bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma
Authors: Liu Ziyu , Lin Yan , Zhang Jinyan , Zhang Yumei , Li Yongqiang , Liu Zhihui , Li Qian , Luo Ming , Liang Rong , Ye Jiazhou 
Published: November 2019

Abstract
Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.
Interleukin-8 promotes integrin β3 upregulation and cell invasion through PI3K/Akt pathway in hepatocellular carcinoma
Authors: Sun Fengkai , Wang Jianping , Sun Qi , Li Fanni , Gao Hengjun , Xu Lin , Zhang Jiao , Sun Xiaoyan , Tian Yanan , Zhao Qiujie , Shen Huimin , Zhang Kai , Liu Jun 
Published: November 2019

Abstract

Background
Interleukin-8 (IL-8) plays a vital role in the invasion and metastasis of hepatocellular carcinoma (HCC), and is closely associated with poor prognosis of HCC patients. Integrin αvβ3, a member of the integrin family, has been reported to be overexpressed in cancer tissues and mediate the invasion and metastasis of HCC cells. However, the relationship between IL-8 and integrin αvβ3 in HCC and the underlying mechanism of IL-8 and integrin αvβ3 in the invasion of HCC remains unclear.

Methods
The expression of IL-8, integrin αv and integrin β3 in HCC cells and tissues was detected by quantitative real-time PCR, Western blot and immunohistochemistry. Transwell assay and Western blot was used to detect the invasiveness, the expression of integrin β3 and the activation of PI3K/Akt pathway of HCC cells pretreated with IL-8 knockdown or exogenous IL-8.

Results
IL-8, integrin αv and integrin β3 were overexpressed in highly metastatic HCC cell lines compared with low metastatic cell lines. There was a positive correlation between integrin β3 and IL-8 expression in HCC tissues. IL-8 siRNA transfection reduced HCC cell invasion and the levels of integrin β3, p-PI3K and p-Akt. IL-8 induced HCC cell invasion and integrin β3 expression was significantly inhibited by transfection with CXCR1 siRNA or CXCR2 siRNA. When we stimulated HCC cells with exogenous IL-8, cell invasion and the levels of integrin β3, p-PI3K, and p-Akt increased, which could be effectively reversed by adding PI3K inhibitor LY294002.

Conclusions
Our results suggest that IL-8 promotes integrin β3 upregulation and the invasion of HCC cells through activation of the PI3K/Akt pathway. The IL-8/CXCR1/CXCR2/PI3K/Akt/integrin β3 axis may serve as a potential treatment target for patients with HCC.
Maintenance therapy for recurrent epithelial ovarian cancer: current therapies and future perspectives – a review
Authors: Gupta Sudeep , Nag Shona , Aggarwal Shyam , Rauthan Amit , Warrier Narayanankutty 
Published: November 2019

Abstract
Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The efficacy of different targeted therapies reduces with each recurrence. Hence there is need of effective maintenance therapy in recurrent EOC. Recently, polyADP-ribose polymerase (PARP) inhibitors (PARPi) have been approved both for initial treatment of EOC and as its maintenance treatment. PARPi have also been found to act regardless of BRCA status or homologous recombination (HR) deficiency. Several trials testing PARPi early in maintenance therapy are in progress and their results will shed light on the optimal timing of maintenance therapy that gives the most benefit with least toxicity. Right patient selection for maintenance treatment is also a challenge. Hence, though PARPi are emerging as a promising maintenance treatment in recurrent EOC with prolongation of progression free survival (PFS), results from further trials and overall survival (OS) data from current trials are awaited to fulfill the gaps in understanding the role of this pathway in treatment of EOC. This review discusses the current therapies for EOC, challenges in the treatment of recurrent EOC, recent developments and trials in recurrent EOC maintenance with special focus on PARPi and future perspectives.
Application of NICE or SNC guidelines may reduce the need for computerized tomographies in patients with mild traumatic brain injury: a retrospective chart review and theoretical application of five guidelines
Authors: Svensson Sebastian , Vedin Tomas , Clausen Linus , Larsson Per-Anders , Edelhamre Marcus 
Published: November 2019

