bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers
Authors: Yi Ming , Niu Mengke , Zhang Jing , Li Shiyu , Zhu Shuangli , Yan Yongxiang , Li Ning , Zhou Pengfei , Chu Qian , Wu Kongming 
Published: September 2021

Abstract
Background
Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn2+) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101.

Methods
The effect of Mn2+ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn2+ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment.

Results
Mn2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn2+ plus anti-PD-L1 therapy, Mn2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn2+ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn2+ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy.

Conclusion
Combining Mn2+ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.
Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target
Authors: Qian Wenjing , Zhao Mingfang , Wang Ruoyu , Li Heming 
Published: September 2021

AbstractImmune checkpoint therapy has achieved significant efficacy by blocking inhibitory pathways to release the function of T lymphocytes. In the clinic, anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) have progressed to first-line monotherapies in certain tumor types. However, the efficacy of anti-PD-1/PD-L1 mAbs is still limited due to toxic side effects and de novo or adaptive resistance. Moreover, other immune checkpoint target and biomarkers for therapeutic response prediction are still lacking; as a biomarker, the PD-L1 (CD274, B7-H1) expression level is not as accurate as required. Hence, it is necessary to seek more representative predictive molecules and potential target molecules for immune checkpoint therapy. Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related protein secreted by the liver. Multiple studies have confirmed that FGL1 is a newly emerging checkpoint ligand of lymphocyte activation gene 3 (LAG3), emphasizing the potential of targeting FGL1/LAG3 as the next generation of immune checkpoint therapy. In this review, we summarize the substantial regulation mechanisms of FGL1 in physiological and pathological conditions, especially tumor epithelial to mesenchymal transition, immune escape and immune checkpoint blockade resistance, to provide insights for targeting FGL1 in cancer treatment.
circHMGCS1–016 reshapes immune environment by sponging miR-1236-3p to regulate CD73 and GAL-8 expression in intrahepatic cholangiocarcinoma
Authors: Xu Ya-Ping , Dong Ze-Ning , Wang Si-Wei , Zheng Yi-Min , Zhang Chi , Zhou Ying-Qun , Zhao Yu-Jie , Zhao Yan , Wang Feng , Peng Rui , Tang Mao-Chun , Bai Dou-sheng , Huang Xiao-Yong , Guo Chuan-Yong 
Published: September 2021

Abstract
Background
Accumulating evidence indicates that circRNAs may serve as essential regulators in the progression of several human cancers, but the function and mechanism of circRNAs in intrahepatic cholangiocarcinoma (ICC) are largely unknown.

Methods
RNA-seq was used to assess differentially expressed circRNAs between 4 ICC and peritumor tissues. Quantitative RT-PCR and in situ hybridization were used to determine the circHMGCS1–016 expression in ICC tissues. The function and mechanism of circHMGCS1–016 were further identified via in vivo experiments. The clinical characteristics and prognostic significance of circHMGCS1–016 were analyzed by a retrospective study. The functions of circHMGCS1–016 were assessed via modifying circRNA expression in ICC cells. Moreover, the molecular mechanisms of circHMGCS1–016 in ICC cells were explored by circRNA precipitation, miRNA immunoprecipitation, SILAC and luciferase reporter assays.

Results
We identified that compared with peritumor tissues, ICC tissues expressed hsa_circ_0008621 (circHMGCS1–016) high by RNA-seq, which was further identified by qRT-PCR and in situ hybridization. Moreover, the expression of circHMGCS1–016 was revealed to be associated with survival and recurrence of ICC patients. By regulating circHMGCS1–016 expression, we found that elevated circHMGCS1–016 promoted ICC development both in vitro and in vivo. By SILAC and circRNA-pull down, we demonstrated that circHMGCS1–016 induced ICC cell invasion and reshaped the tumor immune microenvironment via the miR-1236-3p/CD73 and GAL-8 axis. In ICC tissues, we uncovered that a high level of circHMGCS1–016 was positively associated with CD73 and GAL-8 expression and negatively related to the CD8+ T cells infiltration, which was further validated by establishing a humanized mouse tumor model. Importantly, we displayed that ICC patients with high levels of circHMGCS1–016 in tumor tissues benefited less from anti-PD1 treatment compared to those with low levels of circHMGCS1–016.

