bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined use of apatinib mesylate and vinorelbine versus vinorelbine alone in recurrent or metastatic triple-negative breast cancer: study protocol for a randomized controlled clinical trial
Authors: Wu Shuo , Zhang Liang , Li Huan , Xu Junnan , Jiang Cui , Sun Tao
Published: May 2020

Background

The emergence of new molecular targeted drugs provides new prospects for the treatment of advanced breast cancer; the future therapeutic trend includes chemotherapy combined with molecular targeted therapy. Apatinib mesylate, a novel, small anti-angiogenic agent, highly selectively inhibits the activity of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib mesylate also blocks the signaling of vascular endothelial growth factor binding to its receptor, thereby strongly inhibiting tumor angiogenesis and exerting an anti-tumor effect. However, there have been no reports of a randomized controlled clinical trial of apatinib combined with vinorelbine for the treatment of triple-negative breast cancer (TNBC). We will compare the therapeutic effect of vinorelbine alone or in combination with apatinib mesylate, in patients with recurrent or metastatic TNBC in North China who have received at least two drug treatments, including anthracyclines and taxanes.

Methods/analysis

This study is a triple-blind, randomized, placebo-controlled, parallel-group clinical trial. We plan to include 238 female patients with locally recurrent or metastatic TNBC, admitted to the Liaoning Cancer Hospital & Institute, Northeast China. All enrolled patients will be randomized to oral vinorelbine alone (40 mg, thrice a week (Mondays, Wednesdays, and Fridays) in each 3-week cycle), or in combination with oral apatinib mesylate (500 mg, once daily in each 3-week cycle). Radiographic assessment will be performed every 6 weeks for 36 weeks and every 9 weeks thereafter. The primary outcome is progression-free survival and secondary outcomes include overall survival, disease control rate, objective response rate, and incidence of adverse events at grades 3 and 4, as defined by the National Cancer Institute Common Toxicity Criteria Version 4.0. Outcome measures will be evaluated at baseline (< 2 weeks before starting treatment), every 6 weeks during treatment, and at 4 weeks and every 3 months after treatment discontinuation.

Discussion

Based on the data from this trial, we hope to identify a treatment plan that is suitable for female patients with TNBC, who have been treated with anthracyclines and taxanes, in Northeast China.

Trial registration

ClinicalTrials.gov: NCT03932526. Registered on 30 April 2019.
Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial
Authors: Wang Yeming , Zhou Fei , Zhang Dingyu , Zhao Jianping , Du Ronghui , Hu Yi , Cheng Zhenshun , Gao Ling , Jin Yang , Luo Guangwei , Fu Shouzhi , Lu Qiaofa , Du Guanhua , Wang Ke , Lu Yang , Fan Guohui , Zhang Yi , Liu Ying , Ruan Shunan , Liu Wen , Jaki Thomas , Hayden Frederick G. , Horby Peter W. , Cao Bin , Wang Chen
Published: May 2020

Background

Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19.

Methods

The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed.

Discussion

This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020.

Trial registration

ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.
Optimal partner wavelength combination method applied to NIR spectroscopic analysis of human serum globulin
Authors: Han Yun , Zhong Yun , Zhou Huihui , Kuang Xuesong
Published: May 2020

Human serum globulin (GLB), which contains various antibodies in healthy human serum, is of great significance for clinical trials and disease diagnosis. In this study, the GLB in human serum was rapidly analyzed by near infrared (NIR) spectroscopy without chemical reagents. Optimal partner wavelength combination (OPWC) method was employed for selecting discrete information wavelength. For the OPWC, the redundant wavelengths were removed by repeated projection iteration based on binary linear regression, and the result converged to stable number of wavelengths. By the way, the convergence of algorithm was proved theoretically. Moving window partial least squares (MW-PLS) and Monte Carlo uninformative variable elimination PLS (MC-UVE-PLS) methods, which are two well-performed wavelength selection methods, were also performed for comparison. The optimal models were obtained by the three methods, and the corresponding root-mean-square error of cross validation and correlation coefficient of prediction (SECV, RP,CV) were 0.813 g L−1 and 0.978 with OPWC combined with PLS (OPWC-PLS), and 0.804 g L−1 and 0.979 with MW-PLS, and 1.153 g L−1 and 0.948 with MC-UVE-PLS, respectively. The OPWC-PLS and MW-PLS methods achieved almost the same good results. However, the OPWC only contained 28 wavelengths, so it had obvious lower model complexity. Thus it can be seen that the OPWC-PLS has great prediction performance for GLB and its algorithm is convergent and rapid. The results provide important technical support for the rapid detection of serum.
Cartilage-binding antibodies initiate joint inflammation and promote chronic erosive arthritis
Authors: Li Yanpeng , Tong Dongmei , Liang Peibin , Lönnblom Erik , Viljanen Johan , Xu Bingze , Nandakumar Kutty Selva , Holmdahl Rikard
Published: May 2020

Background

Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage.

Methods

Purified antibodies specific to unmodified or citrullinated collagen type II (CII), collagen type XI (CXI), and cartilage oligomeric matrix protein (COMP) were produced as culture supernatant, affinity purified, pooled as antibody cocktails (Cab3 and Cab4), and injected intravenously into mice to induce arthritis. An adjuvant (lipopolysaccharide or mannan) was subsequently injected intraperitoneally on either day 5 or day 60 to enhance arthritis. Antibody binding and complement activation on the cartilage surface were analyzed by immunohistochemical methods. Bone erosions and joint deformations were analyzed by histological assessments, enzyme-linked immunosorbent assays, and micro-CT. Luminex was used to detect CII-triple helical epitope-specific antibody responses.

