened self-awareness of memory changes) may possibly be identified or provided with the necessary intervention during stages at which objective cognitive impairment remains clinically unapparent., Competing Interests: The authors have no conflict of interest to report

The mechanism of high-grade transformation in gastrointestinal stromal tumors (GISTs) remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these had been screened from 263 GISTs to represent the early stage of GIST high-grade transformation, characterized by juxtaposed low-grade and high-grade regions in the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in situ hybridization (FISH), NanoString analyses, telomere analysis, and gene expression profiling were carried out, followed by in silico analyses, cell line study, and immunohistochemical validation. Using gene expression analysis, downregulation of SFRP1 was revealed to be the main event in GIST high-grade transformation (p = 0.013), accompanied by upregulation of EZH2. In silico analyses revealed that downregulation of SFRP1 was a common feature in GIST progression across several different series. Immunohistochemically, the expression of SFRP1 was validated to be significantly lower in high-grade GISTs (WHO risk group 3a or higher) than in low-grade GISTs (p < 0.001), and attenuation/loss of SFRP1 was associated with GIST tumor progression (p < 0.001). By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent large-scale chromosome aberration in biphasic GISTs, with a correlation with SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, KIT/PDGFRA mutation, and alternative lengthening of telomeres did not play a significant role in GIST high-grade transformation. In conclusion, high-grade transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).

Background: The issue of whether there exists an own-effect on facial recognition in the elderly remains equivocal. Moreover, currently the literature of this issue in pathological aging is little., Objective: Our study was thus to explore the issue in both of healthy older people and patients with ADMethods:In study 1, 27 older and 31 younger healthy adults were recruited; in study 2, 27 healthy older adults and 80 patients (including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups) were recruited. Participants received the Taiwan Facial Emotion Recognition Task (FER Task), and a clinical neuropsychological assessment., Results: No significant differences on the FER test were found among our groups, except for sadness recognition in which our MCI and AD patients' scores were remarkably lower than their healthy counterparts. The own-age effect was not significantly evident in healthy younger and older adults, except for recognizing neutral photos. Our patients with MCI and AD tended to have the effect, particularly for the sad recognition in which the effect was significantly evident in terms of error features (mislabeling it as anger in younger-face and neutral in older-face photos)., Conclusion: Our results displayed no remarkable own-age effect on facial emotional recognition in the healthy elderly (including SCD). However, it did not appear the case for MCI and AD patients, especially their recognizing those sadness items, suggesting that an inclusion of the FER task particularly involving those items of low-intensity emotion in clinical neuropsychological assessment might be contributory to the early detection of AD-related pathological individuals.

Several databases of epidemiologic studies in patients with idiopathic pulmonary fibrosis (IPF) have been analyzed in the Western community. However, few studies have been reported in Asia. The objective of this study was to investigate the epidemiology of IPF in Taiwan. We collected and analyzed patients with IPF from the Taiwan National Health Insurance Research Database from 2001 to 2011. We estimated the annual incidence and cumulative prevalence of IPF and mean survival time of patients and determined the causes of death. The annual incidence rates of IPF remained stable after 2005, ranging from 0.7 to 1.3 cases per 100,000 people per year, whereas the cumulative prevalence rates increased steadily from 3.1 to 6.4 cases per 100,000 people per year during 2006-2011 based on a narrow case definition. Men older than 75 years had higher incidence compared with other age groups. The mean survival after diagnosis was 6.9 years. Old age, male sex, and respiratory hospitalization were associated with shorter survival time after diagnosis. Both the incidence and prevalence rates of IPF were lower in Taiwanese patients than Western ones. Moreover, the survival time was higher in the Asian population compared with the Western population. These results may suggest the heterogeneity of the IPF definition in different study populations and geographic locations.

Objectives: To evaluate changes in microbial composition and the evolution of gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc)., Methods: Adult SSc patients provided stool specimens every 3 months over the course of 1 year. Participants completed the University of California, Los Angeles (UCLA) GIT 2.0 questionnaire to assess GIT symptom severity at each stool collection. The microbiota from these samples were determined by Illumina HiSeq 2500 16S ribosomal RNA sequencing (Illumina, Inc., San Diego, California, USA). Mixed effect models evaluated changes in GIT symptoms and microbial composition over time., Results: Among 19 patients with SSc (female; 89.5%; median age: 51.3 years), the median disease duration was 7 years and the baseline total GIT 2.0 score was 0.7 (standard deviation: 0.6). The majority of participants (63%) provided at least four stool samples over the course of the 12-month study. Patients with longer disease durations had increased GIT symptoms over the course of the study. There was no difference in the course of GIT symptoms over time between patients with limited versus diffuse cutaneous disease. The relative abundances of specific genera did not change over time within individual subjects. After controlling for age, sex, ethnicity, disease duration, and SSc subtype (i.e., limited versus diffuse), low abundance of Bacteroides was associated with increased GIT symptoms over time., Conclusion: This study is the first to have longitudinally characterised the lower GIT microbiome in SSc patients and demonstrated relative stability of genera abundance over the course of 1 year. The findings provide additional evidence that specific genera are associated with SSc-GIT symptoms and warrant further evaluation in larger SSc studies., Competing Interests: Disclosure: The authors have declared no conflicts of interest.

