bluuebunny/crossref_metadata_2025 huggingface dataset:
5-Aminolevulinic acid fermentation using engineered Saccharomyces cerevisiae
Authors: Hara Kiyotaka Y. , Saito Masaru , Kato Hiroko , Morikawa Kana , Kikukawa Hiroshi , Nomura Hironari , Fujimoto Takanori , Hirono-Hara Yoko , Watanabe Shigeyuki , Kanamaru Kengo , Kondo Akihiko
Published: November 2019

Background

5′-Aminolevulinic acid (ALA) is widely used in the pharmaceutical industry, healthcare, and food production, and is a substrate for the biosynthesis of heme, which is required for respiration and photosynthesis. Enhancement of ALA biosynthesis has never been developed in Saccharomyces cerevisiae, which is a well-known model microorganism used for bioproduction of many value-added compounds.

Results

We demonstrated that metabolic engineering significantly improved ALA production in S. cerevisiae. First, we found that overexpression of HEM1, which encodes ALA synthetase, increased ALA production. Furthermore, addition of an optimal amount of glycine, a substrate for ALA biosynthesis, or levulinic acid, an inhibitor of ALA dehydrogenase, effectively increased ALA production. Next, we developed an assay for multiple metabolites including ALA and found that aconitase, encoded by ACO1 and ACO2, is the rate-limiting enzyme of ALA biosynthesis when sufficient glycine is supplied. Overexpression of ACO2 further enhanced ALA production in S. cerevisiae overexpressing HEM1.

Conclusions

In this study, ALA production in S. cerevisiae was enhanced by metabolic engineering. This study also shows a strategy to identify the rate-limiting step of a target synthetic pathway by assay for multiple metabolites alongside the target product. This strategy can be applied to improve production of other valuable products in the well-studied and well-industrialized microorganism S. cerevisiae.
High production of valencene in Saccharomyces cerevisiae through metabolic engineering
Authors: Chen Hefeng , Zhu Chaoyi , Zhu Muzi , Xiong Jinghui , Ma Hao , Zhuo Min , Li Shuang
Published: November 2019

Background

The biological synthesis of high value compounds in industry through metabolically engineered microorganism factories has received increasing attention in recent years. Valencene is a high value ingredient in the flavor and fragrance industry, but the low concentration in nature and high cost of extraction limits its application.Saccharomyces cerevisiae, generally recognized as safe, is one of the most commonly used gene expression hosts. Construction ofS. cerevisiaecell factory to achieve high production of valencene will be attractive.

Results

Valencene was successfully biosynthesized after introducing valencene synthase intoS. cerevisiaeBJ5464. A significant increase in valencene yield was observed after down-regulation or knock-out of squalene synthesis and other inhibiting factors (such aserg9,rox1) in mevalonate (MVA) pathway using a recyclable CRISPR/Cas9 system constructed in this study through the introduction of Cre/loxP. To increase the supplement of the precursor farnesyl pyrophosphate (FPP), all the genes of FPP upstream in MVA pathway were overexpressed in yeast genome. Furthermore, valencene expression cassettes containing different promoters and terminators were compared, and PHXT7-VS-TTPI1was found to have excellent performance in valencene production. Finally, after fed-batch fermentation in 3 L bioreactor, valencene production titer reached 539.3 mg/L with about 160-fold improvement compared to the initial titer, which is the highest reported valencene yield.

Conclusions

This study achieved high production of valencene inS. cerevisiaethrough metabolic engineering and optimization of expression cassette, providing good example of microbial overproduction of valuable chemical products. The construction of recyclable plasmid was useful for multiple gene editing as well.
Exosomal microRNA-205 is involved in proliferation, migration, invasion, and apoptosis of ovarian cancer cells via regulating VEGFA
Authors: Wang Lijun , Zhao Fei , Xiao Zhongqing , Yao Liang
Published: November 2019

Background

Recently, the impact of microRNAs (miRNAs) and exosome on ovarian cancer has been assessed in many studies. We aim to explore the mechanism of exosomes transferring miR-205 in ovarian cancer, and confirm its diagnostic value in ovarian cancer.

Methods

The expression of miR-205 of ovarian cancer patients and healthy people was detected by RT-qPCR, and the diagnostic value of miR-205 was evaluated. The exosomes derived from SKOV3 cells were identified. Ovarian cancer SKOV3 donor cells and receptor cells were used to measure the proliferation, migration, invasion, apoptosis and cell cycle by a series of experiments. The binding site between miR-205 and vascular endothelial growth factor A (VEGFA) was evaluated by bioinformatics tool and dual-luciferase reporter gene assay.

Results

MiR-205 was up-regulated in ovarian cancer, and up-regulated miR-205 could enhance the risk of ovarian cancer and was one of its risk factors. After SKOV3 cells-derived exosomes were transiently introduced with miR-205 mimics, the cell proliferation, migration and invasion in ovarian cancer were elevated, the apoptosis of ovarian cancer cells was attenuated, and the epithelial–mesenchymal transition (EMT) protein E-cadherin was down-regulated, while Vimentin was elevated. VEGFA was identified to be a target gene of miR-205.