Conclusions
CircHMGCS1–016 is a forceful contributor in ICC development and immune tolerance via miR-1236-3p/CD73 and GAL-8 axis. CircHMGCS1–016 can be explored as a new potential biomarker and therapeutic target for PD1-resistant ICC.
Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression
Authors: Bowman Emily M. L. , Cunningham Emma L. , Page Valerie J. , McAuley Daniel F. 
Published: September 2021

AbstractDelirium is a clinical syndrome occurring in heterogeneous patient populations. It affects 45–87% of critical care patients and is often associated with adverse outcomes including acquired dementia, institutionalisation, and death. Despite an exponential increase in delirium research in recent years, the pathophysiological mechanisms resulting in the clinical presentation of delirium are still hypotheses. Efforts have been made to categorise the delirium spectrum into clinically meaningful subgroups (subphenotypes), using psychomotor subtypes such as hypoactive, hyperactive, and mixed, for example, and also inflammatory and non-inflammatory delirium. Delirium remains, however, a constellation of symptoms resulting from a variety of risk factors and precipitants with currently no successful targeted pharmacological treatment. Identifying specific clinical and biological subphenotypes will greatly improve understanding of the relationship between the clinical symptoms and the putative pathways and thus risk factors, precipitants, natural history, and biological mechanism. This will facilitate risk factor mitigation, identification of potential methods for interventional studies, and informed patient and family counselling. Here, we review evidence to date and propose a framework to identify subphenotypes. Endotype identification may be done by clustering symptoms with their biological mechanism, which will facilitate research of targeted treatments. In order to achieve identification of delirium subphenotypes, the following steps must be taken: (1) robust records of symptoms must be kept at a clinical level. (2) Global collaboration must facilitate large, heterogeneous research cohorts. (3) Patients must be clustered for identification, validation, and mapping of subphenotype stability.
Total or partial tonsillar resection (tonsillectomy or tonsillotomy) to change the quality of life for adults with recurrent or chronic tonsillitis: study protocol for a randomised controlled trial
Authors: Laajala Aleksi , Tokola Paulus , Autio Timo J. , Koskenkorva Timo , Tastula Mikko , Ohtonen Pasi , Läärä Esa , Alho Olli-Pekka 
Published: September 2021

Abstract
Background
Tonsillar surgery has been used for decades to treat recurrent and chronic tonsillitis in adults. Recurrent and chronic tonsillitis result in disturbing symptoms, treatment costs, sick leave, and impaired quality of life (QoL). Theoretically, removing all or part of the altered pathological palatal lymphoid tissue alleviates the symptoms and enhances the QoL. Whether this is true with total or partial tonsillar resection (tonsillectomy (TE) and tonsillotomy (TT), respectively) has not been reported in a randomised trial yet.

Methods
We conduct a multicentre, partly blinded, randomised, 6-month, parallel-group clinical study including 285 adult participants referred to surgical treatment for chronic or recurrent tonsillitis. The participants will either have TE, TT or watchful waiting (WW). The primary outcome will be the difference between the mean disease-specific Tonsillectomy Outcome Inventory-14 (QoL questionnaire) scores at 6 months. Comparison is made firstly between the combined TE+TT and WW groups (superiority analysis), and secondly between the TE and TT groups (non-inferiority analysis).

Discussion
This study will add significant new information to the effects and harms of TE and TT procedures in the treatment of adults with chronic or recurrent tonsillitis.

Trial registration
ClinicalTrials.gov: NCT04657549
Normalising comparative effectiveness trials as clinical practice
Authors: Briffa Tom , Symons Tanya , Zeps Nikolajs , Straiton Nicola , Tarnow-Mordi William Odita , Simes John , Harris Ian A. , Cruz Melinda , Webb Steven A. , Litton Edward , Nichol Alistair , Williams Christopher M. 
Published: September 2021

AbstractThere is a lack of high-quality evidence underpinning many contemporary clinical practice guidelines embedded in the healthcare systems, leading to treatment uncertainty and practice variation in most medical disciplines. Comparative effectiveness trials (CETs) represent a diverse range of research that focuses on optimising health outcomes by comparing currently approved interventions to generate high-quality evidence to inform decision makers. Yet, despite their ability to produce real-world evidence that addresses the key priorities of patients and health systems, many implementation challenges exist within the healthcare environment.This manuscript aims to highlight common barriers to conducting CETs and describes potential solutions to normalise their conduct as part of a learning healthcare system.
Sporadic intra-abdominal desmoid tumor with a very unusual onset: two case reports
Authors: Kuwabara Hiroshi , Katayanagi Sou , Koganezawa Itsuki , Nakagawa Masashi , Katsumata Kenji , Tsuchida Akihiko , Kawachi Shigeyuki 
Published: September 2021

Abstract
Background
Intra-abdominal desmoid tumors are rare soft tissue tumors that arise mainly in the mesentery and pelvis. Their etiology may include genetic mutations, estrogen-associated changes after childbirth, and mechanical factors such as a history of abdominal surgery. However, there are cases of intra-abdominal desmoid tumors that develop in the absence of such causes. Since they are rare, diagnosis is often difficult based on clinical findings. We encountered two cases of patients with sporadic intra-abdominal desmoid tumors with a very unusual onset and contrasting features.