AbstractBackgroundTraumatic brain injuries continue to be a significant cause of mortality and morbidity worldwide. Most traumatic brain injuries are classified as mild, with a low but not negligible risk of intracranial hemorrhage. To help physicians decide which patients might benefit from a computerized tomography (CT) of the head to rule out intracranial hemorrhage, several clinical decision rules have been developed and proven effective in reducing the amount of negative CTs, but they have not been compared against one another in the same cohort as to which one demonstrates the best performance.MethodsThis study involved a retrospective review of the medical records of patients seeking care between January 1 and December 31, 2017 at Helsingborg Hospital, Sweden after head trauma. The Canadian CT Head Rule (CCHR), the New Orleans Criteria (NOC), the National Emergency X-Radiography Utilization Study II (NEXUS II), the National Institute of Health and Care Excellence (NICE) guideline and the Scandinavian Neurotrauma Committee (SNC) guideline were analyzed. A theoretical model for each guideline was constructed and applied to the cohort to yield a theoretical CT-rate for each guideline. Performance parameters were calculated and compared.ResultsOne thousand three hundred fifty-three patients were included; 825 (61%) CTs were performed, and 70 (5.2%) cases of intracranial hemorrhage were found. The CCHR and the NOC were applicable to a minority of the patients, while the NEXUS II, the NICE, and the SNC guidelines were applicable to the entire cohort. A theoretical application of the NICE and the SNC guidelines would have reduced the number of CT scans by 17 and 9% (P = < 0.0001), respectively, without missing patients with intracranial hemorrhages requiring neurosurgical intervention.ConclusionA broad application of either NICE or the SNC guidelines could potentially reduce the number of CT scans in patients suffering from mTBI in a Scandinavian setting, while the other guidelines seemed to increase the CT frequency. The sensitivity for intracranial hemorrhage was lower than in previous studies for all guidelines, but no fatality or need for neurosurgical intervention was missed by any guideline when they were applicable.
The Danish prehospital emergency healthcare system and research possibilities
Authors: Lindskou Tim Alex , Mikkelsen Søren , Christensen Erika Frischknecht , Hansen Poul Anders , Jørgensen Gitte , Hendriksen Ole Mazur , Kirkegaard Hans , Berlac Peter Anthony , Søvsø Morten Breinholt 
Published: November 2019

Abstract
The emergency medical healthcare system outside hospital varies greatly across the globe - even within the western world. Within the last ten years, the demand for emergency medical service systems has increased, and the Danish emergency medical service system has undergone major changes.
Therefore, we aimed to provide an updated description of the current Danish prehospital medical healthcare system.
Since 2007, Denmark has been divided into five regions each responsible for health services, including the prehospital services. Each region may contract their own ambulance service providers. The Danish emergency medical services in general include ambulances, rapid response vehicles, mobile emergency care units and helicopter emergency medical services. All calls to the national emergency number, 1-1-2, are answered by the police, or the Copenhagen fire brigade, and since 2011 forwarded to an Emergency Medical Coordination Centre when the call relates to medical issues. At the Emergency Medical Coordination Centre, healthcare personnel assess the situation guided by the Danish Index for Emergency Care and determine the level of urgency of the situation, while technical personnel dispatch the appropriate medical emergency vehicles. In Denmark, all healthcare services, including emergency medical services are publicly funded and free of charge. In addition to emergency calls, other medical services are available for less urgent health problems around the clock. Prehospital personnel have since 2015 utilized a nationwide electronic prehospital medical record. The use of this prehospital medical record combined with Denmark’s extensive registries, linkable by the unique civil registration number, enables new and unique possibilities to do high quality prehospital research, with complete patient follow-up.
A new therapy in Epstein-Barr virus-associated lymphoproliferative disease: a case report and a revision of the literature
Authors: Xu Lingling , Ba Hongjun , Lin Hongrong , Zhong Liangying , Li Suping , Tang Wen , Ke Zhiyong , Ye Ziyin 
Published: November 2019

Abstract

Background
Systemic chronic active Epstein-Barr virus infection is an extremely rare childhood disease. Since chronic active Epstein-Barr virus infection can trigger the onset of Epstein-Barr virus-associated lymphoproliferative disease. The clinical manifestations of the disease vary according to the site of involvement; therefore, management may be challenging. Currently, there are no standardized guidelines for treating Chronic active Epstein-Barr virus infection effectively.

Case presentation
We report a case of chronic active Epstein-Barr virus infection in a 5-year-old Chinese boy with intestinal, vascular, and neurological involvement. At age of 2 years and 7 months old, he had hepatomegaly and been diagnosed with Epstein-Barr virus infection. After treatment, he showed some clinical improvement. At age of 3 years and 3 months old, he presented with recurrent fever and diarrhea. Then he received methylprednisolone for 1 year and his symptoms ameliorated. At the age of 5 years, his symptoms recurred and had gastrointestinal hemorrhage and developed polyuria, frequent convulsions and hyponatremia. He was transferred to our hospital for further management. He was unconscious on admission and was diagnosised Epstein-Barr virus-lymphoproliferative disorder, based on the results in situ hybridization of EBV-encoded miRNA in sigmoid colon. Three-dimensional CT angiography demonstrated an aneurysm in the right internal carotid artery. Abdominal CT showed dilatation of vessels in part of the intestinal wall. He was also diagnosised Epstein-Barr virus encephalitis based on the elevated Epstein-Barr virus antibody titers and presence of Epstein-Barr virus DNA in the Cerebrospinal Fluid.
A repeated duodenal artery embolization and symptomatic therapy could not control the hemorrhage after admission. He subsequently received treatment with ganciclovir, glucocorticoid, thalidomide, and propranolol. Hemorrhage was controlled in 5 days; his symptoms improved. The fever did not recur and the CSF pressure was also normalized. A follow-up CT at 3 months after admission showed regression of the aneurysm in the right internal carotid artery and the vascular lesion in the duodenum.