Neuroimaging evidence has suggested that Chinese-language processing differs from that of its alphabetic-language counterparts. However, the underlying white matter pathway correlations between semantic and phonological fluency in Chinese-language processing remain unknown. Thus, we investigated the differences between two verbal fluency tests on 50 participants with amnestic mild cognitive impairment (aMCI) and 36 healthy controls (HC) with respect to five groups (ventral and dorsal stream fibers, frontal-striatal fibers, hippocampal-related fibers, and the corpus callosum) of white matter microstructural integrity. Diffusion spectrum imaging was used. The results revealed a progressive reduction in advantage in semantic fluency relative to phonological fluency from HC to single-domain aMCI to multidomain aMCI. Common and dissociative white matter correlations between tests of the two types of fluency were identified. Both types of fluency relied on the corpus callosum and ventral stream fibers, semantic fluency relied on the hippocampal-related fibers, and phonological fluency relied on the dorsal stream and frontal-striatal fibers. The involvement of bilateral tracts of interest as well as the association with the corpus callosum indicate the uniqueness of Chinese-language fluency processing. Dynamic associations were noted between white matter tract involvement and performance on the two fluency tests in four time blocks. Overall, our findings suggest the clinical utility of verbal fluency tests in geriatric populations, and they elucidate both task-specific and language-specific brain-behavior associations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Key Message: We found that a rice NADPH oxidase gene OsRbohB contributes drought tolerance and its functions are involved in the interaction of the OsRbohB-mediated ROS production and ABA signaling. The plasma membrane NADPH oxidases, also known as respiratory burst oxidase homologs, are the key producers of ROS under both normal and stress conditions in plants. However, their functions in rice development and stress tolerance are still under investigation. Here, we found that a rice NADPH oxidase gene OsRbohB, also named OsNOX1, is expressed in all tissues examined throughout the development stages with higher transcripts in leaves. The transcriptional expression of OsRbohB is also strongly stimulated by dehydration, salt and several phytohormonal treatments. Compared with wide-type and the OsRbohB-overexpressing transgenic plants, osrbohB, a Tos17 insertion knockout mutant of OsRbohB, shows lower ROS production, abscisic acid (ABA) content and transcripts of a series of stress-related genes. The osrbohB mutant also exhibits lower seed germination rate, organ size and thousand seed weight, but higher stomatal aperture and sensitivity to drought. Moreover, a number of genes involved in plant development, stress response, transcriptional regulation, and particularly ABA signaling are differentially expressed in osrbohB plants under both normal growth and drought conditions. All these results suggest the roles of OsRbohB in drought tolerance of rice, which probably performed through the interaction of the OsRbohB-mediated ROS production and ABA signaling.

The breast cancer screening program has continued in Taiwan during the COVID-19 pandemic. Our nationwide data showed that the total number of screenings decreased by 22.2%, which was more pronounced for in-hospital examinations (-37.2%), while outreach showed a 12.9% decrease. This decline in screening participation happened at all levels of hospitals, more significantly at the highest level. Our report revealed that outreach services could maintain relatively stable breast cancer screening under this kind of public health crisis. Building a flexible, outreach system into the community might need to be considered when policymakers are preparing for future possible pandemics., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study used functional magnetic resonance imaging to explore the neural networks of pain during labor and its relief. It was hypothesized that epidural analgesia would affect the neural activities and the underlying network connectivity. Analysis using dynamic causal modelling and functional connectivity was performed to investigate the spatial activity and network connection of labor pain with and without epidural analgesia. This Institutional Review Board approved study acquired Magnetic Resonance Imaging from 15 healthy women of spontaneous normal delivery (with/without epidural analgesia = 7/8, aged 29.6 ± 2.3 and 29.3 ± 4.8 years old respectively) using a 1.5 Tesla scanner. Numerical rating score of pain was evaluated by a research nurse in the beginning of the first stage of labor and approximately 30 min after imaging examination. Six regions of interested from the activated clusters and literature were selected for dynamic causal modelling, which included primary and secondary somatosensory cortex, middle frontal gyrus, anterior cingulate cortex, insula and lentiform. Functional connectivity was calculated from selected sensory and affective regions. All analyses were performed by using software of statistical parametric mapping version 8 and CONN functional connectivity toolbox. The result showed that the experience of labor pain can lead to activations within a distributed brain network. The pain relief from epidural analgesia can be accompanied with altered functional connectivity, which was most evident in the cingulo-frontal system. The present study, therefore, provides an overview of a pain-related neural network that occur during labor and upon epidural analgesia.

Background: Hepatic decompensation is a fatal on-treatment side effect during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Prompt bilirubin testing can reveal hepatic failure in susceptible patients, and clinical parameters precipitating early elevation of bilirubin can warn clinicians to avoid PrOD prescription., Methods: This retrospective study included 169 Hepatitis C virus (HCV)-genotype 1b patients who underwent a 12-week course of PrOD with or without ribavirin. Laboratory data underwent χ analysis with Fisher's exact test to determine the precipitating factors causing hyperbilirubinemia in patients who had received 1 week of treatment., Results: Sustained viral response was achieved in 164 patients (97.0%). Total bilirubin was ≥2 mg/dL (21.3%) in 36 patients after 1 week of treatment. Pretreatment white blood cell (WBC) <4500/µL and platelet <100,000/µL correlated with total bilirubin ≥2 mg/dL (relative risk [RR]: 21.64, 95% CI: 5.23-89.64, p < 0.001) after 1 week of treatment. Pretreatment platelet ≥100 000/µL and WBC <4500/µL correlated with direct bilirubin ≥0.45 mg/dL (RR: 6.56, 95% CI: 1.42-30.38, p = 0.016) and indirect bilirubin ≥0.6 mg/dL (RR: 4.77, 95% CI: 1.03-22.15, p = 0.046). Pretreatment platelet <100,000/µL with F3/F4 fibrosis correlated with first week total bilirubin ≥2 mg/dL (RR: 3.57, 95% CI: 1.35-9.09, p = 0.010)., Conclusion: PrOD is an effective antiviral regimen for HCV genotype 1b patients. Total bilirubin ≥2 mg/dL after 1 week of treatment serves as an early warning of irreversible progression toward hepatic decompensation, and the current study provides a guide by which to monitor chronic hepatitis C patients undergoing PrOD treatment.

