bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is there a need for a clear advice? A retrospective comparative analysis of ethics consultations with and without recommendations in a maximum-care university hospital
Authors: Schmitz Dagmar , Groß Dominik , Pauli Roman 
Published: March 2021

AbstractBackgroundThe theory and practice of ethics consultations (ECs) in health care are still characterized by many controversies, including, for example, the practice of giving recommendations. These controversies are complicated by an astonishing lack of evidence in the whole field. It is not clear how often a recommendation is issued in ethics consultations and when and why this step is taken. Especially in a facilitation model in which giving recommendations is optional, more data would be helpful to evaluate daily practice, ensure that this practice is in line with the overarching goals of this approach and support the development of standards.MethodsWe analyzed all consultations requested from an EC service working under a facilitation approach at a maximum-care university hospital in Germany over a period of more than 10 years. Our aim was to better understand why—and under what circumstances—some consultation requests result in a recommendation, whereas others can be sufficiently addressed solely by facilitated meetings. We especially wanted to know when and why clients felt the need for clear advice from the EC service while in other cases they did not. We compared ethics consultations in terms of the differences between cases with and without recommendations issued by the ethics consultants using χ2difference tests and Welch’s t-test.ResultsA total of 243 ECs were carried out between September 2008 and December 2019. In approximately half of the cases, a recommendation was given. All recommendations were issued upon the request of clients. When physicians asked for an EC, the consultation was significantly more likely to result in a recommendation than when the EC was requested by any other party. ECs in cases on wards with ethics rounds resulted in comparably fewer recommendations than those in wards without ethics rounds. When interpersonal conflicts were part of the problem or relatives were present in the meeting, clients less frequently asked for a recommendation.ConclusionFrom the client’s point of view, there does not seem to be only one “right” way to provide ethics consultations, but rather several. While facilitated meetings are obviously appreciated by clients, there also seem to be situations in which a recommendation is desired (especially by physicians). Further empirical and theoretical research is needed to validate our single-center results and re-evaluate the role of recommendations in ethics consultations.
Fermentative production of enantiopure (S)-linalool using a metabolically engineered Pantoea ananatis
Authors: Nitta Nobuhisa , Tajima Yoshinori , Yamamoto Yoko , Moriya Mika , Matsudaira Akiko , Hoshino Yasushi , Nishio Yousuke , Usuda Yoshihiro 
Published: March 2021

Abstract
Background
Linalool, an acyclic monoterpene alcohol, is extensively used in the flavor and fragrance industries and exists as two enantiomers, (S)- and (R)-linalool, which have different odors and biological properties. Linalool extraction from natural plant tissues suffers from low product yield. Although linalool can also be chemically synthesized, its enantioselective production is difficult. Microbial production of terpenes has recently emerged as a novel, environmental-friendly alternative. Stereoselective production can also be achieved using this approach via enzymatic reactions. We previously succeeded in producing enantiopure (S)-linalool using a metabolically engineered Pantoea ananatis, a member of the Enterobacteriaceae family of bacteria, via the heterologous mevalonate pathway with the highest linalool titer ever reported from engineered microbes.

Results
Here, we genetically modified a previously developed P. ananatis strain expressing the (S)-linalool synthase (AaLINS) from Actinidia arguta to further improve (S)-linalool production. AaLINS was mostly expressed as an insoluble form in P. ananatis; its soluble expression level was increased by N-terminal fusion of a halophilic β-lactamase from Chromohalobacter sp. 560 with hexahistidine. Furthermore, in combination with elevation of the precursor supply via the mevalonate pathway, the (S)-linalool titer was increased approximately 1.4-fold (4.7 ± 0.3 g/L) in comparison with the original strain (3.4 ± 0.2 g/L) in test-tube cultivation with an aqueous-organic biphasic fermentation system using isopropyl myristate as the organic solvent for in situ extraction of cytotoxic and semi-volatile (S)-linalool. The most productive strain, IP04S/pBLAAaLINS-ispA*, produced 10.9 g/L of (S)-linalool in “dual-phase” fed-batch fermentation, which was divided into a growth-phase and a subsequent production-phase. Thus far, this is the highest reported titer in the production of not only linalool but also all monoterpenes using microbes.

