bluuebunny/crossref_metadata_2025_split huggingface dataset:
89Zirconium-labelled girentuximab (89Zr-TLX250) PET in Urothelial Cancer Patients (ZiPUP): protocol for a phase I trial of a novel staging modality for urothelial carcinoma
Authors: Al-Zubaidi Mohammed , Viswambaram Pravin , McCombie Steve , Liow Elizabeth , Lenzo Nat , Ferguson Tom , Redfern Andrew D , Gauci Richard , Hayne Dickon 
Published: April 2022

IntroductionBladder cancer is a lethal disease with a rising incidence on a background of limited conventional imaging modalities for staging (either CT of the chest-abdomen-pelvis or 18F-fluorodeoxyglucose positron emitting tomography (FDG-PET/CT)). CT is known to have relatively low sensitivity for detecting low volume metastatic disease, an important goal when considering surgical interventions entailing significant potential morbidity. FDG is also limited, being predominantly renally excreted and, therefore, producing intense non-specific activity in the urinary tract, which limits its utility to detect bladder and upper tract lesions, or nodal metastases in close proximity to the urinary tract. 89Zirconium-labelled girentuximab (89Zr-TLX250) may have utility in the accurate staging of bladder and urothelial carcinomas, with less renal excretion as compared with FDG; however, this has not previously been investigated.Methods and analysis89Zirconium-labelled girentuximab PET in Urothelial Cancer Patients is a single-arm phase I trial examining the feasibility of using 89Zr-TLX250-PET/CT as a staging modality for urothelial and bladder carcinomas by examining isotope uptake by the cancer. This trial will also examine the safety and utility of 89Zr-TLX250-PET/CT in patients either undergoing preoperative staging of bladder or other urothelial carcinomas for curative intent, or with known metastatic urothelial carcinomas. All participants will undergo 89Zr-TLX250-PET/CT and will need to have undergone recent FDG-PET/CT for comparison. This trial aims to recruit 10 participants undergoing preoperative staging and 10 participants with known metastatic disease. The primary endpoint is feasibility defined by the ability to recruit to the target sample size within the study duration; secondary endpoints are safety, tolerability, sensitivity and specificity in detecting lymph node metastases compared with FDG-PET/CT.Ethics and disseminationEthics approval has been obtained from the South Metropolitan Health Service Human Research Ethics Committee (RGS0000003940). Eligible patients will only be enrolled after providing written informed consent. Patients will be given a full explanation, in lay terms, of the aims of the study and potential risks including as a written patient information sheet.Trial registration numbersACTRN12621000411842, NCT05046665.
Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis
Authors: Voskens Caroline , Stoica Diane , Rosenberg Marita , Vitali Francesco , Zundler Sebastian , Ganslmayer Marion , Knott Heike , Wiesinger Manuel , Wunder Jutta , Kummer Mirko , Siegmund Britta , Schnoy Elisabeth , Rath Timo , Hartmann Arndt , Hackstein Holger , Schuler-Thurner Beatrice , Berking Carola , Schuler Gerold , Atreya Raja , Neurath Markus F 
Published: April 2022

ObjectiveUlcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.DesignThe patient received a single infusion of 1×106autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer.ResultsThe patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3+/FoxP3+and CD3+/IL-10+T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again.ConclusionThese findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC.Trial registration numberNCT04691232.
Improving care of melanoma patients through efficient, integrated cellular-molecular pathology workflows using tissue samples with low tumour nuclear content
Authors: Finall Alison , Murphy Kate , Frazer Ricky Dylan 
Published: April 2022