Discussion and conclusions
A new treatment protocol including thalidomide and propranolol resulted in a marked improvement in his clinical symptoms, and shows promise as a novel and effective therapeutic approach for Chronic active Epstein-Barr virus infection-associated lymphoproliferative disorder.
Scrub typhus ecology: a systematic review of Orientia in vectors and hosts
Authors: Elliott Ivo , Pearson Isabelle , Dahal Prabin , Thomas Nigel V. , Roberts Tamalee , Newton Paul N. 
Published: November 2019

AbstractScrub typhus, caused byOrientia tsutsugamushi, is an important and neglected vector-borne zoonotic disease with an expanding known distribution. The ecology of the disease is complex and poorly understood, impairing discussion of public health interventions. To highlight what we know and the themes of our ignorance, we conducted a systematic review of all studies investigating the pathogen in vectors and non-human hosts. A total of 276 articles in 7 languages were included, with 793 study sites across 30 countries. There was no time restriction for article inclusion, with the oldest published in 1924. Seventy-six potential vector species and 234 vertebrate host species were tested, accounting for over one million trombiculid mites (‘chiggers’) and 83,000 vertebrates. The proportion ofO. tsutsugamushipositivity was recorded for different categories of laboratory test and host species. Vector and host collection sites were geocoded and mapped. Ecological data associated with these sites were summarised. A further 145 articles encompassing general themes of scrub typhus ecology were reviewed. These topics range from the life-cycle to transmission, habitats, seasonality and human risks. Important gaps in our understanding are highlighted together with possible tools to begin to unravel these. Many of the data reported are highly variable and inconsistent and minimum data reporting standards are proposed. With more recent reports of humanOrientiasp. infection in the Middle East and South America and enormous advances in research technology over recent decades, this comprehensive review provides a detailed summary of work investigating this pathogen in vectors and non-human hosts and updates current understanding of the complex ecology of scrub typhus. A better understanding of scrub typhus ecology has important relevance to ongoing research into improving diagnostics, developing vaccines and identifying useful public health interventions to reduce the burden of the disease.
Development of a recombinase polymerase amplification (RPA) fluorescence assay for the detection of Schistosoma haematobium
Authors: Rostron Penelope , Pennance Tom , Bakar Faki , Rollinson David , Knopp Stefanie , Allan Fiona , Kabole Fatma , Ali Said M. , Ame Shaali M. , Webster Bonnie L. 
Published: November 2019

Abstract

Background
Accurate diagnosis of urogenital schistosomiasis is vital for surveillance and control programmes. While a number of diagnostic techniques are available there is a need for simple, rapid and highly sensitive point-of-need (PON) tests in areas where infection prevalence and intensity are low. Recombinase Polymerase Amplification (RPA) is a sensitive isothermal molecular diagnostic technology that is rapid, portable and has been used at the PON for several pathogens.

Results
A real time fluorescence RPA assay (RT-ShDra1-RPA) targeting the Schistosoma haematobium Dra1 genomic repeat region was developed and was able to detect 1 fg of S. haematobium gDNA. Results were obtained within 10 minutes using a small portable battery powered tube scanner device that incubated reactions at 40 °C, whilst detecting DNA amplification and fluorescence over time. The assay’s performance was evaluated using 20 urine samples, with varying S. haematobium egg counts, from school children from Pemba Island, Zanzibar Archipelago, Tanzania. Prior to RPA analysis, samples were prepared using a quick crude field DNA extraction method, the Speed Extract Kit (Qiagen, Manchester, UK). Positive assay results were obtained from urine samples with egg counts of 1–926 eggs/10 ml, except for two samples, which had inconclusive results. These two samples had egg counts of two and three eggs/10 ml of urine.