Blood cysts are benign tumors in nature and seldom need surgical removal. Herein, we report an 86-year-old patient with a blood cyst originating from the fossa ovalis accompanied by an atrial septal defect. The patient used the bizarre sleeping postures, including prostrating and worshiping, to relieve chest tightness. The septal base defect kept the tumor progressively enlarged with time, which contributed to a "ball-valve "effect and caused tricuspid flow obstruction. It was resolved after excision. This case report emphasizes that long-term follow-up and increased awareness are required for unpredictable intracardiac blood cyst development.

Objective: To determine the tumor genomic, immunologic expression, and risk factors of treatment outcomes for patients with double head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC)., Methods: We reviewed patients with double HNSCC and ESCC between 1995 and 2014. The TP53 genomic mutation, CD8+ tumor infiltrating lymphocytes (TIL) and tumor programmed cell death ligand 1 (PD-L1) expression of paired HNSCC and ESCC were analyzed., Results: A total of 116 patients (57 metachronous and 59 synchronous) were included. There were 88 (75.86%) patients with HNSCC and 80 (68.97%) with ESCC harboured TP53 disruptive mutation. Nearly 106 (91.38%) patients had different clonality of TP53 mutation in paired HNSCC and ESCC. The immunologic expression of synchronous and metachronous patients was significantly different. Compared to the metachronous patients, the synchronous patients had significantly higher HNSCC CD8+ TIL (p = 0.03), ESCC CD8+ TIL (p < 0.001), HNSCC PD-L1+ tumor proportion score (TPS, p = 0.04), and ESCC PD-L1+ TPS (p = 0.04). Furthermore, among the synchronous patients, the immunologic expression between HNSCC and ESCC was significantly correlated. The CD8+ TIL and PD-L1 TPS had strongly (r = 0.63, p < 0.0001) and moderately (r = 0.42, p = 0.001) positive correlations, respectively. Finally, advanced stage (III/IV) HNSCC was a significant factor for disease-free (p = 0.03) and overall survival (p = 0.005)., Conclusion: In patients with double HNSCC and ESCC, nearly all HNSCC and ESCC were of multicentric origin. For the synchronous patients, there was more adaptive immune resistance in HNSCC and ESCC. The immunologic expression between paired HNSCC and ESCC was also significantly correlated., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated., Methods: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells., Results: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown-induced cell migration and invasion of gastric cancer cells., Conclusions: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.

Using TiO i Pr 4 with a pyrazole ligand for one-pot LA polymerization improved catalytic activity compared with using TiO i Pr 4 only. At 60 °C, TiO i Pr 4 with fur Pz exhibited a higher catalytic activity (approximately 3-fold) than TiO i Pr 4 . At room temperature, TiO i Pr 4 with Bu Pz exhibited a higher catalytic activity (approximately 17-fold) than TiO i Pr 4 . High molecular mass PLA ( M n GPC = 51 100, and Đ = 1.10) could be produced by using TiO i Pr 4 with fur Pz in melt polymerization ([TiO i Pr 4 ] : [ fur Pz] = 1000 : 1 : 1 at 100 °C, 240 min). The crystal structure of Me Pz 2 Ti 2 O i Pr 7 revealed the cooperative activation between two Ti atoms during LA polymerization., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Virtual microscopy (VM) has been utilized to improve students' learning experience in microscope laboratory sessions, but minimal attention has been given to determining how to use VM more effectively. The study examined the influence of VM on academic performance and teacher and student perceptions and compared laboratory test scores before and after VM incorporation. A total of 662 third-year students studying histology and 651 fourth-year students studying pathology were divided into two groups. The light microscopy (LM) group used a light microscope in 2014 and 2015, while the LM + VM group used the VM platform and a light microscope in 2016 and 2017. Four factors positively predict laboratory scores (R square, 0.323; P < 0.001): (i) the pathology course and test-enhanced learning, (ii) the VM platform and experience, (iii) medical students and lecture scores, and (iv) female students. The LM + VM group exhibited less score variability on laboratory examinations relative to their mean than the LM group. The LM + VM group was also associated with fewer failing grades (F grade; odds ratio, 0.336; P < 0.001) and higher scores (A grade; odds ratio, 2.084; P < 0.001) after controlling for sex, school, course, and lecture grades. The positive effect of the VM platform on laboratory test grades was associated with prior experience using the VM platform and was synergistic with more interim tests. Both teachers and students agreed that the VM platform enhanced laboratory learning. The incorporation of the VM platform in the context of test-enhanced learning may help more students to master microscopic laboratory content., (© 2019 American Association of Anatomists.)