AimsThe aim of this quality improvement project was to improve the turnaround time of B-raf proto-oncogene (BRAF) mutation testing in patients with malignant melanoma to support oncologists in making timely treatment decisions.MethodsThis is a prospective in-house verification of the Idylla BRAF test as compared with DNA panel next-generation sequencing (NGS) performed at an external laboratory.ResultsThe Idylla BRAF test had an overall concordance of 95% compared with NGS. This was considered sufficiently good for use in patients with a poor performance status who were at risk of rapid clinical deterioration. Reliable results can be generated using the Idylla BRAF test in tissue sections with tumour neoplastic cell content below 50%. We present a multidisciplinary clinical care algorithm to support dual testing.ConclusionsThe Idylla BRAF test has the potential to make a significant positive impact on progression-free survival of malignant melanoma patients due to its rapid turnaround time. The Idylla BRAF test can be used as an adjunct to NGS for timely management of patients, particularly those with a poor performance status at presentation.
Efficient targeting of NY-ESO-1 tumor antigen to human cDC1s by lymphotactin results in cross-presentation and antigen-specific T cell expansion
Authors: Le Gall Camille , Cammarata Anna , de Haas Lukas , Ramos-Tomillero Iván , Cuenca-Escalona Jorge , Schouren Kayleigh , Wijfjes Zacharias , Becker Anouk M D , Bödder Johanna , Dölen Yusuf , de Vries I Jolanda M , Figdor Carl G , Flórez-Grau Georgina , Verdoes Martijn 
Published: April 2022

BackgroundType 1 conventional dendritic cells (cDC1s) are characterized by their ability to induce potent CD8+T cell responses. In efforts to generate novel vaccination strategies, notably against cancer, human cDC1s emerge as an ideal target to deliver antigens. cDC1s uniquely express XCR1, a seven transmembrane G protein-coupled receptor. Due to its restricted expression and endocytic nature, XCR1 represents an attractive receptor to mediate antigen-delivery to human cDC1s.MethodsTo explore tumor antigen delivery to human cDC1s, we used an engineered version of XCR1-binding lymphotactin (XCL1), XCL1(CC3). Site-specific sortase-mediated transpeptidation was performed to conjugate XCL1(CC3) to an analog of the HLA-A*02:01 epitope of the cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1). While poor epitope solubility prevented isolation of stable XCL1-antigen conjugates, incorporation of a single polyethylene glycol (PEG) chain upstream of the epitope-containing peptide enabled generation of soluble XCL1(CC3)-antigen fusion constructs. Binding and chemotactic characteristics of the XCL1-antigen conjugate, as well as its ability to induce antigen-specific CD8+T cell activation by cDC1s, was assessed.ResultsPEGylated XCL1(CC3)-antigen conjugates retained binding to XCR1, and induced cDC1 chemoattraction in vitro. The model epitope was efficiently cross-presented by human cDC1s to activate NY-ESO-1-specific CD8+T cells. Importantly, vaccine activity was increased by targeting XCR1 at the surface of cDC1s.ConclusionOur results present a novel strategy for the generation of targeted vaccines fused to insoluble antigens. Moreover, our data emphasize the potential of targeting XCR1 at the surface of primary human cDC1s to induce potent CD8+T cell responses.
Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls
Authors: Perrem Lucy , Stanojevic Sanja , Solomon Melinda , Grasemann Hartmut , Sweezey Neil , Waters Valerie , Sanders Don B , Davis Stephanie D , Ratjen Felix 
Published: April 2022

BackgroundThe limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change.MethodsIn a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up.ResultsClinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up.ConclusionThe limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.
Constraints on running vacuum models with the baryon-to-photon ratio
Authors: Yu Hao , Yang Ke , Li Jin 
Published: April 2022