Results

The new cartilage antibody cocktails induced an earlier and more severe disease than anti-CII antibody cocktail. Many of the mouse strains used developed severe arthritis with 3 antibodies, binding to collagen II, collagen XI, and cartilage oligomeric matrix protein (the Cab3 cocktail). Two new models of arthritis including Cab3-induced LPS-enhanced arthritis (lpsCAIA) and Cab3-induced mannan-enhanced arthritis (mCAIA) were established, causing severe bone erosions and bone loss, as well as epitope spreading of the B cell response. Cab4, with addition of an antibody to citrullinated collagen II, induced arthritis more efficiently in moderately susceptible C57BL/6 J mice.

Conclusions

The new mouse model for RA induced with cartilage antibodies allows studies of chronic development of arthritis and epitope spreading of the autoimmune response and bone erosion.
Effects of dihydrotestosterone on osteoblast activity in curdlan-administered SKG mice and osteoprogenitor cells in patients with ankylosing spondylitis
Authors: Jo Sungsin , Lee Eun-Ju , Nam Bora , Kang Juyeon , Lee Seunghun , Youn Jeehee , Park Ye-Soo , Kim Yong-Gil , Kim Tae-Hwan
Published: May 2020

Background

Ankylosing spondylitis (AS) is characteristically male-predominant, and progressive spinal ankylosis affects male patients more severely; however, the hormonal effects in males with AS are poorly understood.

Methods

In the present study, the regulatory effects of dutasteride, a 5-α reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (DHT), were examined in curdlan-administered male SKG mice to determine spinal bone formation, bone metabolism-related markers, and interleukin (IL)-17A cytokine and T cell populations. In addition, the effects of DHT on primary osteoprogenitors from the facet joints of AS patients were assessed based on osteoblast-related parameters. DHT level was measured, and the correlation with modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was analyzed in AS patients.

Results

In curdlan-administered SKG mice, dutasteride treatment resulted in an increased accumulation of hydroxyapatite in the spine which was positively correlated with serum IL-17A levels. In the analysis of bone metabolism-related molecules, a decrease in sclerostin levels was observed in the sera in the dutasteride group. Continuous exposure to DHT resulted in fewer calcium deposits in AS osteoprogenitors during osteoblast differentiation. DHT-treated AS osteoprogenitors showed decreased osteocalcin and increased DKK1 and SOST1 mRNA expression, supporting the results of the in vivo experiments. Treatment with dutasteride upregulated bone formation in the spine of curdlan-administered SKG mice and DHT treatment downregulated osteoblast differentiation in vitro.

Conclusions

Treatment with dutasteride affected the bone formation in the spine of curdlan-treated SKG mice, and DHT treatment attenuated osteoblast differentiation in vitro. Therefore, contrary to what could be expected if osteoblasts contributed to spinal ankylosis, DHT inhibition might increase rather than decrease the progression of spinal ankylosis despite the higher levels of DHT observed in many AS patients.
Point-of-care ultrasound to complete physical exam and to reach the diagnosis in a young man with syncope
Authors: Rasooli Fatemeh , Zahraie Mehrnoosh Aligholi , Bahreini Maryam
Published: May 2020

Background

Cardiac syncope can result from an atrial myxoma due to outflow obstruction. Myxoma is the most common primary cardiac tumor that may cause sudden death and the nonspecific symptoms may make early diagnosis difficult.

Case presentation

A 27-year-old man presented to our emergency department after two episodes of syncope and severe fatigue. He had no complaint of fever, weight loss, sweating, chest pain or dyspnea. Vital signs were within normal limits. A loud heart S1 was detected and normal neck veins. Other systemic examinations including neurological assessment were normal. Electrocardiography showed normal sinus rhythm. An obvious variability in heart rate was noticed on cardiac monitor changing by the patient’s position. Point-of-care ultrasonography (PoCUS) showed a large hyperechoic lesion with a well-defined stalk originating from the left atrium (LA). Thus, the patient was transferred to a cardiac surgery center for surgical intervention. Histopathology reported an LA mass compatible with myxoma.

Conclusions

Emergency physicians should be familiar with the vague presentations of cardiac tumors to improve patient outcomes. It is beneficial to take advantage of bedside ultrasound for prompt diagnosis and subsequent treatment.
Weight-for-age distributions among children with HIV on antiretroviral therapy in the International epidemiology Databases to Evaluate AIDS (IeDEA) multiregional consortium
Authors:   IeDEA, Jesson Julie , Desmonde Sophie , Yiannoutsos Constantin T. , Patten Gabriela , Malateste Karen , Duda Stephany N. , Kumarasamy Nagalingeswaran , Yotebieng Marcel , Davies Mary-Ann , Musick Beverly , Leroy Valeriane , Ciaranello Andrea
Published: May 2020

Objective

Pediatric antiretroviral therapy (ART) for children with HIV (CHIV) must be dosed appropriately for children’s changing weights as they grow. To inform accurate estimates of ART formulations and doses needed, we described weight-for-age distributions among CHIV on ART in the IeDEA global pediatric collaboration between 2004 and 2016, using data from six regions (East, West, Central, and Southern Africa, Asia–Pacific, and Central/South America and the Caribbean).