Objectives: Retinal vein occlusions (RVO) are associated with systemic risk factors. However, the ocular occlusive events might also influence a patient's systemic condition. This study tried to investigate serum biomarkers associated with oxidative stress, before and after intravitreal anti-vascular endothelial growth factor (aVEGF) therapy in patients with RVOs., Methods: Newly-onset RVO patients were categorized into two groups: comorbid with macular edema requiring aVEGF therapy (treatment group) and no edema (observation group). Age and sex-matched patients (who received cataract surgery) were included as the control group. Intravitreal ranibizumab with a pro-re-nata regimen were administered. Serum samples were collected prior to treatment, at 6 and 12 months after therapy/observation and were collected once before controls who received cataract surgery. mRNA expression of sirtuin-1, its downstream genes, anti-oxidative biomarkers, and proinflammatory cytokines were measured., Results: There were 32, 26, and 34 patients enrolled in the treatment, observation, and control groups, respectively. The expressions of sirtuin-1 and its downstream genes were significantly lower in patients with RVO compared with the control group. Sirtuin-1 gene expression increased after 1 year of aVEGF therapy in the treatment group but remained unchanged in the observation group. Biomarkers of oxidative stress and proinflammatory cytokines were reduced after 1 year of aVEGF therapy. These biomarkers remained with no changes in the observation group., Conclusions: Our study showed that the systemic oxidative stress increased in RVO patients. The aVEGF therapy could alter the gene expression of anti-oxidative proteins and reduce systemic oxidative stress in these patients., Competing Interests: The authors declare there are no conflicts of interest.

Background: Due to the potential consequences of post-traumatic epilepsy (PTE) exacerbating secondary injury following traumatic brain injury (TBI), the use of antiepileptic drugs (AEDs) is an accepted option for seizure prophylaxis. However, there is only a paucity of data that can be found regarding outcomes surrounding the use of AEDs. The purpose of this retrospective study is to evaluate whether the prophylactic administration of AEDs significantly decreased the incidence of PTE, when considering the severity of TBI., Methods: All trauma patients who had been newly diagnosed with TBI from January 1, 2010 to December 31, 2017 were retrospectively analyzed. Statistical comparisons were made using the chi-square test, Mann-Whitney U test, and Cox regression modeling. After excluding any exposed subjects with no appropriate match, patients who had received AED prophylaxis were matched by propensity score with those who did not receive AEDs. All of the TBI populations were followed up until June 30, 2018., Results: We identified 1316 patients who met the inclusion and exclusion criteria in our matched cohort through their propensity scores, where 138 patients had been receiving prophylactic AEDs and 138 patients had not. Baseline characteristics were similar in gender, age, Glasgow Coma Scale (GCS) scores, and risk factors of PTE including skull fracture, chronic alcoholism, subdural hematoma, epidural hematoma, and intracerebral hematoma. After adjusting for those risk factors, the relative incidence of seizure was not statistically significant in either of the groups (p = 0.566)., Conclusion: In our cohort analysis, AED prophylaxis was ineffective in preventing seizures, as the rate of seizures was similar whether patients had been receiving the drugs or not. We therefore concluded that the benefits of routine prophylactic anticonvulsant therapy in patients with TBI need to be re-evaluated.

A psychrotolerant actinobacterium, designated strain J5903 T , was isolated from an alkaline soil sample from the rhizosphere of Suaeda salsa collected in desertification land surrounding Jiuliancheng Nur in Hebei Province, PR China. Cells of the isolate were Gram-stain-positive, aerobic, non-motile and non-spore-forming cocci. Strain J5903 T grew optimally at 20‒25 °C, at pH 7.0‒7.5 and with <1 % (w/v) NaCl. The cell-wall peptidoglycan type was B2γ with d-2,4-diaminobutyric acid and l-2,4-diaminobutyric acid as diagnostic amino acids. The muramyl residue was acetyl type. The menaquinones were MK-11, MK-12, MK-10 and MK-13. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and one unidentified glycolipid. The major whole-cell fatty acids were anteiso-C 15 : 0 , iso-C 16 : 0 and anteiso-C 17 : 0 . The genomic DNA G+C content was 69.1 mol%. It shared the highest average nucleotide identity and digital DNA-DNA hybridization values with Planctomonas deserti 13S1-3 T . Phylogenies based on genome sequence showed that strain J5903 T and P. deserti 13S1-3 T formed a robust cluster with high bootstrap support. Strain J5903 T shared typical chemotaxonomic characteristics with P. deserti 13S1-3 T . Combining the polyphasic taxonomic evidence, strain J5903 T represents a novel species of the genus Planctomonas , for which the name Planctomonas psychrotolerans sp. nov. is proposed. The type strain is J5903 T (=DSM 101894 T =CGMCC 1.15523 T ).