Conclusions
The RT-ShDra1-RPA assay proved robust for S. haematobium gDNA detection and was able to amplify and detect S. haematobium DNA in urine samples from infected patients. The assay’s speed and portability, together with the use of crude sample preparation methods, could advance the rapid molecular diagnosis of urogenital schistosomiasis at the PON within endemic countries.
Efficacy of a moxidectin/imidacloprid spot-on formulation (Advocate®) for the treatment of Troglostrongylus brevior in naturally infected cats in a field study in Greece
Authors: Diakou Anastasia , Morelli Simone , Dimzas Dimitris , Di Cesare Angela , Capelli Gioia , Parrinello Chiara , Pollmeier Matthias , Schaper Roland , Traversa Donato 
Published: November 2019

Abstract

Background
Troglostrongylus brevior is a lungworm of wild felids that recently has been recognized as agent of severe respiratory disease in domestic cats in Mediterranean and Balkan countries. Nevertheless, the information on treatment options for feline troglostrongylosis is still poor. The aim of this pilot field trial was to evaluate the efficacy of the spot-on formulation containing 1% w/v moxidectin and 10% w/v imidacloprid (Advocate® spot-on solution for cats, Bayer Animal Health GmbH) in the treatment of T. brevior infection in naturally infected cats in Greece.

Methods
The trial was a negative control, multicentre, clinical efficacy study conducted according to the standards of Good Scientific Practice (GSP). Sixteen cats in two study sites, naturally infected with T. brevior, were allocated to an untreated control group (G1, n = 8) or a treatment group (G2, n = 8), according to a randomization list. Animals assigned to G2 were treated with Advocate® for cats on days 0 and 28 at the recommended dose rate and animals assigned to G1 received a rescue treatment with the same product on days 56 and 84. Efficacy was assessed on days 28 and 56 in G2 and on days 84 and 112 in G1 by faecal larval counts. The primary efficacy criterion was the absence of T. brevior first-stage larvae (L1) following treatment. Other efficacy parameters were the quantitative comparison of L1 presence before (baseline) and after one or two treatments in both groups.

Results
All G2 cats were negative for T. brevior L1 at the first post-treatment evaluation (100% efficacy) while G1 cats were persistently shedding L1. The difference of the mean number of L1 per gram between G2 and G1 was statistically significant (P < 0.001). All G1 cats were negative (100% efficacy) for T. brevior L1 at the first post-rescue-treatment evaluation. Therefore, treatment efficacy at study completion was 100% in both groups in terms of stopping the L1 shedding in the faeces of the animals. No adverse effects were observed during the study.

Conclusions
These results indicate that Advocate® spot-on solution for cats represents an option for treating cats naturally infected with T. brevior.
The life-cycle of the avian haemosporidian parasite Haemoproteus majoris, with emphasis on the exoerythrocytic and sporogonic development
Authors: Ilgūnas Mikas , Romeiro Fernandes Chagas Carolina , Bukauskaitė Dovilė , Bernotienė Rasa , Iezhova Tatjana , Valkiūnas Gediminas 
Published: November 2019

Abstract

Background
Haemoproteus parasites (Haemosporida, Haemoproteidae) are cosmopolitan in birds and recent molecular studies indicate enormous genetic diversity of these pathogens, which cause diseases in non-adapted avian hosts. However, life-cycles remain unknown for the majority of Haemoproteus species. Information on their exoerythrocytic development is particularly fragmental and controversial. This study aimed to gain new knowledge on life-cycle of the widespread blood parasite Haemoproteus majoris.

Methods
Turdus pilaris and Parus major naturally infected with lineages hPHYBOR04 and hPARUS1 of H. majoris, respectively, were wild-caught and the parasites were identified using microscopic examination of gametocytes and PCR-based testing. Bayesian phylogeny was used to determine relationships between H. majoris lineages. Exoerythrocytic stages (megalomeronts) were reported using histological examination and laser microdissection was applied to isolate single megalomeronts for genetic analysis. Culicoides impunctatus biting midges were experimentally exposed in order to follow sporogonic development of the lineage hPHYBOR04.

Results
Gametocytes of the lineage hPHYBOR04 are indistinguishable from those of the widespread lineage hPARUS1 of H. majoris, indicating that both of these lineages belong to the H. majoris group. Phylogenetic analysis supported this conclusion. Sporogony of the lineage hPHYBOR04 was completed in C. impunctatus biting midges. Morphologically similar megalomeronts were reported in internal organs of both avian hosts. These were big roundish bodies (up to 360 μm in diameter) surrounded by a thick capsule-like wall and containing irregularly shaped cytomeres, in which numerous merozoites developed. DNA sequences obtained from single isolated megalomeronts confirmed the identification of H. majoris.

Conclusions
Phylogenetic analysis identified a group of closely related H. majoris lineages, two of which are characterized not only by morphologically identical blood stages, but also complete sporogonic development in C. impunctatus and development of morphologically similar megalomeronts. It is probable that other lineages belonging to the same group would bear the same characters and phylogenies based on partial cytb gene could be used to predict life-cycle features in avian haemoproteids including vector identity and patterns of exoerythrocytic merogony. This study reports morphologically unique megalomeronts in naturally infected birds and calls for research on exoerythrocytic development of haemoproteids to better understand pathologies caused in avian hosts.