Conclusion

This study suggests that exosomes from donor ovarian cancer cell SKOV3 shuttled miR-205 could participate in the regulation of the proliferation, migration, invasion, apoptosis as well as EMT progression of receptor SKOV3 cells by targeting VEGFA.
ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis
Authors: Lin Qiushi , Chen Xuesong , Meng Fanzheng , Ogawa Kosuke , Li Min , Song Ruipeng , Zhang Shugeng , Zhang Ziran , Kong Xianglu , Xu Qinggang , He Fuliang , Bai Xuewei , Sun Bei , Hung Mien-Chie , Liu Lianxin , Wands Jack , Dong Xiaoqun
Published: November 2019

Background

Aspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer.

Methods

Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied.

Results

Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis.

Conclusions

ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.
Serum and follicular fluid thyroid hormone levels and assisted reproductive technology outcomes
Authors: Cai Yun Ying , Lin Na , Zhong Lan Ping , Duan Hui Juan , Dong Yun Hua , Wu Ze , Su Heng
Published: November 2019

Objective

The objective ofthis study was to assess the association between thyroid hormone (TH) levels in follicular fluid (FF) and serum and to determine whether THs impact assisted reproductive technology (ART) outcomes.

Methods

This study enrolled 299 women undergoing ART. Blood samples were drawn on the day of human chorionic gonadotrophin (HCG) administrationand analysed for thyroid-stimulating hormone (TSH), thyroxine(T4), triiodothyronine(T3),free T4 (fT4),free T3(fT3), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) levels. FF was obtained on the oocyte pick up (OPU) day and analysed forTSH, T4, T3, fT4, fT3, TPOAb, TgAb and estradiol levels.

Results

(1) There were significant positive correlations between serum and FF TH and thyroid autoantibody levels. Statistically significant differences were discovered in serum and FF levels of TSH (p ≤ 0.001), T4 (p ≤ 0.001), T3 (p ≤ 0.001), TPOAbs (p ≤ 0.001) and TGAbs (p = 0.021).

(2) Serum T4 levels [121.9(104.8,140.8) vs 114.1(98.6,130.6) nmol/l,p = 0.026], serum fT4 levels[(19.0(17.7,21.8) vs 18.6(17.0,20.1) pmol/l,p = 0.026], serum T4/T3 ratios [62.5 (55.7, 66.2) vs 59.4 (53.4, 64.9),p = 0.029], FF fT4 levels [19.0(17.5,21.3) vs 18.1(16.8,19.9) pmol/l,p = 0.009] and FF T4/T3 ratios [52.6 (46.4, 57.3) vs 50.0 (43.7, 53.1),p = 0.004] were significantly higher in the successful pregnancy group than the implantation failure group.

(3) Spearman’s rank correlation analysis revealed positive associations of both the FF T4/T3 ratio and serum TSH levels with the numbers of retrieved oocytes (total or MII) and embryos (fertilized, cleavage, and good quality).

Conclusions

TH levels in FF are strongly correlated with those in serum on the HCG day, and THs on the HCG day may affect ART outcomes.
Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway
Authors: Zuo Xiao-xiao , Yang Ya , Zhang Yue , Zhang Zhi-gang , Wang Xiao-fei , Shi Yong-gang
Published: November 2019

Background

Integrin-mediated platelet-tumor cell contacting plays an important role in promoting epithelial-mesenchymal transition (EMT) transformation of tumor cells and cancer metastasis, but whether it occurs in breast cancer cells is not completely clear.

Objective

The purpose of this study was to investigate the role of integrin α2β1 in platelet contacting to human breast cancer cell line MCF-7 and its effect on the EMT and the invasion of MCF-7 cells.

Methods

Human platelets were activated by thrombin, and separated into pellets and releasates before the co-incubation with MCF-7 cells. Cell invasion was evaluated by transwell assay. The surface integrins on pellets and MCF-7 cells were inhibited by antibodies. The effect of integrin α2β1 on Wnt-β-catenin pathway was assessed by integrin α2β1-silencing and Wnt-β-catenin inhibitor XAV. The therapeutic effect of integrin α2β1-silencing was confirmed in the xenograft mouse model.

Results

Pellets promote the invasion and EMT of MCF-7 cells via direct contacting of surface integrin α2β1. The integrin α2β1 contacting activates Wnt-β-catenin pathway and promotes the expression of EMT proteins in MCF-7 cells. The activated Wnt-β-catenin pathway also promotes the autocrine of TGF-β1 in MCF-7 cells. Both Wnt-β-catenin and TGF-β1/pSmad3 pathways promote the expression of EMT proteins. Integrin α2β1-silencing inhibits breast cancer metastasis in vivo.