Results

Overall, 59,862 children contributed to the analysis. Age and weight data were available from 530,080 clinical encounters for girls and 537,894 for boys. For each one-year age stratum from 0 to 15 years, we calculated the proportion of children in each of the weight bands designated by the World Health Organization as relevant to pediatric ART formulations: 0 to  < 3 kg, 3 to  < 6 kg, 6 to  < 10 kg, 10 to  < 14 kg, 14 to  < 20 kg, 20 to  < 25 kg, 25 to  < 30 kg, 30 to  < 35 kg, 35 to  < 40 kg, 40 to  < 45 kg, 45 to  < 50 kg, 50 to  < 55 kg, 55 to  < 60 kg, and ≥ 60 kg. Data are reported for the entire cohort, as well as stratified by sex and IeDEA region, calendar year of ART use, and duration on ART at time of assessment (< 12 or ≥ 12 months), provided in data tables. These data are critical to improve the accuracy of forecasting and procurement of pediatric ART formulations as the pediatric HIV epidemic and pediatric HIV treatment strategies evolve.
Biphasic human insulin 30 thrice daily, is it reasonable?
Authors: Saadeh Nesreen A. , Al-Azzeh Ola Y. , Khader Yousef S.
Published: May 2020

Objective

To evaluate the efficacy and safety of thrice daily Biphasic Human Insulin 30 (BHI 30) versus the traditional twice-daily regimen in type 2 diabetes mellitus (T2DM) patients. It’s a cross over single clinical study. Twenty-two diabetic patients who were already using BHI 30 in twice or thrice daily regimens with or without metformin were included. At the 1st interval; patients continued on their usual insulin regimen as twice or thrice daily injections with adjustment of insulin doses guided by their glucose readings. On the 2nd interval; patients were switched to the other regimen with the same total daily insulin dose redistributed.

Results

There was a significant decrease in HbA1c level (p < 0.05) at the end of the first 3 months of trial regardless on which regimen the patient started, but there was no significant difference in the mean HbA1c reduction in patients when they were on twice daily insulin injections (1.1 ± 1.3) versus the time they were on thrice daily insulin injections (0.8 ± 1.71), p > 0.05. On the other hand, patients had lower average blood glucose readings (mg/dl) when they were on thrice daily insulin injections (161.4 ± 62.7) compared to twice daily regimen (166.0 ± 69.5), p < 0.05.
High malaria parasitemia among outpatient febrile children in low endemic area, East-Central Tanzania in 2013
Authors: Chipwaza Beatrice , Sumaye Robert D.
Published: May 2020

Objective

This study investigated the prevalence and distribution patterns of malaria in Kilosa district as part of non-malaria causes of febrile illnesses in children study. We enrolled febrile patients aged 2–13 years presenting at the outpatient department during the rainy and dry seasons, in 2013. For each participant, we tested for malaria parasites and identified parasite species using microscopy. We then calculated parasite density and estimated geometric mean parasite density.

Results

The overall malaria prevalence in febrile children was 23.7% (n = 609). Plasmodium falciparum accounted for 98.6% of malaria positives. There was a heterogeneous distribution of malaria cases among the 17 wards constituting the catchment area. A high proportion (69.4%, n = 144) of malaria positive individuals had high parasite densities. Individuals who were enrolled in the rainy season had higher geometric mean parasite density (15415.1 parasites/µl, 95% CI 10735.3–22134.9) compared to the dry season (6115.3 parasites/µl, 95% CI 4237.8–8824.6). The relatively high malaria prevalence recorded in Kilosa, an area considered low endemicity, calls for concerted effort in documenting malaria burden at fine geographical scales and tailor preventive and control strategies that target hotspots of high malaria transmission.
Preliminary study on HIV status disclosure to perinatal infected children: retrospective analysis of administrative records from a pediatric HIV clinic in the southern United States
Authors: Budhwani Henna , Mills Lori , Marefka Lauren E. B. , Eady Sequoya , Nghiem Van T. , Simpson Tina
Published: May 2020

Objective

The World Health Organization recommends disclosing HIV-status between 6 and 12 years; American Academy of Pediatrics recommends that children are informed at “school age.” Neither suggests an optimal age when children should learn of their status to improve viral load suppression. Considering that virally suppressed people do not transmit HIV and that interrupting the transmission cycle is critical to ending the HIV epidemic, our objective is to examine the relationship between age of disclosure and viral load suppression by evaluating data from a pediatric HIV clinic in the southern United States. Records from perinatal infected patients seen between 2008 and 2018 were analyzed (N = 61).