Conclusions
This study demonstrates the potential of our metabolically engineered P. ananatis strain as a platform for economically feasible (S)-linalool production and provides insights into the stereoselective production of terpenes with high efficiency. This system is an environmentally friendly and economically valuable (S)-linalool production alternative. Mass production of enantiopure (S)-linalool can also lead to accurate assessment of its biological properties by providing an enantiopure substrate for study.
Prognostic biomarker TUBA1C is correlated to immune cell infiltration in the tumor microenvironment of lung adenocarcinoma
Authors: Bian Tingting , Zheng Miaosen , Jiang Daishan , Liu Jian , Sun Hui , Li Xiaoli , Liu Lei , Zhang Jianguo , Liu Yifei 
Published: March 2021

AbstractBackgroundTUBA1C is a microtubule component that is involved in a variety of cancers. Our main objective was to investigate TUBA1C expression, its prognostic value, its potential biological functions, and its impact on the immune system of patients with lung adenocarcinoma (LUAD).MethodsThe Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA) and Immunohistochemistry Analysis were used to analyze TUBA1C expression, its clinicopathology, overall survival (OS), and disease-free survival (DFS) in LUAD patients. We also determined the correlation between TUBA1C and tumor-infiltrating immune cells (TIICs) by using CIBERSORT and GEPIA databases. To determine the expression of TUBA1C in LUAD, we analyzed a collection of immune infiltration levels and cumulative survival of LUAD tissues in TIMER database. By using UALCAN, STRING, and GeneMANIA databases, we investigated the protein-coding genes related to TUBA1C and its co-expression genes in LUAD tissues. Gene set enrichment analysis (GSEA) was performed by using the TCGA dataset.ResultsThe mRNA and the protein expression of TUBA1C were found to be up-regulated in LUAD tissues. The univariate analysis indicated that an increased expression of TUBA1C was significantly correlated to the following parameters: age, stage, and lymph node metastasis. An over-expression of TUBA1C was associated with a poor prognosis of LUAD. In TIMER and CIBERSORT databases, we found that TUBA1C is correlated with 13 types of TIICs: activated B cell, activated CD4 T cell, central memory CD4 T cell, effector memory CD8 T cell, eosinophils, immature B cell, gamma-delta T cell, immature dendritic cell, mast cell, memory B cell, natural killer T cell, regulatory T cell, and type 2T helper cell. By performing GSEA, we found that TUBA1C is closely correlated to cell cycle, p53 signaling pathway, glycolysis, and gluconeogenesis.ConclusionsOur findings indicate that TUBA1C is associated with TIICs in tumor microenvironment. Therefore, it serves as a novel prognostic biomarker and a target for future treatment methods of LUAD.
Genetic diversity and natural selection on the thrombospondin-related adhesive protein (TRAP) gene of Plasmodium falciparum on Bioko Island, Equatorial Guinea and global comparative analysis
Authors: Lin Li-Yun , Huang Hui-Ying , Liang Xue-Yan , Xie Dong-De , Chen Jiang-Tao , Wei Hua-Gui , Huang Wei-Yi , Ehapo Carlos Salas , Eyi Urbano Monsuy , Li Jian , Wang Jun-Li , Zheng Yu-Zhong , Zha Guang-Cai , Wang Yu-Ling , Chen Wei-Zhong , Liu Xiang-Zhi , Mo Huan-Tong , Chen Xin-Yao , Lin Min 
Published: March 2021

Abstract
Background
Thrombospondin-related adhesive protein (TRAP) is a transmembrane protein that plays a crucial role during the invasion of Plasmodium falciparum into liver cells. As a potential malaria vaccine candidate, the genetic diversity and natural selection of PfTRAP was assessed and the global PfTRAP polymorphism pattern was described.

Methods
153 blood spot samples from Bioko malaria patients were collected during 2016–2018 and the target TRAP gene was amplified. Together with the sequences from database, nucleotide diversity and natural selection analysis, and the structural prediction were preformed using bioinformatical tools.

Results
A total of 119 Bioko PfTRAP sequences were amplified successfully. On Bioko Island, PfTRAP shows its high degree of genetic diversity and heterogeneity, with π value for 0.01046 and Hd for 0.99. The value of dN–dS (6.2231, p < 0.05) hinted at natural selection of PfTRAP on Bioko Island. Globally, the African PfTRAPs showed more diverse than the Asian ones, and significant genetic differentiation was discovered by the fixation index between African and Asian countries (Fst > 0.15, p < 0.05). 667 Asian isolates clustered in 136 haplotypes and 739 African isolates clustered in 528 haplotypes by network analysis. The mutations I116T, L221I, Y128F, G228V and P299S were predicted as probably damaging by PolyPhen online service, while mutations L49V, R285G, R285S, P299S and K421N would lead to a significant increase of free energy difference (ΔΔG > 1) indicated a destabilization of protein structure.