Conclusions

The direct interaction between platelets and tumor cells exerts its pro-metastatic function via surface integrin α2β1 contacting and Wnt-β-catenin activation. Integrin α2β1-silencing has the potential effect of inhibiting breast cancer metastasis.
Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection
Authors: Pokorna Formanova Petra , Palus Martin , Salat Jiri , Hönig Vaclav , Stefanik Michal , Svoboda Pavel , Ruzek Daniel
Published: November 2019

Background

Tick-borne encephalitis (TBE) is a severe neuropathological disorder caused by tick-borne encephalitis virus (TBEV). Brain TBEV infection is characterized by extensive pathological neuroinflammation. The mechanism by which TBEV causes CNS destruction remains unclear, but growing evidence suggests that it involves both direct neuronal damage by the virus infection and indirect damage caused by the immune response. Here, we aimed to examine the TBEV-infection-induced innate immune response in mice and in human neural cells. We also compared cytokine/chemokine communication between naïve and infected neuronal cells and astrocytes.

Methods

We used a multiplexed Luminex system to measure multiple cytokines/chemokines and growth factors in mouse serum samples and brain tissue, and in human neuroblastoma cells (SK-N-SH) and primary cortical astrocytes (HBCA), which were infected with the highly pathogenic TBEV strain Hypr. We also investigated changes in cytokine/chemokine production in naïve HBCA cells treated with virus-free supernatants from TBEV-infected SK-N-SH cells and in naïve SK-N-SH cells treated with virus-free supernatants from TBEV-infected HBCA cells. Additionally, a plaque assay was performed to assess how cytokine/chemokine treatment influenced viral growth following TBEV infection.

Results

TBEV-infected mice exhibited time-dependent increases in serum and brain tissue concentrations of multiple cytokines/chemokines (mainly CXCL10/IP-10, and also CXCL1, G-CSF, IL-6, and others). TBEV-infected SK-N-SH cells exhibited increased production of IL-8 and RANTES and downregulated MCP-1 and HGF. TBEV infection of HBCA cells activated production of a broad spectrum of pro-inflammatory cytokines, chemokines, and growth factors (mainly IL-6, IL-8, CXCL10, RANTES, and G-CSF) and downregulated the expression of VEGF. Treatment of SK-N-SH with supernatants from infected HBCA induced expression of a variety of chemokines and pro-inflammatory cytokines, reduced SK-N-SH mortality after TBEV infection, and decreased virus growth in these cells. Treatment of HBCA with supernatants from infected SK-N-SH had little effect on cytokine/chemokine/growth factor expression but reduced TBEV growth in these cells after infection.

Conclusions

Our results indicated that both neurons and astrocytes are potential sources of pro-inflammatory cytokines in TBEV-infected brain tissue. Infected/activated astrocytes produce cytokines/chemokines that stimulate the innate neuronal immune response, limiting virus replication, and increasing survival of infected neurons.
Quercetin prevents necroptosis of oligodendrocytes by inhibiting macrophages/microglia polarization to M1 phenotype after spinal cord injury in rats
Authors: Fan Hong , Tang Hai-Bin , Shan Le-Qun , Liu Shi-Chang , Huang Da-Geng , Chen Xun , Chen Zhe , Yang Ming , Yin Xin-Hua , Yang Hao , Hao Ding-Jun
Published: November 2019

Background

Oligodendrocytes (OLs) death after spinal cord injury (SCI) contributes to demyelination, even leading to a permanent neurological deficit. Besides apoptosis, our previous study demonstrated that OLs underwent receptor-interacting serine-threonine kinase 3(RIP3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. Considering that necroptosis is always accompanied with pro-inflammatory response and quercetin has long been used as anti-inflammatory agent, in the present study we investigated whether quercetin could inhibit necroptosis of OLs and suppress the M1 macrophages/microglia-mediated immune response after SCI as well as the possible mechanism.

Methods

In this study, we applied quercetin, an important flavonoid component of various herbs, to treat rats with SCI and rats injected with saline were employed as the control group. Locomotor functional recovery was evaluated using Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay. In vivo, the necroptosis, apoptosis, and regeneration of OLs were detected by immunohistochemistry, 5′-bromo-2′-deoxyuridine (BrdU) incorporation. The loss of myelin and axons after SCI were evaluated by Luxol fast blue (LFB) staining, immunohistochemistry, and electron microscopic study. The polarization of macrophages/microglia after SCI and the underlying mechanisms were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. In vitro, the ATP and reactive oxygen species (ROS) level examination, propidium iodide (PI) labeling, and Western blotting were used to analyze the necroptosis of cultured OLs, while the signaling pathways-mediated polarization of cultured macrophages/microglia was detected by qRT-PCR and Western blotting.

Results

We demonstrated that quercetin treatment improved functional recovery in rats after SCI. We then found that quercetin significantly reduced necroptosis of OLs after SCI without influencing apoptosis and regeneration of OLs. Meanwhile, myelin loss and axon loss were also significantly reduced in quercetin-treated rats, as compared to SCI + saline control. Further, we revealed that quercetin could suppress macrophages/microglia polarized to M1 phenotype through inhibition of STAT1 and NF-κB pathway in vivo and in vitro, which contributes to the decreased necroptosis of OLs.