Case presentation
The first patient was a 51-year-old asian man who presented with sudden onset of abdominal pain. He was referred to our department because of a giant tumor detected on abdominal ultrasonography. Imaging revealed a 19-cm tumor with internal tumoral hemorrhage; however, no definitive diagnosis was made. Tumor resection was performed for diagnostic and therapeutic purposes. The second patient was a 41-year-old asian man, and right hydronephrosis was detected on abdominal ultrasonography during a periodic medical checkup. We diagnosed invasion of the primary mesenteric tumor into the right ureter using diagnostic imaging and performed ileocecal resection with partial right ureteral resection for a definitive diagnosis and therapeutic purposes. Although the tumors of both patients had developed from the ileal mesentery, the tumors were substantially different from each other based on their imaging findings, macroscopic morphology, and progression pattern. Meanwhile, they showed similar pathological characteristics. Both consisted of bundles of collagen fibrils of spindle-shaped fibroblasts with low cell atypia. Moreover, they were diagnosed as desmoid tumors using positive immunohistochemical staining for β-catenin.

Conclusions
Neither patient had susceptibility factors for desmoid tumors, and to our knowledge, there have been very few reports to date of intra-abdominal desmoid tumors that were diagnosed because of acute abdominal pain caused by tumoral hemorrhage or asymptomatic obstructive uropathy. Furthermore, it is clinically interesting that the two patients showed contrasting progression patterns and imaging findings. Intra-abdominal desmoid tumors are rare and may present with various symptoms and findings similar to those observed in our patients. Diagnosis therefore requires experience and knowledge that is not bound by preconceptions.
Extracellular vesicles derived from mesenchymal stem cells as a potential therapeutic agent in acute kidney injury (AKI) in felines: review and perspectives
Authors: Kraińska Magdalena M. , Pietrzkowska Natalia , Turlej Eliza , Zongjin Li , Marycz Krzysztof 
Published: September 2021

AbstractMesenchymal stem cells (MSCs), known from their key role in the regeneration process of tissues, and their abilities to release bioactive factors like extracellular vesicles (EVs) could be considered as a potential, modern tool in the treatment of AKI (acute kidney injury) in both human and veterinary patients. The complex pathophysiology of a renal function disorder (AKI) makes difficult to find a universal therapy, but the treatment strategy is based on MSCs and derived from them, EVs seem to solve this problem. Due to their small size, the ability of the cargo transport, the ease of crossing the barriers and the lack of the ability to proliferate and differentiate, EVs seem to have a significant impact on the development such therapy. Their additional impact associated with their ability to modulate immune response and inflammation process, their strong anti-fibrotic and anti-apoptotic effects and the relation with the releasing of the reactive oxygen species (ROS), that pivotal role in the AKI development is undoubtedly, limits the progress of AKI. Moreover, the availability of EVs from different sources encourages to extend research with using EVs from MSCs in AKI treatment in felines; in that, the possibilities of kidney injuries treatment are still limited to the classical therapies burdened with dangerous side effects. In this review, we underline the significance of the processes, in whose EVs are included during the AKI in order to show the potential benefits of EVs-MSCs-based therapies against AKI in felines.
Computation of Fourier transform representations involving the generalized Bessel matrix polynomials
Authors: Abdalla M. , Akel M. 
Published: September 2021

AbstractMotivated by the recent studies and developments of the integral transforms with various special matrix functions, including the matrix orthogonal polynomials as kernels, in this article we derive the formulas for Fourier cosine and sine transforms of matrix functions involving generalized Bessel matrix polynomials. With the help of these transforms several results are obtained, which are extensions of the corresponding results in the standard cases. The results given here are of general character and can yield a number of (known and new) results in modern integral transforms.
Factors behind consumers' choices for healthy fruits: a review of pomegranate and its food derivatives
Authors: Stiletto Alice , Trestini Samuele 
Published: September 2021