Results

Longitudinal suppression was low across all groups when benchmarked against the UNAIDS 90% global target; black patients were less likely to achieve suppression compared to white patients (41% vs. 75%, p = 0.04). Adopted children were more likely to achieve suppression than children living with biological family (71% vs. 44%, p < 0.05). Children who learned of their status between 10 and 12 had the highest rate of suppression (65%) compared to peers who learned of their status younger (56%) or older (38%). Our preliminary study is designed to spark research on refining the current recommendations on HIV-status disclosure to perinatal infected children.
Novel visualized quantitative epigenetic imprinted gene biomarkers diagnose the malignancy of ten cancer types
Authors: Shen Rulong , Cheng Tong , Xu Chuanliang , Yung Rex C. , Bao Jiandong , Li Xing , Yu Hongyu , Lu Shaohua , Xu Huixiong , Wu Hongxun , Zhou Jian , Bu Wenbo , Wang Xiaonan , Si Han , Shi Panying , Zhao Pengcheng , Liu Yun , Deng Yongjie , Zhu Yun , Zeng Shuxiong , Pineda John P. , Lin Chunlin , Zhou Ning , Bai Chunxue
Published: May 2020

Background

Epigenetic alterations are involved in most cancers, but its application in cancer diagnosis is still limited. More practical and intuitive methods to detect the aberrant expressions from clinical samples using highly sensitive biomarkers are needed. In this study, we developed a novel approach in identifying, visualizing, and quantifying the biallelic and multiallelic expressions of an imprinted gene panel associated with cancer status. We evaluated the normal and aberrant expressions measured using the imprinted gene panel to formulate diagnostic models which could accurately distinguish the imprinting differences of normal and benign cases from cancerous tissues for each of the ten cancer types.

Results

The Quantitative Chromogenic Imprinted Gene In Situ Hybridization (QCIGISH) method developed from a 1013-case study which provides a visual and quantitative analysis of non-coding RNA allelic expressions identified the guanine nucleotide-binding protein, alpha-stimulating complex locus (GNAS), growth factor receptor-bound protein (GRB10), and small nuclear ribonucleoprotein polypeptide N (SNRPN) out of five tested imprinted genes as efficient epigenetic biomarkers for the early-stage detection of ten cancer types. A binary algorithm developed for cancer diagnosis showed that elevated biallelic expression (BAE), multiallelic expression (MAE), and total expression (TE) measurements for the imprinted gene panel were associated with cell carcinogenesis, with the formulated diagnostic models achieving consistently high sensitivities (91–98%) and specificities (86–98%) across the different cancer types.

Conclusions

The QCIGISH method provides an innovative way to visually assess and quantitatively analyze individual cells for cancer potential extending from hyperplasia and dysplasia until carcinoma in situ and invasion, which effectively supplements standard clinical cytologic and histopathologic diagnosis for early cancer detection. In addition, the diagnostic models developed from the BAE, MAE, and TE measurements of the imprinted gene panel GNAS, GRB10, and SNRPN could provide important predictive information which are useful in early-stage cancer detection and personalized cancer management.
Separating mouse malignant cell line (EL4) from neonate spermatogonial stem cells utilizing microfluidic device in vitro
Authors: Ashtari Behnaz , Shams Azar , Esmaeilzadeh Narges , Tanbakooei Sara , Koruji Morteza , Moghadam Mojtaba Johari , Ansari Javad Mohajer , Moghadam Adel Johari , Shabani Ronak
Published: May 2020

Background

Some children who have survived cancer will be azoospermic in the future. Performing isolation and purification procedures for spermatogonial stem cells (SSC) is very critical. In this regard, performing the process of decontamination of cancerous cells is the initial step. The major objective of the present study is to separate the malignant EL4 cell line in mice and spermatogonial stem cells in vitro.

Methods

The spermatogonial stem cells of sixty neonatal mice were isolated, and the procedure of co-culturing was carried out by EL4 which were classified into 2 major groups: (1) the control group (co-culture in a growth medium) and (2) the group of co-cultured cells which were separated using the microfluidic device. The percentage of cells was assessed using flow cytometry technique and common laboratory technique of immunocytochemistry and finally was confirmed through the laboratory technique of reverse transcription-polymerase chain reaction (RT-PCR).

Results

The actual percentage of EL4 and SSC after isolation was collected at two outlets: the outputs for the smaller outlet were 0.12% for SSC and 42.14% for EL4, while in the larger outlet, the outputs were 80.38% for SSC and 0.32% for EL4; in the control group, the percentages of cells were 21.44% for SSC and 23.28% for EL4 (based onttest (p ≤ 0.05)).

Conclusions

The present study demonstrates that the use of the microfluidic device is effective in separating cancer cells from spermatogonial stem cells.
Preconditioning is an effective strategy for improving the efficiency of mesenchymal stem cells in kidney transplantation
Authors: Zhao Lingfei , Hu Chenxia , Han Fei , Cai Fanghao , Wang Junni , Chen Jianghua
Published: May 2020

The inevitable side effects caused by lifelong immunosuppressive agents in kidney transplantation patients spurred the exploration of novel immunosuppressive strategies with definite curative effects and minimal adverse effects. Mesenchymal stem cells (MSCs) have become a promising candidate due to their role in modulating the immune system. Encouraging results obtained from experimental models have promoted the translation of this strategy into clinical settings. However, the demonstration of only marginal or transient benefits by several recent clinical controlled studies has made physicians hesitant to adopt the routine utilization of this procedure in clinical settings. Impaired MSC function after infusion in vivo was thought to be the main reason for their limited effects. For this reason, some preconditioning methods were developed. In this review, we aim to outline the current understanding of the preconditioning methods being explored as a strategy to improve the therapeutic effects of MSCs in kidney transplantation and promote its clinical translation.
Human bone marrow mesenchymal stem cell-derived exosomes stimulate cutaneous wound healing mediates through TGF-β/Smad signaling pathway
Authors: Jiang Tiechao , Wang Zhongyu , Sun Ji
Published: May 2020

Background

Cutaneous wound healing represents a morphogenetic response to injury and is designed to restore anatomic and physiological function. Human bone marrow mesenchymal stem cell-derived exosomes (hBM-MSC-Ex) are a promising source for cell-free therapy and skin regeneration.