Conclusions

Quercetin treatment alleviated necroptosis of OLs partially by inhibiting M1 macrophages/microglia polarization after SCI. Our findings suggest that necroptosis of OLs may be a potential therapeutic target for clinical SCI.
Patient with severe fever with thrombocytopenia syndrome virus infection and central nervous system disturbance in Dongyang, Zhejiang Province, China, 2017
Authors: Sun Yi , Guo Bin , Yan Hao , Wu Ai Lan , Yao Wen Wu , Chen Kang , Pan Jun Hang , Li Zhao Xia , Mao Hai Yan , Zhang Yan Jun
Published: November 2019

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever that was first described in China in 2011. We report a patient who died of Severe fever with thrombocytopenia syndrome virus (SFTSV) infection, with a rapidly progressive central nervous system (CNS) disturbance, in Dongyang, Zhejiang Province, China, in 2017.

Case presentation

A 64-year-old man was admitted to hospital after 4 days of fever. SFTSV was detected 1 day after the patient was admitted to hospital. The patient presented with CNS disturbance and died 4 days after admission. Detailed clinical and epidemiological investigations and laboratory tests were conducted. Reduced platelet, white blood cell, lymphocyte, and neutrophil counts, elevated lactate dehydrogenase, creatine kinase, aspartate aminotransferaseand alanine aminotransferase concentrations, and an increased activated partial thromboplastin time were observed. In a phylogenetic analysis, the isolate clustered close to a strain derived from South Korea.

Conclusions: This is the first case of SFTSV infection with CNS disturbance in Dongyang, Zhejiang Province, China. The surveillance of suspected cases of SFTS is important in SFTSV endemic regions.
Vulvar myeloid sarcoma as the presenting symptom of acute myeloid leukemia: a case report and literature review of Chinese patients, 1999–2018
Authors: Zhang Xilin , Huang Peichen , Chen Zhuo , Bi Xinling , Wang Ying , Wu Jianhua
Published: November 2019

Background

Myeloid sarcoma (MS), which represents a rare malignancy that comprises of myeloid blasts occurring at extra-medullary sites, closely correlates with the onset and relapse of acute myeloid leukemia (AML) and other hemopoietic neoplasm. Female genital system is an uncommon location of MS, with the vulvar MS being even rarer that only eight cases have been reported in English-written literature.

Case presentation

A 47-year-old woman presented with chronic ulceration on her vulva for one and a half month. Microscopic examination of incisional biopsy revealed dermal infiltration of myeloid precursor cells, which were positive for MPO, lysozyme, CD43, CD68, CD38 and CD117. Bone marrow flowcytometric analysis showed myeloblast count of 74%, which expressed CD13, CD33, CD117 and HLA-DR. A diagnosis of AML (M2 type) was made and vulvar MS was the earliest symptom. The patient achieved complete remission after chemotherapy with no evidence of recurrence in a 27-month follow-up. We reviewed the literature and identified 54 cases of Chinese patients with gynecological MS between 1999 and 2018, and discovered that in Chinese population, MS most frequently involved uterine cervix followed by the ovary and vulva, and ovarian MS onset much earlier than other sites. Remarkably, vulvar MS exhibited a high rate of concurrent AML and secondary myeloid leukemia within a short time of its occurrence. Despite its limited distribution, MS should be tackled aggressively with chemotherapy followed by allogeneic hematopoietic stem cell transplantation if the appropriate donor is available.

Conclusions

Female genital MS, especially vulvar MS, should be included in the differential diagnosis of gynecological neoplasm, which will facilitate its early diagnosis and prompt management.
Comparison of the outcomes of stereotactic body radiotherapy versus surgical treatment for elderly (≥70) patients with early-stage non-small cell lung cancer after propensity score matching
Authors: Dong Baiqiang , Wang Jin , Zhu Xuan , Chen Yuanyuan , Xu Yujin , Shao Kainan , Zheng Lei , Ying Hangjie , Chen Ming , Cao Jianping
Published: November 2019

Background

The optimal treatment for elderly patients with early-stage non-small cell lung cancer (NSCLC) remains inconclusive. Previous studies have shown that stereotactic body radiotherapy (SBRT) provides encouraging local control though higher incidence of toxicity in elderly than younger populations. The objective of this study was to compare the outcomes of SBRT and surgical treatment in elderly patients with clinical stage I-II NSCLC.

Methods

This retrospective analysis included 205 patients aged ≥70 years with clinical stage I NSCLC who underwent SBRT or surgery at Zhejiang Cancer Hospital (Hangzhou, China) from January 2012 to December 2017. A propensity score matching analysis was performed between the two groups. In addition, we compared outcomes and related toxicity in both study arms.