AbstractDue to the rising interest in healthy products, superfoods such as pomegranate have begun to spread widely on the international market in recent years. Identification of the consumer choice determinants is a key factor behind the success of innovative products. Nevertheless, to date, there has been no comprehensive analysis of consumers’ preferences for pomegranate. The aim of this study is to understand the characteristics of pomegranate and its derivatives that are most preferred by consumers and to identify the buyers’ profiles by performing a systematic review (SR). The results suggest that there is not equal interest in the literature in all areas of the review. Indeed, most efforts have been made in characterizing the products, whereas consumers’ profiles and their willingness to pay for the various products features have been scarcely investigated. The SR highlights that consumer preference is first correlated with taste and, in particular, with the sweetness (positively) and astringency (negatively) of the product. The red colour and uniform shape of the husk are attractive attributes for consumers, as is the juiciness of the arils. Some innovative methods of product storage, such as intermittent heating (for fruits) and the use of pectin methyl esterase (for arils), guarantee higher consumer acceptability due to the maintenance of product genuineness. Moreover, familiarity with the product seems to be the main driver influencing consumers’ purchase decisions; in addition, people who are more “future oriented” are more willing to pay for pomegranate because of the nutraceutical attributes stressed on the label.
Gender differences in symptom presentation and treatment outcome in children and youths with eating disorders
Authors: Coelho Jennifer S. , Suen Janet , Marshall Sheila , Burns Alex , Geller Josie , Lam Pei-Yoong 
Published: September 2021

Abstract
Background
To address the gaps in the literature examining eating disorders among males and gender minority youths, a prospective study was designed to assess gender differences in eating disorder symptom presentation and outcomes. Muscularity concerns may be particularly relevant for male youths with eating disorders, and were included in assessment of eating disorder symptom presentation.

Methods
All cisgender male youths who presented for specialized eating disorder treatment at one of two sites were invited to participate, along with a group of matched cisgender females, and all youths who did not identify with the sex assigned to them at birth. Youths completed measures of eating disorder symptoms, including muscularity concerns, and other psychiatric symptoms at baseline and end of treatment.

Results
A total of 27 males, 28 females and 6 trans youths took part in the study. At baseline, Kruskal–Wallis tests demonstrated that trans youths reported higher scores than cisgender male and female youths on measures of eating pathology (Eating disorder examination-questionnaire (EDE-Q) and the body fat subscale of the male body attitudes scale (MBAS)). These analyses demonstrated that there were no differences between cisgender male and female youths on eating disorder symptoms at baseline. However, repeated measures ANOVA demonstrated that males had greater decreases in eating pathology at discharge than did females, based on self-reported scores on the EDE-Q, MBAS, and Body Change Inventory.

Conclusions
Gender differences in eating pathology appeared at baseline, with trans youths reporting higher levels of eating pathology than cisgender youths, though no differences between cisgender males and females emerged at baseline for eating disorder symptom presentation. Contrary to expectations, there were no gender differences in measures of muscularity concerns. Males demonstrated greater eating disorder symptom improvements than females, suggesting that male adolescents may have better treatment outcomes than females in some domains.
Tripleurospermum disciforme (C.A.Mey.) Sch.Bip., Tanacetum parthenium (L.) Sch.Bip, and Achillea biebersteinii Afan.: efficiency, chemical profile, and biological properties of essential oil
Authors: Ghavam Mansureh 
Published: September 2021

AbstractBackgroundTripleurospermum disciforme(C.A.Mey.) Sch.Bip.,Tanacetum parthenium(L.) Sch.Bip., andAchillea biebersteiniiAfan. are the most important species of the Asteraceae family that are used in traditional medicine as antiseptics, analgesics, and anti-ulcers. This study aimed to evaluate and compare the yield, chemical profile, and antibacterial and antifungal properties of the essential oils of these three species for the first time. For this purpose, plant materials were collected in June 2019 from Javinan region (Kashan, Iran).ResultsBased on the ANOVA results the species had a significant effect on yield, chemical composition, and diameter of the inhibition zone of some microorganisms (P ≤ 0.01). The highest yield belonged toT. disciformeessential oil (~ 1.433%). Analysis of essential oil compounds showed that inT. disciforme, anisole,p-1-cyclohexen-1-yl- (55.95%), modephene (10.00%), andcis-β-farnesene (11.94%), inT. parthenium, camphor (43.43%), camphene (9.40%), and bornyl acetate (6.76%), and inA. biebersteiniilinalool (34.49%),p-cymene (15.31%), and α-terpineol (7.43%) were the main and predominant compounds. The highest inhibition zone diameter by the essential oil ofT. partheniumandA. biebersteiniiagainstAspergillus brasiliensis(~ 13 mm) was observed. The strongest inhibitory and lethal activity was related toT. disciformeessential oil againstKlebsiella pneumoniae,Shigella dysenteriae,Escherichia coli(~ 8.50 mm), andCandida albicans(MIC and MBC = 62.5 μg/mL), which were equivalent to rifampin and twice as potent as nystatin, respectively.ConclusionsTherefore, the essential oil of the studied species of Asteraceae may be a promising and potential strategy for controlling some microorganisms and a possible natural alternative to some antibiotics.Graphic Abstract