Background: Peters anomaly is a rare form of anterior segment ocular dysgenesis, the antenatal image of Peters anomaly had not been reported. We herein showcased a discordant finding of Peters anomaly in a monozygotic twin complicated with twin-twin transfusion syndrome (TTTS) and exhibited its antenatal sonographic images, CASE PRESENTATION: A 38-year-old gravida 2 para 1 pregnant woman visited our clinic at the gestational age of 18 weeks where TTTS stage III was diagnosed and the following laser therapy was done successfully. Ten days after the surgery, the follow-up ultrasound detected the opacity of both fetal eyeballs in the donor twin and thus congenital cataract was suspected initially. Then magnetic resonance imaging (MRI) examination was arranged at the gestational age of 23 weeks, and no central nervous system or other anomaly was found. At the 29 weeks of gestation, the opacity of both fetal eyeballs of the donor twin did not clear. The pregnancy resulted in cesarean section at the gestational age of 37 weeks indicated by malpresentation where two male live births were born. Examination under anesthesia was arranged for donor twin after delivery and Peters anomaly was diagnosed based on central corneal opacity with iridocorneal and corneolenticular adhesions., Conclusions: The prenatal image of Peters anomaly may present as the opacity of the fetal eyeballs similar to congenital cataract. Some cases of the Peters anomaly had been reported with a genetic abnormality, but since our case presented discordant presentation in monozygotic twin pregnancy where both twins are supposed to share the same genetic make-up, therefore other factors that are epigenetic may be held accountable. Nevertheless, a genetic origin of the anomaly in our case cannot be excluded.

The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41-0.71) and erlotinib (HR 0.62, 95% CI 0.46-0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08-2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.

Immunotherapy is a highly promising approach for the treatment of gastric cancer, the third-leading cause of overall cancer death worldwide. In particular, tumor-infiltrating lymphocytes and peripheral blood mononuclear cells are believed to mediate host immune responses, although this activity may vary depending on the activation status and/ or their microenvironments. Here, we examined the expression of a specific zinc finger transcription factor, Helios (IKZF2), in gastric tumor-infiltrating lymphocytes by immunohistochemistry and the correlation with survival. Segregation of gastric cancer patients into high- vs. low-Helios-expressing tumor-infiltrating lymphocytes showed those with high expression to exhibit longer survival in gastric cancer patients, Helicobacter pylori-infected gastric cancer patients and advanced stage (III-IV) gastric cancer patients. In particular, Helios expression was an independent factor for survival in advanced gastric cancer patients. We performed immunofluorescence staining to detect Helios expression in tumor-infiltrating lymphocytes and peripheral blood mononuclear cells. We found that Helios is expressed more in CD4+ T cells and little in CD8+ T cells in infiltrated lymphocytes in gastric cancer. In summary, we believe that the study of specific characteristics of tumor-infiltrating lymphocytes can delineate the interactions of immune and tumor cells to improve upon immunotherapy strategies.

Purpose: The presence of CD8+ tumor-infiltrating lymphocytes (TILs) has been reported to be associated with treatment outcomes in many types of solid tumors. However, the results vary due to the various methods of visual estimation and subjective interpretation. The current study is the first to use digital image analyses to evaluate the density of CD8+/CD3+ TILs in tongue squamous cell carcinoma (TSCC)., Patients and Methods: From 2005 to 2015, a cohort of 258 TSCC patients were consecutively enrolled in this study. After immunohistochemistry on representative sections, the density of CD8+/CD3+ TILs at tumor invasive margins was evaluated by digital image analysis. The subjects were stratified by the median values of CD3+ cell density, CD8+ cell density, CD8/CD3, and scores (0, 1, and 2) to demonstrate the association with various clinicopathological manifestations., Results: Low CD8+ TIL counts were associated with advanced tumor stages ( p =0.034), and low CD8/CD3 ratios were associated with perineural invasion ( p =0.043). Both parameters were also associated with increased tumor depths ( p =0.034 and 0.004, respectively). Univariate analyses revealed that advanced tumor stages, perineural invasion, extranodal extension, tumor depth, lower CD8 counts, and lower scores (score 0 vs 2) were associated with poorer overall survival, and multivariate analysis further indicated that extranodal extension and low scores (score 0 vs 2) were both independent factors for overall survival (p < 0.0001 and p = 0.0369, respectively)., Conclusion: The use of digital image analysis to assess CD8+ TILs at the invasive margins provides an objective indicator of prognoses including overall survival., Competing Interests: The authors report no conflicts of interest for this work., (© 2020 Huang et al.)

As the coronavirus disease 2019 (COVID-19, also called severe acute respiratory syndrome coronavirus-2) outbreak accelerates, vigorous and diverse efforts were made in developing treatment strategies. In addition to direct acting agents, increasing evidence showed some potential adjuvant therapies with promising efficacy against COVID-19. These therapies include immunomodulators (i.e. intravenous immunoglobulin, thymosin α-1, interleukin [IL]-6, tocilizumab, cyclosporine, thalidomide, fingolimod), Chinese medicines (i.e. glycyrrhizin, baicalin, Xuebijing), anti-vascular endothelial growth factors (bevacizumab), estrogen modulating drugs, statins, and nutritional supplements (i.e. vitamins A, B, C, D, E and zinc). This article reviewed the pharmacological development of potential adjuvants for COVID-19 treatment.

Sodium glucose cotransporter-2 inhibitors (SGLT2i), a novel antidiabetic drug blocks the reabsorption of glucose in proximal tubules of kidney, are demonstrated to have cardiovascular and renal benefits for people with diabetes. The benefits are associated with the significant increase of intrarenal angiotensin-converting enzyme II (ACE2) expression and blood volume contraction. However, the increased ACE2 may be detrimental to patients infected with the coronavirus infection 2019 (COVID-19), which is found to invade cells via the entry receptor of ACE2. Besides, an SGLT2i-induced natriuretic effect may also increase the risk of acute kidney injury and affect the hemodynamic stability during systemic infection disease. In this article, we explain the mechanisms why the use of SGLT2i in people with diabetes may lead to worse outcomes and suggest clinician to judiciously use it during COVID-19 pandemic.