Methods

In this study, we investigated the cell regeneration effects and its underlying mechanism of hBM-MSC-Ex on cutaneous wound healing in rats. In vitro studies, we evaluated the role of hBM-MSC-Ex in the two types of skin cells: human keratinocytes (HaCaT) and human dermal fibroblasts (HDFs) for the proliferation. For in vivo studies, we used a full-thickness skin wound model to evaluate the effects of hBM-MSC-Ex on cutaneous wound healing in vivo.

Results

The results demonstrated that hBM-MSC-Ex promote both two types of skin cells’ growth effectively and accelerate the cutaneous wound healing. Interestingly, we found that hBM-MSC-Ex significantly downregulated TGF-β1, Smad2, Smad3, and Smad4 expression, while upregulated TGF-β3 and Smad7 expression in the TGF-β/Smad signaling pathway.

Conclusions

Our findings indicated that hBM-MSC-Ex effectively promote the cutaneous wound healing through inhibiting the TGF-β/Smad signal pathway. The current results provided a new sight for the therapeutic strategy for the treatment of cutaneous wounds.
On the formation of centreline shrinkage porosity in the continuous casting of steel
Authors: Vynnycky Michael
Published: May 2020

A recent asymptotic model for solidification shrinkage-induced macrosegregation in the continuous casting of binary alloys is extended for the purposes of understanding the link between solute segregation and centreline shrinkage porosity, a defect that commonly occurs in the continuous casting of steel. In particular, the analysis elucidates the relationship between microsegregation, mushy-zone permeability, heat transfer and centreline pressure, yielding an inequality that constitutes a criterion for whether or not centreline porosity will form. The possibilities for developing this approach to take account of gas porosity and the implementation of mechanical soft reduction to reduce macrosegregation and shrinkage porosity are also discussed.
Neuron-specific enolase has potential value as a biomarker for [18F]FDG/[68Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients
Authors: Rosar Florian , Ribbat Kalle , Ries Martin , Linxweiler Johannes , Bartholomä Mark , Maus Stephan , Schreckenberger Mathias , Ezziddin Samer , Khreish Fadi
Published: May 2020

Background

PSMA-targeted radioligand therapy (PSMA-RLT) yielded impressive results in the metastasized castration-resistant prostate carcinoma (mCRPC) setting. High expression of PSMA is essential for successful PSMA-RLT. However, some patients develop [18F]FDG-avid lesions with low or no PSMA expression ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in the course of treatment. Those lesions are not affected by PSMA-RLT and a change in therapy management is needed. To enable early mismatch detection, possible blood parameters as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT were evaluated.

Methods

Retrospective study of N = 66 advanced mCRPC patients with dual [68Ga]Ga-PSMA-11 and [18F]FDG PET/CT imaging within 4 weeks, who were referred for or received [177Lu]Lu-PSMA-617 radioligand therapy. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP) were tested as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings. Additional to absolute values, relative changes (ΔPSA, ΔNSE, ΔGGT, ΔALP) over a period of 4 ± 1 weeks prior to [18F]FDG PET/CT were analyzed.

Results

In total, 41/66 (62%) patients revealed at least one [18F]FDG/[68Ga]Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients by screening for and in 28/41 (68%) patients during PSMA-RLT. NSE serum level (55.4 ± 44.6 μg/l vs. 18.5 ± 8 μg/l, p < 0.001) and ΔNSE (93.8 ± 124.5% vs. 2.9 ± 39.5%, p < 0.001) were significantly higher in the mismatch group than in the non-mismatch group. No significant differences were found for serum PSA (p = 0.424), ΔPSA (p = 0.417), serum ALP (p = 0.937), ΔALP (p = 0.611), serum GGT (p = 0.773), and ΔGGT (p = 0.971). For NSE and ΔNSE, the maximum value of the Youden index in ROC analysis was at a cut-off level of 26.8 μg/l (sensitivity 78%, specificity 96%) and at + 13.9% (sensitivity 84%, specificity 75%), respectively. An introduced scoring system of both parameters achieved a sensitivity of 90% and a specificity of 88% for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch.

Conclusion

We observed a significantly higher absolute serum concentration and a higher relative increase of NSE in advanced mCRPC patients with [18F]FDG-avid and insufficient PSMA expressing metastases ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in our cohort. NSE might be used as a potential laboratory indicator for [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings, if this observation is confirmed in future, ideally prospective, studies in larger patient cohorts.
Independent attenuation correction of whole body [18F]FDG-PET using a deep learning approach with Generative Adversarial Networks
Authors: Armanious Karim , Hepp Tobias , Küstner Thomas , Dittmann Helmut , Nikolaou Konstantin , La Fougère Christian , Yang Bin , Gatidis Sergios
Published: May 2020

Background

Attenuation correction (AC) of PET data is usually performed using a second imaging for the generation of attenuation maps. In certain situations however—when CT- or MR-derived attenuation maps are corrupted or CT acquisition solely for the purpose of AC shall be avoided—it would be of value to have the possibility of obtaining attenuation maps only based on PET information. The purpose of this study was to thus develop, implement, and evaluate a deep learning-based method for whole body [18F]FDG-PET AC which is independent of other imaging modalities for acquiring the attenuation map.