AbstractWe study the influence of running vacuum on the baryon-to-photon ratio in running vacuum models (RVMs). The photon and baryon number densities, from photon decoupling to the present day, are obtained in the context of RVMs by assuming that photons and baryons can be coupled to running vacuum, respectively. Both cases lead to a time-evolving baryon-to-photon ratio, whose values at different epochs of the universe are strictly constrained by observations. It is found that if the dominant dynamical term of running vacuum is indeed coupled to photons or baryons, the corresponding coefficient must be far less than the upper limit given by previous research, and so it is difficult to distinguish RVMs from the standard $${\varLambda }$$
Λ
CDM model. Such RVMs which are barely distinguishable from the $${\varLambda }$$
Λ
CDM model seem to be unconvincing. Therefore, if RVMs are reliable cosmological models, running vacuum is unlikely to be coupled to photons or baryons, and then the coefficient of the dominant dynamical term of running vacuum no longer needs to be extremely small.
Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities
Authors: Yousefi Maryam , Boross Gábor , Weiss Carly , Murray Christopher W. , Hebert Jess D. , Cai Hongchen , Ashkin Emily L. , Karmakar Saswati , Andrejka Laura , Chen Leo , Wang Minwei , Tsai Min K. , Lin Wen-Yang , Li Chuan , Yakhchalian Pegah , Colón Caterina I. , Chew Su-Kit , Chu Pauline , Swanton Charles , Kunder Christian A. , Petrov Dmitri A. , Winslow Monte M. 
Published: April 2022

Abstract

Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma.

Significance:
To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities.
Social Work Evaluations Among Pediatric Patients Transferred for Burn Care
Authors: Barré Alyssa M. , Tyler Lauren A. , Rhodes Marvin A. , McEvoy Christian S. , Ricca Robert L. 
Published: April 2022

Introduction Regionalization efforts aim to improve healthcare by designating specialty centers for a geographic area. Regionalization may play a role in determining patient treatment plans and outcomes. We hypothesize that these factors may be influenced by race, socioeconomics, insurance, and longitudinal follow-up. Methods Retrospective review of 81 patients ages 0-18 years evaluated at our Level 2 Trauma Center between February 2016-December 2020 who met criteria for transfer to a Regional Burn Center. Results 67% of patients were transferred to the Regional Burn Center. There was no difference in the percentage of transferred patients with respect to age, race, ethnicity, insurance type, or rurality of home address. Secondary analysis showed that 57.4% of children were transferred without evaluation by social work. Five patients’ injuries were due to non-accidental trauma (NAT); two of these patients were transferred without social work evaluations. 28% of those transferred had documented involvement of Child Protective Services (CPS). Of the 31 transferred patients without social work evaluation, 67% had incomplete or missing notes from the burn center, including 100% of those subsequently confirmed to be due to NAT. Only 32% of patients received follow-up at our institution. Conclusion We identified no differences in transfer percentages with respect to race, ethnicity, or insurance type. Secondary analysis demonstrated a significant gap in care regarding access to records and social work involvement. As NAT and social concerns are common amongst children with burns, we propose policies to ensure that these concerns are not overlooked during regionalization efforts.
Older Adults’ Perspectives on Voluntary Assisted Death: An In-Depth Qualitative Investigation in Australia
Authors: Gringart Eyal , Adams Claire , Woodward Faye 
Published: April 2022

Interest in voluntary assisted death (VAD) has been growing among researchers, policy makers and the public. This study aimed to explore older adults’ perspectives on VAD in Australia. Using purposive sampling, 15 adults ≥65 years participated in in-depth semi-structured interviews. Interpretative phenomenological analysis identified four themes: cultural reflections; beliefs and worldviews; health aspects; and fabric of life. Participants expressed a desire to have control over end-of-life options, challenged by religious beliefs. Participants expressed concern that VAD legislation could leave people vulnerable to coercion and saw a need for safeguards. Reasons for and against supporting and utilising VAD were discussed. Physical illness was seen a more compelling reason for VAD than mental ill-health. Finally, connections to life and other were discussed, and being able to do the things one loved were named aspects of what it meant to live a good life. Implications are discussed along with future research directions.
Impact of Glucagon-Like Peptide 1 Receptor Agonists in Patients with Hemoglobin A1c of 9% or Greater
Authors: Tran Victor , Tran Henry , Demirel Shaban , Thompson-Moore Nathaniel 
Published: April 2022