Purpose: To identify factors associated with resilience in primary caregivers of patients with advanced oral cavity cancer within the first 6 months post-treatment., Design: A cross-sectional study., Methods: We recruited patient-primary caregiver dyads from the outpatient radiation department of a medical center in Northern Taiwan. Patients were assessed using a set of structured questionnaires to measure performance status and demographic and clinical characteristics. Primary caregivers were measured in their social support, resilience, and care characteristics., Results: Of the 148 dyads surveyed, 33.8% of primary caregivers reported moderately low to moderate resilience, and 61.5% reported low resilience. Greater resilience of primary caregivers was associated with the primary caregiver factors of younger age, lower educational level, and more affectionate social support; and greater resilience was associated with the patient factors of better performance status and older age. These factors explained 40.4% of the variance in resilience., Conclusions: Patients' performance status and primary caregivers' affectionate social support strongly influence overall resilience and each domain of resilience., Clinical Relevance: Providing primary caregivers with sufficient social resources and a support group can help them cope with the demands of caregiving for loved ones with oral cavity cancer., (© 2020 Sigma Theta Tau International.)

Background: Current guidelines recommend bismuth-containing quadruple therapy (BQT) and quinolone-containing therapy after failure of first-line Helicobacter pylori eradication therapy. However, the optimum regimen of second-line eradication therapy remains elusive. We conducted a network meta-analysis to compare the relative efficacy of 16 second-line H. pylori eradication regimens., Methods: Three major bibliographic databases were reviewed to enrol relevant randomised controlled trials between January 2000 and September 2018. Network meta-analysis was conducted by STATA software and we performed subgroup analysis in countries with high clarithromycin resistance and high levofloxacin resistance, and in patients with documented failure of first-line triple therapy., Results: Fifty-four studies totalling 8752 participants who received 16 regimens were eligible for analysis. Compared with a 7-day BQT, use of probiotic add-on therapy during, before, and after second-line antibiotic regimens, quinolone-based sequential therapy for 10-14 days, quinolone-based bismuth quadruple therapy for 10-14 days, bismuth quadruple therapy for 10-14 days, and quinolone-based triple therapy for 10-14 days were significantly superior to the other regimens. Subgroup analysis of countries with high clarithromycin resistance and high levofloxacin resistance revealed that the ranking of second-line eradication regimens was distributed similarly in each group, as well as in patients with failure of first-line triple therapy., Conclusion: We conducted a detailed comparison of second-line H. pylori regimens according to different antibiotic resistance rates and the results suggest alternative treatment choices with potential benefits beyond those that could be achieved using salvage therapies recommended by guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cryptococcal meningitis is a prevalent invasive fungal infection that causes around 180 000 deaths annually. Currently, treatment for cryptococcal meningitis is limited and new therapeutic options are needed. Historically, medicinal plants are used to treat infectious and inflammatory skin infections. Tryptanthrin is a natural product commonly found in these plants. In this study, we demonstrated that tryptanthrin had antifungal activity with minimum inhibitory concentration (MIC) of 2 μg/ml against Cryptococcus species and of 8 μg/ml against Trichophyton rubrum. Further analysis demonstrated that tryptanthrin exerted fungistatic and potent antifungal activity at elevated temperature. In addition, tryptanthrin exhibited a synergistic effect with the calcineurin inhibitors FK506 and cyclosporine A against Cryptococcus neoformans. Furthermore, our data showed that tryptanthrin induced cell cycle arrest at the G1/S phase by regulating the expression of genes encoding cyclins and the SBF/MBF complex (CLN1, MBS1, PCL1, and WHI5) in C. neoformans. Screening of a C. neoformans mutant library further revealed that tryptanthrin was associated with various transporters and signaling pathways such as the calcium transporter (Pmc1) and protein kinase A signaling pathway. In conclusion, tryptanthrin exerted novel antifungal activity against Cryptococcus species through a mechanism that interferes with the cell cycle and signaling pathways., Lay Summary: The natural product tryptanthrin had antifungal activity against Cryptococcus species by interfering cell cycle and exerted synergistic effects with immunosuppressants FK506 and cyclosporine A. Our findings suggest that tryptanthrin may be a potential drug or adjuvant for the treatment of cryptococcosis., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

A general protocol for the synthesis of multisubstituted 2,3-dihydrofuran-2-carbonitriles and 4,5-dihydrofuran-3-carbonitriles was demonstrated under a metal-free regime with the same oxidant, TBHP. By simply switching the reaction solvent and base, the reaction proceeds via two pathways. An unexpected -CN group migration rearrangement and hydroxylation have occurred in nonpolar and polar solvents, respectively, under the reported conditions. Furthermore, the source of the hydroxyl group and hydrogen in the reaction is indirectly confirmed with isotope labeling studies.

Background: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib., Materials and Methods: PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments., Results: A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression., Conclusion: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib., Implications for Practice: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information., (© AlphaMed Press 2020.)