Methods

The proposed method is investigated on whole body [18F]FDG-PET data using a Generative Adversarial Networks (GAN) deep learning framework. It is trained to generate pseudo CT images (CTGAN) based on paired training data of non-attenuation corrected PET data (PETNAC) and corresponding CT data. Generated pseudo CTs are then used for subsequent PET AC. One hundred data sets of whole body PETNAC and corresponding CT were used for training. Twenty-five PET/CT examinations were used as test data sets (not included in training). On these test data sets, AC of PET was performed using the acquired CT as well as CTGAN resulting in the corresponding PET data sets PETAC and PETGAN. CTGAN and PETGAN were evaluated qualitatively by visual inspection and by visual analysis of color-coded difference maps. Quantitative analysis was performed by comparison of organ and lesion SUVs between PETAC and PETGAN.

Results

Qualitative analysis revealed no major SUV deviations on PETGAN for most anatomic regions; visually detectable deviations were mainly observed along the diaphragm and the lung border. Quantitative analysis revealed mean percent deviations of SUVs on PETGAN of − 0.8 ± 8.6% over all organs (range [− 30.7%, + 27.1%]). Mean lesion SUVs showed a mean deviation of 0.9 ± 9.2% (range [− 19.6%, + 29.2%]).

Conclusion

Independent AC of whole body [18F]FDG-PET is feasible using the proposed deep learning approach yielding satisfactory PET quantification accuracy. Further clinical validation is necessary prior to implementation in clinical routine applications.
Bacillus subtilis spores as adjuvants against avian influenza H9N2 induce antigen-specific antibody and T cell responses in White Leghorn chickens
Authors: Lee Ji Eun , Kye Yoon-Chul , Park Sung-Moo , Shim Byoung-Shik , Yoo Sungsik , Hwang Eunmi , Kim Hyungkuen , Kim Sung-Jo , Han Seung Hyun , Park Tae Sub , Park Byung-Chul , Yun Cheol-Heui
Published: May 2020

Low-pathogenicity avian influenza H9N2 remains an endemic disease worldwide despite continuous vaccination, indicating the need for an improved vaccine strategy. Bacillus subtilis (B. subtilis), a gram-positive and endospore-forming bacterium, is a non-pathogenic species that has been used in probiotic formulations for both animals and humans. The objective of the present study was to elucidate the effect of B. subtilis spores as adjuvants in chickens administered inactivated avian influenza virus H9N2. Herein, the adjuvanticity of B. subtilis spores in chickens was demonstrated by enhancement of H9N2 virus-specific IgG responses. B. subtilis spores enhanced the proportion of B cells and the innate cell population in splenocytes from chickens administered both inactivated H9N2 and B. subtilis spores (Spore + H9N2). Furthermore, the H9N2 and spore administration induced significantly increased expression of the pro-inflammatory cytokines IL-1β and IL-6 compared to that in the H9N2 only group. Additionally, total splenocytes from chickens immunized with inactivated H9N2 in the presence or absence of B. subtilis spores were re-stimulated with inactivated H9N2. The subsequent results showed that the extent of antigen-specific CD4+ and CD8+ T cell proliferation was higher in the Spore + H9N2 group than in the group administered only H9N2. Taken together, these data demonstrate that B. subtilis spores, as adjuvants, enhance not only H9N2 virus-specific IgG but also CD4+ and CD8+ T cell responses, with an increase in pro-inflammatory cytokine production. This approach to vaccination with inactivated H9N2 together with a B. subtilis spore adjuvant in chickens produces a significant effect on antigen-specific antibody and T cell responses against avian influenza virus.
The cysteine protease ATG4B of Trichinella spiralis promotes larval invasion into the intestine of the host
Authors: Li Yalan , Wang Baiyan , Zhu Yaxin , Tian Zhihua , Yang Zhuo , Duan Jiaqi , Wang Zhongquan
Published: May 2020

The cysteine proteases of parasites are vital contributors that induce parasite migration to and invasion of host tissue. In this study, we analysed the cysteine protease ATG4B of Trichinella spiralis (TsATG4B) isolated from the soluble proteins of Trichinella spiralis (T. spiralis) adult worms to ascertain its biochemical properties and functions during invasion into the intestine of the host. The 43 kDa recombinant cysteine protease ATG4B protein (rTsATG4B) consists of a conserved peptidase_C54 domain and was expressed in Escherichia coli. Gelatine zymography showed that rTsATG4B could hydrolyse gelatine and that the hydrolytic activity was prevented by the cysteine protease inhibitor E-64 (pH 5.2). Immunofluorescence assays showed that TsATG4B is expressed at different stages and is localized at the cuticles and stichosomes of worms. Far-Western blotting and confocal microscopy revealed that rTsATG4B interacts with intestinal epithelial cells (IECs) and that it was subcellularly localized to the membrane and cytoplasm in IECs. Real‑time quantitative PCR (qPCR) results indicated that the transcription level of the TsATG4B gene was the higher in 6-day-old adult worms (6 days AW) than in any other stage. An in vitro larval invasion assay verified that rTsATG4B promoted larval invasion and that invasion was inhibited when rTsATG4B was pre-incubated with E-64, whereas anti-rTsATG4B serum inhibited larval invasion in a dose-dependent manner. Collectively, these results suggested that the enzymatic activity of TsATG4B significantly influences the hydrolysis process, which is necessary for larval invasion of the host intestinal epithelium.
Systematic identification of chicken type I, II and III interferon-stimulated genes
Authors: Dai Manman , Xie Tingting , Liao Ming , Zhang Xiquan , Feng Min
Published: May 2020