Results

Each group included 35 patients who met the inclusion criteria. Median follow-up was 50.1 (0.8–74.4) months for surgery and 35.5 (11.5–71.4) months for SBRT. The rate of cancer-specific survival was similar between the two treatment arms (p = 0.958). In patients who underwent surgery, the corresponding 3- and 5-year cancer-specific survival rates were 85.3 and 81.7%, respectively. In those who received radiotherapy, these rates were 91.3 and 74.9%, respectively. Moreover, the 3- and 5-year locoregional control in patients who underwent surgery were 90.0 and 80.0%, respectively. In those who received radiotherapy, these rates were 91.1 and 84.1%, respectively. Notably, the observed differences in progression-free survival were not statistically significant (p = 0.934). In the surgery group, grade 1–2 complications were observed in eleven patients (31%). One patient died due to perioperative infection within 30 days following surgery. There was no grade 3–5 toxicity observed in the SBRT group.

Conclusions

The outcomes of surgery and SBRT in elderly patients with early-stage NSCLC were similar.
The impact of mild renal dysfunction on isolated cardiopulmonary coronary artery bypass grafting: a retrospective propensity score matching analysis
Authors: Wang Xian , Zhu Yifan , Chen Wen , Li Liangpeng , Chen Xin , Wang Rui
Published: November 2019

Background

Mild preoperative renal dysfunction (RD) is not rare in patients receiving isolated cardiopulmonary coronary artery bypass grafting (CCABG). However, there are not too many studies about the impact of mild preoperative RD on in-hospital and follow-up outcomes after isolated CCABG. This single-centre, retrospective propensity score matching study designed to study the impact of mild preoperative RD on in-hospital and long-term outcomes after first isolated CCABG.

Methods

After propensity score matching, 1144 patients with preoperative estimated glomerular filtration rate (eGFR) of more than 60 ml/min/1.73 m2 receiving first isolated CCABG surgery from January 2012 to December 2015 entered the study, who were divided into 2 groups: A group (eGFR ≥90 ml/min/1.73 m2, n = 572) and B group (eGFR of 60–89 ml/min/1.73 m2, n = 572). The in-hospital and long-term outcomes were recorded and analyzed. The mean follow-up time was 54.4 ± 10.7 months. Acute kidney injury (AKI) was defined and classified according to the Acute Kidney Injury Network (AKIN) criteria.

Results

The 2 propensity score-matched groups had similar baseline and procedure except the baseline eGFR. There were 8 patients died in A group (mortality is 1.4%) and 14 died in B group (mortality is 2.5%) during the in hospital and 30-day postoperatively(χ2 = 1.159, p = 0.282). There were totally 38 patients lost to follow-up, 18 in group A and 20 in group B. 21 patients died in group A and 37 died in group B during the follow-up, and long-term survival in group A was higher than in group B (96.2% vs 93.1%, χ2 = 4.336, p = 0.037). Comparing with group A, group B was associated with an increased rates and severity of AKI postoperatively (total AKI: 62 vs 144. AKIN stageI: 54 vs 113; AKIN stageII: 6 vs 22; AKIN stageIII: 2 vs 9, p<0.0001). During follow-up, group B also had a higher rate of new onset of dialysis (0 vs 6, χ2 = 4.432, p = 0.039). Multivariable logistic regression showed that comparing with A group, the HR for long-term mortality and new onset of dialysis in B group was 1.67 and 1.52 respectively (95%CI 1.09–2.90, p = 0.035; 95%CI 1.14–2.49, p = 0.027).

Conclusions

Comparing with normal preoperative renal function, patients with mild preoperative RD had a similar in-hosptial mortality, but with an increased in-hosptial rates and severity of AKI, and with a decreased long-term survival and increased long-term new onset of dialysis.
Untypical autoimmune pancreatitis and pancreatic cancer: differential diagnosis experiences extracted from misdiagnose of two cases
Authors: Li Gaopeng , Liu Ting , Zheng Jian , Kang Wenqin , Xu Jun , Gao Zefeng , Ma Jinfeng
Published: November 2019

Background

Differentiation between pancreatic cancer (PC) and focal form of autoimmune pancreatitis (AIP) is very challenging, with similar clinical presentations, laboratory results and morphologic imagings of US, CT, EUS, MRI, ERCP, PET-CT. Even serum IgG4 and biopsy sometimes cannot give clear-cut differential accurate diagnostis. Considering the totally different management strategy of the two diseases, accurate diagnostic value is urgently needed to remind the clinicians of the rare diagnosis of untypical AIP among frequent PC-suspected patients.

Results

We present 2 laparotomy cases of AIP that had a high similar characteristic to PC and retrospectively extracted the warning signs that may help select untypical AIP in PC-suspected patients.