Conclusions
Evidences in the present investigation supported that PfTRAP gene from Bioko Island and other malaria endemic countries is highly polymorphic (especially at T cell epitopes), which provided the genetic information background for developing an PfTRAP-based universal effective vaccine. Moreover, some mutations have been shown to be detrimental to the protein structure or function and deserve further study and continuous monitoring.
Osteosarcoma: a review of current and future therapeutic approaches
Authors: Zhao Xin , Wu Qirui , Gong Xiuqing , Liu Jinfeng , Ma Yujie 
Published: March 2021

AbstractOsteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong invasiveness, rapid disease progression, and extremely high mortality rate; it is considered as a serious threat to the human health globally. The incidence of OS is common in the metaphysis of long tubular bones, but rare in the spine, pelvis, and sacrum areas; moreover, majority of the OS patients present with only a single lesion. OS has a bimodal distribution pattern, that is, its incidence peaks in the second decade of life and in late adulthood. We examine historical and current literature to present a succinct review of OS. In this review, we have discussed the types, clinical diagnosis, and modern and future treatment methods of OS. The purpose of this article is to inspire new ideas to develop more effective therapeutic options.
Transarterial chemoembolisation in patients with hepatocellular carcinoma: low-dose doxorubicin reduces post-embolisation syndrome without affecting survival—prospective interventional study
Authors: Bessar Ahmed A. , Farag Ahmed , Abdel Monem Sameh M. , Wadea Fady M. , Shaker Shady E. , Ebada Mahmoud Ahmed , Bessar Manar A. 
Published: March 2021

Abstract
Background
No chemotherapeutic agents have been standardised for transarterial chemoembolisation (TACE). In particular, doxorubicin has no defined optimal dosage in TACE procedures. We compared low versus currently used dose of doxorubicin for TACE in patients with hepatocellular carcinoma (HCC) in terms of severity of post-embolisation syndrome (PES) and overall survival (OS).

Methods
From October 2014 to March 2018, we enrolled patients with primary HCC scheduled for TACE. Patients were randomised to receive 50 mg (group A) or 100 mg (group B) of doxorubicin. Outcomes were the rate of patients with PES; free-time-to-PES; changes in laboratory results; tumour response at 1, 3, and 6 months after TACE; and overall survival.

Results
Twenty-eight patients (24 males, 4 females) were enrolled, aged 58.9 ± 6.8 years (mean ± standard deviation). Fifteen of them palliated with 50 mg (group A) and 13 with 100 mg (group B) of doxorubicin for a total of 68 TACE procedures (of 28 patients who had repeated TACE procedures). Visual analogue scale (VAS) and duration of pain were significantly differently lower in group A than in group B (p < 0.001). The median duration of fever was shorter in group A than in group B (p = 0.003). No significant differences between both groups were observed for tumour response to TACE and OS. The doxorubicin dose was significantly correlated with duration of pain, fever, and VAS score.

Conclusion
A lower dose of doxorubicin (50 mg) was associated with fewer PES symptoms compared with 100 mg, without effects on tumour response nor OS.
Value for money in genitourinary oncology.
Authors: O Reilly David Edward , McLaughlin Ronan Andrew , DeFrein Anne-Marie , Ronayne Cian , Macanovic Bojan , McMahon David , Power Derek Gerard , Bambury Richard Martin , Collins Dearbhaile Catherine 
Published: March 2021