Recently, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was quickly identified as the causal pathogen leading to the outbreak of SARS-like illness all over the world. As the SARS-CoV-2 infection pandemic proceeds, many efforts are being dedicated to the development of diverse treatment strategies. Increasing evidence showed potential therapeutic agents directly acting against SARS-CoV-2 virus, such as interferon, RNA-dependent RNA polymerase inhibitors, protease inhibitors, viral entry blockers, neuraminidase inhibitor, vaccine, antibody agent targeting the SARS-CoV-2 RNA genome, natural killer cells, and nucleocytoplasmic trafficking inhibitor. To date, several direct anti-SARS-CoV-2 agents have demonstrated promising in vitro and clinical efficacy. This article reviews the current and future development of direct acting agents against SARS-CoV-2.

Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. In silico analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis-related genes and markers of cancer stem cells (CSC) including aldehyde dehydrogenase (ALDH). In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44 + /CD24 - , ALDH activity, or by tumor sphere formation. In vivo , upregulation of EMP2 promoted tumor growth, whereas knockdown reduced the ALDH high CSC population as well as retarded tumor growth. Mechanistically, EMP2 functionally regulated the response to hypoxia through the upregulation of HIF-1α, a transcription factor previously shown to regulate the self-renewal of ALDH high CSCs. Furthermore, in syngeneic mouse models and primary human tumor xenografts, mAbs directed against EMP2 effectively targeted CSCs, reducing the ALDH + population and blocking their tumor-initiating capacity when implanted into secondary untreated mice. Collectively, our results show that EMP2 increases the proportion of tumor-initiating cells, providing a rationale for the continued development of EMP2-targeting agents., (©2020 American Association for Cancer Research.)

Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors essential for cytokine signaling. Our previous study showed that interleukin-3 (IL-3) induced STAT5 translocation to mitochondria and binding to mitochondrial DNA (mtDNA) in vitro. In this report, we further demonstrated in vivo binding of endogenous STAT5a to mtDNA transcriptional control region and reduced gene expression from all three mtDNA promoters after IL-3 stimulation. To specifically define the function of mitochondrial STAT5a, we generated mitochondrial-targeting wild-type and mutant STAT5a proteins. Compared with non-targeting STAT5a, mitochondrial-targeting wild-type STAT5a significantly reduced mitochondrial gene expression in transfected HEK293 cells. The level of attenuation was amplified in cells expressing constitutively active STAT5a, but abrogated in cells expressing DNA-binding-defective STAT5a. STAT5a-mediated repression of mtDNA expression also positively correlated with STAT5a binding to the E2 subunit of pyruvate dehydrogenase complex (PDC-E2), both a gate-keeping metabolic enzyme and a component of mtDNA nucleoid in mitochondrial matrix. Metabolic shift away from mitochondrial respiration is known in many cytokine-stimulated cells and cancer cells. STAT5a-mediated repression of mitochondrial gene expression and its interaction with PDC-E2 may provide important insights into its underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Porcine epidemic diarrhea, a disease caused by porcine epidemic diarrhea virus (PEDV), results in large economic losses to the global swine industry. To manage this disease effectively, it is essential to detect PEDV early and accurately. We developed a sensitive and accurate droplet digital PCR (ddPCR) assay to detect PEDV. The optimal primer-to-probe concentration and melting temperature were identified as 300:200 nM and 59.2°C, respectively. The specificity of the ddPCR assay was confirmed by negative test results for common swine pathogens. The detection limit for the ddPCR was 0.26 copies/μL, which is a 5.7-fold increase in sensitivity compared to that of real-time PCR (rtPCR). Both ddPCR and rtPCR assays exhibited good linearity, although ddPCR provided higher sensitivity for clinical detection compared to that of rtPCR. Our ddPCR methodology provides a promising tool for evaluating the PEDV viral load when used for clinical testing, particularly for detecting samples with low-copy viral loads.

Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a ΔNp63α and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysis-preference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype., (© 2020 The Author(s).)

The emerging outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 continues to spread all over the world. Agents or vaccines of proven efficacy to treat or prevent human coronavirus infection are in urgent need and are being investigated vigorously worldwide. This review summarizes the current evidence of potential therapeutic agents, such as lopinavir/ritonavir, remdesivir, favipiravir, chloroquine, hydroxychloroquine, interferon, ribavirin, tocilizumab, and sarilumab. More clinical trials are being conducted for further confirmation of the efficacy and safety of these agents in treating COVID-19.

Background: A high incidence of posterior reversible encephalopathy syndrome (PRES) has been observed in women with eclampsia on imaging. However this association was documented mostly after convulsions occurred. This study aimed to detect the development of PRES using magnetic resonance imaging (MRI) in women with severe preeclampsia and headache, and evaluate the clinical and radiological findings in obstetric outcomes., Methods: A prospective single-center cohort study comprising 20 pregnant women with severe pre-eclampsia related headache was conducted using Numeric Rating Scale (NRS) score of ≧4. Additionally, non-contrast brain MRI was used to detect PRES and related radiological central nervous system (CNS) abnormalities., Results: Patients were enrolled at a mean gestational age of 32 weeks (range 29-38 weeks). Two women were unable to complete the scanning. Of the 18 MRI scans, 15 (83%) revealed abnormal findings. One patient developed an altered mental state and diffuse PRES, with the occipital, temporal, thalamus, and basal ganglia, the brain stem, and the cerebellum being affected. Two patients had abnormal susceptibility-weighted imaging (SWI) findings, indicating micro-hemorrhages. The majority (12 cases, 66%) of the patients had abnormal cortical hyperintensities in the occipital and temporal lobes. Only three patients had normal MRI pictures. None of the women had eclampsia occurred during the peripartum period, and only one unrelated neonatal death due to congenital anomalies., Conclusion: A high incidence of abnormal cortical hyperintensity changes at locations typical for PRES on MRI was noted in women with severe pre-eclampsia and headache. These early hypertensive neurological signs allowed prompt and efficient obstetrical management, to prevent the development of eclampsia and PRES.