Conclusions

We find that mild fluctuating jaundice with abdominal pain, young age, tumor marker of TPS, TPA and diverse results between variable radiological tests can help to differentiate AIP mass from PC, through retrospectively analyzing work-up process of AIP in two patients who underwent laparotomy for suspected PC.
NOTCH2 negatively regulates metastasis and epithelial-Mesenchymal transition via TRAF6/AKT in nasopharyngeal carcinoma
Authors: Zou You , Yang Rui , Huang Mao-Ling , Kong Yong-Gang , Sheng Jian-Fei , Tao Ze-Zhang , Gao Ling , Chen Shi-Ming
Published: November 2019

Background

Clinically, distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC). Thus, identification of the underlying mechanisms and development of novel therapeutic strategies are urgently needed. NOTCH has been shown to function as a tumor promotor that enhances angiogenesis, cancer invasion and metastasis in NPC. However, the precise roles of the four individual NOTCH receptors and their mechanisms of action are unclear.

Methods

We used Western blot analysis, immunofluorescence, immunohistochemical analysis, phalloidin staining, mouse tumor metastatic dissemination models, gene set enrichment analysis, immunoprecipitation assays and a series of functional assays to determine the potential role of NOTCH2 in regulating NPC metastasis.

Results

NOTCH2 expression in the NPC tissues of patients with cervical lymph node metastasis was lower than that of patients without cervical lymph node metastasis. Correspondingly, NOTCH2 expression was low in metastatic and poorly differentiated NPC cells. NOTCH2 expression correlated negatively with survival time in patients with NPC. Suppression of NOTCH2 expression promoted NPC cell metastasis, whereas NOTCH2 overexpression inhibited this process. Furthermore, NOTCH2 attenuated the TRAF6–AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial–mesenchymal transition (EMT) and eventually suppressed NPC metastasis.

Conclusions

These findings reveal that loss of NOTCH2 activates the TRAF6/AKT axis and promotes metastasis in NPC, suggesting that NOTCH2 may represent a therapeutic target for the treatment of NPC.
Causes of brain dysfunction in acute coma: a cohort study of 1027 patients in the emergency department
Authors: Schmidt Wolf Ulrich , Ploner Christoph J. , Lutz Maximilian , Möckel Martin , Lindner Tobias , Braun Mischa
Published: November 2019

Background

Coma of unknown etiology (CUE) is a major challenge in emergency medicine. CUE is caused by a wide variety of pathologies that require immediate and targeted treatment. However, there is little empirical data guiding rational and efficient management of CUE. We present a detailed investigation on the causes of CUE in patients presenting to the ED of a university hospital.

Methods

One thousand twenty-seven consecutive ED patients with CUE were enrolled. Applying a retrospective observational study design, we analyzed all clinical, laboratory and imaging findings resulting from a standardized emergency work-up of each patient. Following a predefined protocol, we identified main and accessory coma-explaining pathologies and related these with (i.a.) GCS and in-hospital mortality.

Results

On admission, 854 of the 1027 patients presented with persistent CUE. Their main diagnoses were classified into acute primary brain lesions (39%), primary brain pathologies without acute lesions (25%) and pathologies that affected the brain secondarily (36%). In-hospital mortality associated with persistent CUE amounted to 25%. 33% of patients with persistent CUE presented with more than one coma-explaining pathology. In 173 of the 1027 patients, CUE had already resolved on admission. However, these patients showed a spectrum of main diagnoses similar to persistent CUE and a significant in-hospital mortality of 5%.

Conclusion

The data from our cohort show that the spectrum of conditions underlying CUE is broad and may include a surprisingly high number of coincidences of multiple coma-explaining pathologies. This finding has not been reported so far. Thus, significant pathologies may be masked by initial findings and only appear at the end of the diagnostic work-up. Furthermore, even transient CUE showed a significant mortality, thus rendering GCS cutoffs for selection of high- and low-risk patients questionable. Taken together, our data advocate for a standardized diagnostic work-up that should be triggered by the emergency symptom CUE and not by any suspected diagnosis. This standardized routine should always be completed - even when initial coma-explaining diagnoses may seem evident.
RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation
Authors: Saffari Ayden , Arno Matt , Nasser Eric , Ronald Angelica , Wong Chloe C. Y. , Schalkwyk Leonard C. , Mill Jonathan , Dudbridge Frank , Meaburn Emma L.
Published: November 2019

Background

A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC.

Methods

Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis.

Results

In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation.

Limitations

Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis.

Conclusions

Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals.
A multiple classifier system identifies novel cannabinoid CB2 receptor ligands
Authors: Ruano-Ordás David , Burggraaff Lindsey , Liu Rongfang , van der Horst Cas , Heitman Laura H. , Emmerich Michael T. M. , Mendez Jose R. , Yevseyeva Iryna , van Westen Gerard J. P.
Published: November 2019