1 Background: Innovation in the treatment of genitourinary (GU) malignancies is accelerating, however, many of these new treatments are often not available for patients. We sought to investigate patient access, cost and value of new systemic anti-cancer compounds (SACTs) in GU oncology. We compared the US and Europe with a focus on the United Kingdom (UK) and the Republic of Ireland (IRL). Methods: Data on licensing and reimbursement decisions was collected on SACTs approved for GU oncology between 01/01/2010 to 09/01/2020. Overall survival (OS) benefit, progression free survival (PFS) benefit and cost of therapy were included in our analysis. Results: There were 29 regimens/indications approved by the Federal Drug Agency (FDA) for GU malignancies between 2010 and 2020. The majority of these (21/29, 72%) were also approved by the European Medicines Agency (EMA). Nearly all regimens/indications were approved by the FDA prior to the EMA (27/29, 93%), with a median time to EMA approval of 4 months (SD = 6, range -6 to 17). Only a minority of these regimens/indications are reimbursed by the public health systems in the UK (12/29, 41%) and IRL (6/29, 21%). Following EMA approval, public reimbursement of these regimens in the UK and IRL is often delayed with a median time of 8 months (+/- 6.3, range 4 - 21) and 11.5 months (+/- 12.5, range 0 - 33) respectively. Approximately half (15/29, 52%) of all reimbursed regimens/indications have demonstrated an overall survival benefit for patients. Androgen signalling inhibitors (ASIs) are more likely to have a proven OS benefit and had a lower mean cost than non-ASI regimens (See Table). A significant minority of regimens/indications (6/29, 21%) have demonstrated neither an OS or PFS benefit. The median price per month (USA list price) was $15,086 +/- $7,019. Regimens with a proven OS benefit were not more expensive than those without ($14,229 +/- $6,466 versus $16,004 +/- $7,704). There was no significant correlation between the length of OS benefit and the cost of regimens (Pearson’s Correlation Coefficient = -2.72, p = 0.445). Conclusions: Patients in the UK and IRL experience clinically significant delays in accessing FDA approved regimens in GU oncology. Only 52% of these regimens have a proven OS benefit. In our study, ASI regimens are cheaper and more effective than non-ASI regimens. There is no association between overall survival benefit and list prices in the USA. We need to radically overhaul licensing and funding of SACTs in GU oncology to ensure continued access for patients to effective medicines. [Table: see text]
SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic,castrate-refractory prostate cancer (mCRPC)—A phase I/randomized phase II study by the United Kingdom National Cancer Research Institute Prostate Group.
Authors: Jones Robert J. , Bahl Amit , De Bono Johann S. , Ralph Christy , Elliott Tony , Robinson Angus , Westbury Charlotte , Birtle Alison Jane , Staffurth John Nicholas , Protheroe Andrew , Venugopal Balaji , Thomson Fiona , Pou Chantevy , Morris Karen , Tugwood Jonathan , Divers Laura , Hopkins Carol , McCartney Elaine , Kelly Caroline , Crabb Simon J. 
Published: March 2021

107 Background: Saracatinib is an orally-available, highly selective inhibitor of Abl and Src family members. It is an ATP-competitive tyrosine kinase inhibitor. Preclinical data suggested that the combination of a Src kinase inhibitor and docetaxel is synergistic, and Src kinase activity was also implicated in the bone’s metabolic response to cancer metastases. Methods: Patients with mCRPC were initially enrolled in an open-label, dose escalation phase I trial of oral saracatinib (cohorts of 50mg, 125mg and 175mg daily) with docetaxel (75mg/m2) in a 3+3 design. Subsequent patients were randomised 1:1 between saracatinib 175mg and placebo once daily. Pharmacokinetics (PK) of docetaxel were explored in phase I to exclude significant drug-drug interaction. The primary endpoint of phase II was biochemical or radiographic progression free survival (PFS). Secondary endpoints included overall survival (OS), safety and tolerability. Changes in circulating tumour cell (CTC) counts were also measured. The phase II was designed with a 1-sided alpha of 0.2 with 90% power to detect a hazard ratio (HR) for PFS of 0.67. Results: 10 patients were enrolled in phase I and 142 in the randomised phase II. No dose limiting toxicities or PK interactions were observed and the recommended dose for phase II was 175mg saracatinib daily and 75mg/m2docetaxel every 21 days. In phase II, the HR for PFS was 1.35 (80% confidence interval (CI) 1.07 to 1.70). The HR for OS was 1.42 (1.08 – 1.81). 41/71 and 29/71 experienced treatment related toxicities of grade 3 or above in the saracatinib and placebo arms respectively. 10/19 (53%) and 14/27 (52%) evaluable patients demonstrated a reduction in CTCs from ≥5 to < 5 /7.5ml blood at 6 weeks after starting saracatinib and placebo respectively. Conclusions: Saracatinib, in combination with docetaxel, adds toxicity and not efficacy in mCRPC. This combination should not be developed further in combination with docetaxel in the treatment of mCRPC. Clinical trial information: ISRCTN22566729.
A phase I/II study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): Dose escalation results.
Authors: Lau Brandon , Crumbaker Megan , Yam Andrew On Wah , Marastoni Stefano , Luckhurst Mathew , O'Grady Aaron , Wouters Brad , Joshua Anthony M. 
Published: March 2021