Down syndrome is one of the most common chromosomal disorders and yet our understanding about the dysregulated genes in this disease is limited. Through this case study, we investigated the gene expression profile of primary amniotic fluid mesenchymal stem cells (AFMSCs) isolated from the amniotic sac of monozygotic twins discordant for trisomy 21 with one fetal hydrops at 17 weeks of gestation. AFMSCs were cultured to analyze the gene expression profiles for the human transcriptome array. Gene ontology was used to evaluate dysregulated gene functions. Total 25,799 genes were identified such that 65 were up-regulated (0.25%) and 111 were down-regulated (0.43%) with a log 2 fold change trisomy 21/euploidy (log 2 [FC]) > 1, p < 0.01). 16 genes were selected and verified by qRT-PCR, which showed compatible result with transcriptome array. At the chromosome level, chromosome 21 was found to carry the highest percentage of up-regulated genes (2.13%, 7/329 genes) with the highest mean log 2 [FC] (0.23, p < 10 -5 ), particularly on 21q22.3. There were eight segments with significant mean log 2 [FC] on chromosomes 1, 6, 11, and 21 for upregulation, and on chromosomes 16, 17, and 19 for downregulation, indicating a pattern of dysregulated genes clustering in domains along the genome. Gene ontology showed the identified genes associated with extracellular matrix organization (11 genes, p = 5.1 × 10 -6 ) and central nervous system development (8 genes, p = 6.0 × 10 -5 ). Using transcriptome analysis of the AFMSCs of monozygotic twins discordant for trisomy 21, we report the dysregulated genes involved in Down syndrome, their predominance on chromosome 21, and the cluster pattern on the whole genome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In(OTf) 3 -catalyzed intramolecular hydroarylation of α-phenylallyl β-ketosulfones provides sulfonyl 1-benzosuberones and 1-tetralones in moderate to good yields in refluxing (CH 2 Cl) 2 under open-vessel and easy-operation reaction conditions. A plausible mechanism is proposed and discussed. This highly regioselective protocol provides an atom-economic ring-closure route., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The optimal timing to initiate dialysis among patients with an estimated glomerular filtration rate (eGFR) of <5 mL/min/1.73 m2 is unknown. We hypothesized that dialysis initiation time can be deferred in this population even with high uremic burden. A case-crossover study with case (0-30 days before dialysis initiation [DI]) and control (90-120 days before DI) periods was conducted in 1,079 hemodialysis patients aged 18-90 years at China Medical University Hospital between 2006 and 2015. The uremic burden was quantified based on 7 uremic indicators that reached the predefined threshold in case period, namely hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate. Dialysis timing was classified as standard (met 0-2 uremic indicators), late (3-5 indicators), and very late (6-7 indicators). Median eGFR-DI of the 1,079 patients was 3.4 mL/min/1.73 m2 and was 2.7 mL/min/1.73 m2 in patients with very late initiation. The median follow-up duration was 2.42 years. Antibiotics, diuretics, antihypertensive medications, and non-steroidal anti-inflammatory drugs (NSAIDs) were more prevalently used during the case period. The fully adjusted hazards ratios of all-cause mortality for the late and very late groups were 0.97 (95% confidence interval 0.76-1.24) and 0.83 (0.61-1.15) compared with the standard group. It is safe to defer dialysis initiation among patients with chronic kidney disease (CKD) having an eGFR of <5 mL/min/1.73 m2 even when patients having multiple biochemical uremic burdens. Coordinated efforts in acute infection prevention, optimal fluid management, and prevention of accidental exposure to NSAIDs are crucial to prolong the dialysis-free survival., Competing Interests: The authors have declared that no competing interests exist.

Objective and Background: Pattern recognition receptors (PRRs) on immune and parenchymal cells can detect danger-associated molecular patterns (DAMPs) released from cells damaged during ischemia-reperfusion injury (IRI), in heart attack or stroke settings, but also as an unavoidable consequence of solid organ transplantation. Despite IRI being a significant clinical problem across all solid organ transplants, there are limited therapeutics and patient-specific diagnostics currently available., Methods: We screened portal blood samples obtained from 67 human liver transplant recipients both pre- [portal vein (PV) sample] and post-(liver flush; LF) reperfusion for their ability to activate a panel of PRRs, and analyzed this reactivity in relation to biopsy-proven IRI., Results: PV samples from IRI+ orthotopic liver transplantation (OLT) patients (n = 35) decreased activation of hTLR4- and hTLR9-transfected cells, whereas PV from IRI- patients (n = 32) primarily increased hTLR7 and hNOD2 activation. LF samples from OLT-IRI patients significantly increased activation of hTLR4 and hTLR9 over IRI- LF. In addition, the change from baseline reactivity to hTLR4/9/NOD2 was significantly higher in IRI+ than IRI- OLT patients., Conclusions: These results demonstrate that TLR4/7/9 and NOD2 are involved in either promoting or attenuating hepatic IRI, and suggest a diagnostic screening of portal blood for reactivity to these PRRs might prove useful for prediction and/or therapeutic intervention in OLT patients before transplantation.