Drugs have become an essential part of our lives due to their ability to improve people’s health and quality of life. However, for many diseases, approved drugs are not yet available or existing drugs have undesirable side effects, making the pharmaceutical industry strive to discover new drugs and active compounds. The development of drugs is an expensive process, which typically starts with the detection of candidate molecules (screening) after a protein target has been identified. To this end, the use of high-performance screening techniques has become a critical issue in order to palliate the high costs. Therefore, the popularity of computer-based screening (often called virtual screening or in silico screening) has rapidly increased during the last decade. A wide variety of Machine Learning (ML) techniques has been used in conjunction with chemical structure and physicochemical properties for screening purposes including (i) simple classifiers, (ii) ensemble methods, and more recently (iii) Multiple Classifier Systems (MCS). Here, we apply an MCS for virtual screening (D2-MCS) using circular fingerprints. We applied our technique to a dataset of cannabinoid CB2 ligands obtained from the ChEMBL database. The HTS collection of Enamine (1,834,362 compounds), was virtually screened to identify 48,232 potential active molecules using D2-MCS. Identified molecules were ranked to select 21 promising novel compounds for in vitro evaluation. Experimental validation confirmed six highly active hits (> 50% displacement at 10 µM and subsequent Ki determination) and an additional five medium active hits (> 25% displacement at 10 µM). Hence, D2-MCS provided a hit rate of 29% for highly active compounds and an overall hit rate of 52%.
Health shock and preference instability: assessing health-state dependency of willingness-to-pay for corrective eyeglasses
Authors: Islam Muhammed Nazmul , Rabbani Atonu , Sarker Malabika
Published: November 2019

Background

Differences in contingent valuation (CV) estimates for identical healthcare goods can cast considerable doubt on the true economic measures of consumer preferences. Hypothetical nature of CV methods can potentially depend on the salience, context and perceived relevance of the good or service under consideration. Thus, the high demand elasticity for healthcare goods warrants careful selection of study population as the contexts of valuation significantly changes after experiencing health shock.

Methods

In this study, using triple-bounded dichotomous choice (TBDC) experiments, we test how negative health shock (namely, being diagnosed with refractive errors), can alter preference over a common health good (namely, corrective eyeglasses). We compared elicited WTP of diagnosed patients with a synthetically constructed comparable cohort without the same health shock, controlling for the possible self-selection using a number of matching techniques based on the observable socio-demographic characteristics.

Results

The consumers diagnosed with vision problems exhibit a rightward shift in their demand curve compared to observationally identical consumers without such problems resulting in about 17% higher consumer surplus. The consumers without the health shock are willing to pay about BDT 762.4 [95% CI: BDT 709.9 - BDT 814.9] for corrective eyeglasses, which gets 15–30% higher for the matched with-health-shock consumers. Multivariable analyses suggest more educated and wealthier individuals are willing to pay respectively BDT 208 and BDT 119 more for corrective eyeglasses. We have tested the models for different matching protocols. Our results are fairly robust to alternate specifications and various matching techniques.

Conclusion

The preferences for healthcare goods, such as eyeglasses, can significantly depend upon the respondent being diagnosed with refractive errors. Our findings have implications for general cost-benefit analyses often relying on WTP, which can vary depending on the contexts. There are also increasing interests in cost recovery models, which require understanding the demand for healthcare goods and services. We find eliciting the demand needs to consider the health status of the population from which the respondents are sampled.
Systematic review of the use of process evaluations in knowledge translation research
Authors: Scott Shannon D. , Rotter Thomas , Flynn Rachel , Brooks Hannah M. , Plesuk Tabatha , Bannar-Martin Katherine H. , Chambers Thane , Hartling Lisa
Published: November 2019

Background

Experimental designs for evaluating knowledge translation (KT) interventions can provide strong estimates of effectiveness but offer limited insight into how the intervention worked. Consequently, process evaluations have been used to explore the causal mechanisms at work; however, there are limited standards to guide this work. This study synthesizes current evidence of KT process evaluations to provide future methodological recommendations.

Methods

Peer-reviewed search strategies were developed by a health research librarian. Studies had to be in English, published since 1996, and were not excluded based on design. Studies had to (1) be a process evaluation of a KT intervention study in primary health, (2) be a primary research study, and (3) include a licensed healthcare professional delivering or receiving the intervention. A two-step, two-person hybrid screening approach was used for study inclusion with inter-rater reliability ranging from 94 to 95%. Data on study design, data collection, theoretical influences, and approaches used to evaluate the KT intervention, analysis, and outcomes were extracted by two reviewers. Methodological quality was assessed with the Mixed Methods Appraisal Tool (MMAT).

Results

Of the 20,968 articles screened, 226 studies fit our inclusion criteria. The majority of process evaluations used qualitative forms of data collection (43.4%) and individual interviews as the predominant data collection method. 72.1% of studies evaluated barriers and/or facilitators to implementation. 59.7% of process evaluations were stand-alone evaluations. The timing of data collection varied widely with post-intervention data collection being the most frequent (46.0%). Only 38.1% of the studies were informed by theory. Furthermore, 38.9% of studies had MMAT scores of 50 or less indicating poor methodological quality.

Conclusions

There is widespread acceptance that the generalizability of quantitative trials of KT interventions would be significantly enhanced through complementary process evaluations. However, this systematic review found that process evaluations are of mixed quality and lack theoretical guidance. Most process evaluation data collection occurred post-intervention undermining the ability to evaluate the process of implementation. Strong science and methodological guidance is needed to underpin and guide the design and execution of process evaluations in KT science.