114 Background: Preclinical data show hydroxychloroquine (HCQ) and suba-itraconazole (SI) together enhance prostate cancer cell death. The proposed mechanism is lysosome dysfunction including sequestration of cholesterol in endosomes and inhibition of gogi-lyosome trafficking. HCQ/SI could delay androgen deprivation therapy (ADT) and its associated morbidity in men with biochemical relapse of prostate cancer. In this phase I/II study, maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of HCQ/SI was investigated in such patients. Methods: Patients received escalating doses of HCQ with fixed SI 150mg BD in rolling 6 design. This will be followed by a planned phase II Simon 2-stage cohort expansion. Results: Eleven men were treated with HCQ/SI. Median age 73 (range 69-77), baseline PSA 4.4 µg/L (1.6-22.4) and doubling time 5.3 months (3.3-15.3). Two experienced dose-limiting toxicity: grade 3 diarrhoea and grade 3 alanine transferase elevation, both at HCQ 600mg BD. Most common treatment-related adverse events (AEs) were hypertension (91% all grade/18% grade 3), QTc prolongation (55%/0%), diarrhoea (36%/9%), and nausea (36%/0%). There were no grade 4 AEs or deaths. While there were no PSA responses (≥50% fall from baseline), PSA PFS by PCWG3 criteria was 5.5 months (2.0-9.0), and PSA doubling time was prolonged at 4 and 12 weeks in 82% and 45% respectively. ADT-free and metastasis-free survival are 14.3 months (95% CI 4.9-23.8) and 15.9 months (95% CI unevaluable) respectively. PK data will be presented. Conclusions: HCQ/SI demonstrated acceptable safety with MTD 600mg BD and RP2D 400mg BD. There is early signal of activity and phase II enrolment is to begin. Clinical trial information: NCT03513211.
Pretherapeutic first-in-human targeting trial of anti-hK2 antibody h11B6: A potential molecular vector for alpha-particle radioimmunotherapy.
Authors: Morris Michael J. , O' Donoghue Joseph A. , Chetty Dushen , Max Steven , Wanik Danielle , Russell Mike , Nyima Tenzin , Avadhani Anjali Narayan , Divgi Chaitanya R , Pandit-Taskar Neeta 
Published: March 2021

122 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has focused to date on targeting prostate specific membrane antigen, an approach associated with salivary gland toxicity and variable lesion expression. New targets are needed. Human kallikrein-2 (hK2) is overexpressed in most prostate cancer, with minimal normal tissue expression or serum secretion. Humanized monoclonal antibody (mAb) h11B6 exclusively targets hK2 in pre-clinical studies. This phase 0 study (NCT04116164) is a first-in-human trial of [111In]-DOTA-h11B6 to determine the hk2-targeting potential of h11B6. Objective: The purpose of this ongoing protocol is to characterize the biodistribution of [111In]-DOTA-h11B6 and determine a suitable mAb mass that targets mCRPC with minimal non-tumor targeting. Methods: Patients with progressive mCRPC were enrolled. A single slow bolus infusion of 2 mg [111In]-DOTA-h11B6 (nominally 185 MBq [111In]), was administered IV with or without 8 mg h11B6. Patients were observed for adverse events (AE) for at least 2 weeks. Serial gamma camera imaging including at least one SPECT/CT scan was performed up to 8 days post-administration. Serial blood samples were obtained over 2 weeks to determine serum radioactivity and h11B6 protein levels. Dosimetry for normal organs was estimated using OLINDA-EXM. Results: Results for the first 6 patients are summarized in Table. Treatment was tolerated in all patients with no AEs and no evidence of enhanced accumulation in any organ including salivary glands. Initial volume of distribution appeared confined to the vascular compartment. Slow clearance of radioactivity from the vascular compartment was observed with gradual targeting to skeletal and non-skeletal lesions in all patients. Conclusions: h11B6 is a novel mAb that targets hK2, localizes to bone and soft tissue metastases, has no significant normal tissue uptake, and spares salivary glands. An IND for a phase I therapeutic study using [225Ac] has been secured. Clinical trial information: NCT04116164. [Table: see text]