Interferon-stimulated genes (ISGs) play an important role in antiviral innate immune responses. Although many ISGs have been identified in mammals, researchers commonly recognize that many more ISGs are yet to be discovered. Current information is still very limited particularly for the systematic identification of type III ISGs. Similarly, current research on ISGs in birds is still in its infancy. The aim of this study was to systematically identify chicken type I (IFN-α), II (IFN-γ) and III (IFN-λ) ISGs and analyze their respective response elements. RNA sequencing (RNA-Seq) was employed to identify those genes with up-regulated expression following chicken IFN-α, IFN-γ and IFN-λ treatment. Two hundred and five type I ISGs, 299 type II ISGs, and 421 type III ISGs were identified in the chicken. We further searched for IFN-stimulated response elements (ISRE) and gamma-activated sequences (GAS) elements in the promoters region of ISGs. The GAS elements were common in the promoter of type II ISGs and were even detected in type I and III ISGs. However, ISRE were not commonly found in the promoters of chicken ISGs. Furthermore, we demonstrated that ISRE in chicken cells were significantly activated by IFN-α or IFN-λ treatment, and expectedly, that GAS elements were also significantly activated by IFN-γ treatment. Interestingly, we also found that GAS elements were significantly activated by IFN-λ. Our study provides a systematic library of ISGs in the chicken together with preliminary information about the transcriptional regulation of the identified ISGs.
Identification of a new effector-immunity pair of Aeromonas hydrophila type VI secretion system
Authors: Ma Shuiyan , Dong Yuhao , Wang Nannan , Liu Jin , Lu Chengping , Liu Yongjie
Published: May 2020

The type VI secretion system (T6SS) is a multiprotein weapon that kills eukaryotic predators or prokaryotic competitors by delivering toxic effectors. Despite the importance of T6SS in bacterial environmental adaptation, it is still challenging to systematically identify T6SS effectors because of their high diversity and lack of conserved domains. In this report, we discovered a putative effector gene, U876-17730, in the whole genome of Aeromonas hydrophila NJ-35 based on the reported conservative domain DUF4123 (domain of unknown function), with two cognate immunity proteins encoded downstream. Phylogenetic tree analysis of amino acids indicates that AH17730 belongs to the Tle1 (type VI lipase effector) family, and therefore was named Tle1AH. The deletion of tle1AH resulted in significantly decreased biofilm formation, antibacterial competition ability and virulence in zebrafish (Danio rerio) when compared to the wild-type strain. Only when the two immunity proteins coexist can bacteria protect themselves from the toxicity of Tle1AH. Further study shows that Tle1AH is a kind of phospholipase that possesses a conserved lipase motif, Gly-X-Ser-X-Gly (X is for any amino acid). Tle1AH is secreted by T6SS, and this secretion requires its interaction with an associated VgrG (valine-glycine repeat protein G). In conclusion, we identified a T6SS effector-immunity pair and verified its function, which lays the foundation for future research on the role of T6SS in the pathogenic mechanism of A. hydrophila.
Dihydromyricetin attenuates Escherichia coli lipopolysaccharide-induced ileum injury in chickens by inhibiting NLRP3 inflammasome and TLR4/NF-κB signalling pathway
Authors: Chang Yicong , Yuan Liang , Liu Jiarui , Muhammad Ishfaq , Cao Chuanbao , Shi Chenxi , Zhang Yuanyuan , Li Rui , Li Changwen , Liu Fangping
Published: May 2020

Lipopolysaccharide (LPS) as a major component of Escherichia coli cell wall can cause inflammation and cell death. Dihydromyricetin (ampelopsin, DHM) is a natural flavonoid compound with anti-inflammatory, anti-oxidant and anti-bacterial effects. The preventive effects of DHM against ileum injury remain unclear. Here, we explored the protective role of DHM against LPS-induced ileum injury in chickens. In this study, DHM significantly attenuated LPS-induced alteration in diamine oxidase, malondialdehyde, reduced glutathione, glutathione peroxidase and superoxide dismutase levels in chicken plasma and ileum. Histology evaluation showed that the structure of blood vessels in ileum was seriously fragmented and presence of necrotic tissue in the lumen in the LPS group. Scanning electron microscopic observation revealed that the surface of the villi was rough and uneven, the structure was chaotic, and the normal finger shape was lost in the LPS group. In contrast, 0.05% and 0.1% DHM treatment partially alleviated the abnormal morphology. Additionally, DHM maintained the barrier function by restoring the protein expression of occludin, claudin-1 and zonula occludens protein-1. DHM inhibited apoptosis through the reduction of the expression of bax and caspase-3 and restored the expression of bcl-2. Importantly, DHM could reduce ileum NLR family pyrin domain-containing 3 (NLRP3), caspase-1, interleukin (IL)-1β and IL-18 expression to protect tissues from pyroptosis and inhibited toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signalling pathway. In summary, DHM attenuated the ileum mucosal damage, oxidative stress and apoptosis, maintained barrier function, inhibited NLRP3 inflammasome and TLR4/NF-κB signalling pathway activation triggered by Escherichia coli LPS.
Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential
Authors: Cai Jiaxin , Wu Junyong , Wang Jiemin , Li Yongjiang , Hu Xiongbin , Luo Shifu , Xiang Daxiong
Published: May 2020