Registration

This study is not registered with PROSPERO.
Socioeconomic position and body composition across the life course: a systematic review protocol
Authors: Bridger Staatz Charis , Kelly Yvonne , Lacey Rebecca , Hardy Rebecca
Published: November 2019

Introduction

The relation between socioeconomic position (SEP) and obesity measured by body mass index (BMI) has been extensively reviewed, but there is less research on the association between SEP and body composition. Fat distribution and muscle quality have been linked to adverse health outcomes such as cardiovascular disease, diabetes and poor physical capability. There is some evidence of secular changes in body composition with increasing fat-mass and reducing muscle quantity and strength, but it is unclear whether there have been secular changes in social inequalities in body composition. The aim is to perform a systematic review of the existing literature on the association between SEP and body composition and to explore any secular changes.

Methods

The systematic review will be carried out according to PRISMA guidelines. An electronic search of MEDLINE and Embase Classic + Embase will be conducted using OvidSP as the database interface, as well as SPORTDiscus using EBSCO. Two independently working reviewers will initially screen abstracts to exclude papers that are clearly ineligible, followed by a full-text screening to exclude papers not meeting all inclusion criteria. Any disagreements will be resolved through discussion. Data extraction and quality assessment of eligible papers will be carried out by 2 reviewers using a standardised form. The reference lists of identified papers will be searched for additional papers. Original studies in the English language, which examine the association between SEP at any age and body composition at the same or later age will be included if they use any recognised measures of SEP (e.g. income, occupation, over-crowding) and a recognised measure of body composition (total, proportional or location of fat mass and fat-free mass, using any appropriate methods, excluding anthropometry). Due to expected heterogeneity, a narrative synthesis is expected, with a descriptive summary to be provided in tables. If there is consistency in reporting of associations, a random-effects meta-analysis will be used to provide an overall summary estimate.

Discussion

The results of the review will summarise the existing evidence on social inequalities in body composition. Findings will identify gaps in knowledge and where further research is required.

Systematic review registration

PROSPERO CRD42019119937
Determinants of market outlet choices by smallholder teff farmers in Dera district, South Gondar Zone, Amhara National Regional State, Ethiopia: a multivariate probit approach
Authors: Abate Tadie Mirie , Mekie Taye Melese , Dessie Abebe Birara
Published: November 2019

In Ethiopia, teff is an important cereal crop, particularly in Dera district. It is a source of food and provides cash income for majority of smallholder farmers. To commercialize teff producers, selecting an appropriate market channel is mandatory. However, selecting an appropriate market channel is not an easy task because there are different factors that influence market outlet choices. Therefore, this study aimed to identify factors that influence teff market outlet choices. A two-stage random sampling procedure was used and a total of 154 smallholder farmers were randomly and proportionally selected to collect primary data. Multivariate probit model was employed to identify factors affecting teff market outlet choices. The result of the study shows that the probability of teff producers to choose wholesaler, retailer, consumer and cooperative market outlets was 31.82%, 35.71%, 37.01% and 16.88%, respectively. This shows that consumer was the most likely chosen market outlet while cooperative was the less likely chosen market outlet. The joint probability of farmers to choose the four market outlets is (0.1%) lower than the likely of no choosing four market outlets (19.5%). The result of multivariate probit model revealed that age of household head, land size, quantity of teff produced, lagged price of teff, family size (AE), membership of cooperatives and distance to the nearest market were found to be statistically and significantly affecting the market outlet choice behavior of teff producers. This implies that improving the production capacity of farmers and invests on rural cooperatives would help smallholder farmers to choose the rewarding market outlet. Therefore, the study suggested that improving the existing production system, farmers relying on intensive cultivation; giving better price for farmers and being membership of cooperative are important strategies to select the appropriate market channel.
Structural change and output volatility reduction in OECD countries: evidence of the Second Great Moderation
Authors: Duran Hasan Engin
Published: November 2019

In this article, we provide new, novel evidence for a more recent structural break (in 2010) indicating a greater moderation of output volatility compared to the well-known break during the mid-1980s. The period of analysis runs from 1962Q2 to 2018Q3. It covers 26 OECD countries. In terms of methodology, it has mainly been used as the measures of conditional and unconditional volatility and procedures of structural break detection (Inclan–Tiao test and autoregressive conditional heteroscedasticity model). As a result, it has been found that output greatly stabilized following the structural break at 2010Q1 in the post-era of 2008/09 global financial crisis. Moreover, output stabilization is robustly evident for 24 (out of 26) OECD countries. From a political standpoint, it is implied that the Keynesian view may be influential in this moderation. Government expenditures and fiscal programs, regulations of financial markets against the sub-prime lending and limitations to trade of mortgage-backed securities might have been the main driver of stability. Rapid improvement of digitalization and technical productivity may be regarded as another relevant reason that might have contributed to the stabilization process.