Mesenchymal stem cells (MSCs) were known to have excellent properties in cell therapy. However, the risk of immune rejection associated with cell transplant therapy hampers its use. Extracellular vesicles secreted by MSCs derived from different sources that contain therapeutic molecules such as RNA and proteins, which is a novel strategy for cell-free therapy. Recently, researches show EVs from MSCs (MSC-EVs) of different sources have special functions and effects on different diseases. Here, we collected these researches and compared them to each other. In addition, their potential and possible application in clinical treatment are described.
Pathophysiological roles and therapeutic potential of voltage-gated ion channels (VGICs) in pain associated with herpesvirus infection
Authors: Zhang Qiaojuan , Martin-Caraballo Miguel , Hsia Shaochung V.
Published: May 2020

Herpesvirus is ranked as one of the grand old members of all pathogens. Of all the viruses in the superfamily, Herpes simplex virus type 1 (HSV-1) is considered as a model virus for a variety of reasons. In a permissive non-neuronal cell culture, HSV-1 concludes the entire life cycle in approximately 18–20 h, encoding approximately 90 unique transcriptional units. In latency, the robust viral gene expression is suppressed in neurons by a group of noncoding RNA. Historically the lesions caused by the virus can date back to centuries ago. As a neurotropic pathogen, HSV-1 is associated with painful oral lesions, severe keratitis and lethal encephalitis. Transmission of pain signals is dependent on the generation and propagation of action potential in sensory neurons. T-type Ca2+channels serve as a preamplifier of action potential generation. Voltage-gated Na+channels are the main components for action potential production. This review summarizes not only the voltage-gated ion channels in neuropathic disorders but also provides the new insights into HSV-1 induced pain.
Perspective of placenta derived mesenchymal stem cells in acute liver failure
Authors: Saleh Mahshid , Taher Mohammad , Sohrabpour Amir Ali , Vaezi Amir Abbas , Nasiri Toosi Mohsen , Kavianpour Maria , Ghazvinian Zeinab , Abdolahi Shahrokh , Verdi Javad
Published: May 2020

Acute Liver failure (ALF) is a life-threatening disease and is determined by coagulopathy (with INR ≥ 1.5) and hepatic encephalopathy as a result of severe liver injury in patients without preexisting liver disease. Since there are problems with liver transplantation including lack of donors, use of immunosuppressive drugs, and high costs of this process, new therapeutic approaches alongside current treatments are needed. The placenta is a tissue that is normally discarded after childbirth. On the other hand, human placenta is a rich source of mesenchymal stem cells (MSCs), which is easily available, without moral problems, and its derived cells are less affected by age and environmental factors. Therefore, placenta-derived mesenchymal stem cells (PD-MSCs) can be considered as an allogeneic source for liver disease. Considering the studies on MSCs and their effects on various diseases, it can be stated that MSCs are among the most important agents to be used for novel future therapies of liver diseases. In this paper, we will investigate the effects of mesenchymal stem cells through migration and immigration to the site of injury, cell-to-cell contact, immunomodulatory effects, and secretory factors in ALF.
Intravenous fluid therapy in the perioperative and critical care setting: Executive summary of the International Fluid Academy (IFA)
Authors: Malbrain Manu L. N. G. , Langer Thomas , Annane Djillali , Gattinoni Luciano , Elbers Paul , Hahn Robert G. , De laet Inneke , Minini Andrea , Wong Adrian , Ince Can , Muckart David , Mythen Monty , Caironi Pietro , Van Regenmortel Niels
Published: May 2020

Intravenous fluid administration should be considered as any other pharmacological prescription. There are three main indications: resuscitation, replacement, and maintenance. Moreover, the impact of fluid administration as drug diluent or to preserve catheter patency, i.e., fluid creep, should also be considered. As for antibiotics, intravenous fluid administration should follow the four Ds: drug, dosing, duration, de-escalation. Among crystalloids, balanced solutions limit acid–base alterations and chloride load and should be preferred, as this likely prevents renal dysfunction. Among colloids, albumin, the only available natural colloid, may have beneficial effects. The last decade has seen growing interest in the potential harms related to fluid overloading. In the perioperative setting, appropriate fluid management that maintains adequate organ perfusion while limiting fluid administration should represent the standard of care. Protocols including a restrictive continuous fluid administration alongside bolus administration to achieve hemodynamic targets have been proposed. A similar approach should be considered also for critically ill patients, in whom increased endothelial permeability makes this strategy more relevant. Active de-escalation protocols may be necessary in a later phase. The R.O.S.E. conceptual model (Resuscitation, Optimization, Stabilization, Evacuation) summarizes accurately a dynamic approach to fluid therapy, maximizing benefits and minimizing harms. Even in specific categories of critically ill patients, i.e., with trauma or burns, fluid therapy should be carefully applied, considering the importance of their specific aims; maintaining peripheral oxygen delivery, while avoiding the consequences of fluid overload.