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) are effective hemoglobin A1c (HbA1c) and weight-lowering agents. The treatment effect is unknown in patients with HbA1c of 9% or greater. Objective: The purpose of this study was to evaluate glycemic control and weight loss after adding a GLP-1 agonist in patients with a baseline HbA1c of 9% (75 mmol/mol) or greater. Methods: A single-health system retrospective chart review screened adults with type 2 diabetes mellitus with a baseline hemoglobin A1c of 9% (75 mmol/mol) or greater and were prescribed a GLP-1 agonist for eligibility. The primary outcome assessed was the change in HbA1c from baseline to the first HbA1c check. Secondary outcomes included change in weight (kg) from baseline to the first HbA1c check. Results: Three hundred sixty-two patients were screened of which 151 (41.7%) were included in the final analysis. The mean change in HbA1c from baseline to first HbA1c check for all participants was −2.1% (95% CI: −2.3% to −1.8%; P < .001; −23 mmol/mol [95% CI: −25 to −20 mmol/mol]). The mean change in weight from baseline to first HbA1c check was −2.0 kg (95% CI: −2.6 kg to −1.4 kg; P < .001). Conclusion: In patients with type 2 diabetes mellitus with a baseline HbA1c ≥ 9%, GLP-1 agonist initiation resulted in a significant reduction of both HbA1c and weight compared to baseline. Large, prospective, multisite studies are needed to confirm findings of this retrospective study.
Droxidopa in the Management of Hepatorenal Syndrome
Authors: Bejjani Andrea , Zhang Youqi , Behrens Allison , Murray Brian , Shah Neil 
Published: April 2022

Purpose Hepatorenal syndrome (HRS) is renal dysfunction associated with the hemodynamic consequences of advanced liver disease and cirrhosis. HRS is associated with a high mortality, and there remain high failure rates with first-line therapy aimed at improving perfusion. We report the use of droxidopa, an oral norepinephrine precursor, to aid in the management of HRS-AKI refractory to first-line therapy. Summary: A 51-year-old Caucasian male with alcohol-related cirrhosis presented with 1-week history of pre-syncope and falls. He was found to have acute kidney injury meeting diagnostic criteria of HRS based on absence of identifiable contributing factors. After no response to volume expansion, medical management was initiated with midodrine and octreotide and eventually escalated to norepinephrine intravenous infusion. The patient’s renal function and urine output improved initially on norepinephrine, but worsened when attempting to wean to a suitable outpatient regimen, becoming dependent upon norepinephrine. On day 13 of hospitalization, droxidopa was initiated at a dose of 100 mg three times daily and titrated to a dose of 400 mg three times daily. Norepinephrine infusion was weaned and discontinued on day 16 of hospitalization. The patient remained hemodynamically stable and was able to be discharged on droxidopa 400 mg three times daily, midodrine 20 mg three times day, and octreotide 200 mcg three times daily. Conclusion: Droxidopa, an oral norepinephrine precursor, presents a novel adjunctive agent for management of HRS refractory to first-line medical management.
Investigational New Drug Enabling Nonclinical Safety Assessment of the Iminosugar UV-4, a Broad-Spectrum Host-Targeted Antiviral Agent
Authors: Shearer Jeffry , Wolfe Gary , Sampath Aruna , Warfield Kelly L. , Kaufman Brian , Ramstedt Urban , Treston Anthony 
Published: April 2022

The iminosugar UV-4 is a broad-spectrum antiviral drug candidate with activity in vitro and in vivo against multiple, diverse viruses. The toxicological profile of UV-4, dosed as the hydrochloride salt, was evaluated in single-dose and repeat-dose oral toxicity studies in mice, rats, dogs, and non-human primates (NHP). No moribundity or deaths were associated with the drug up to the maximum tolerated dose. No treatment-related adverse effects were observed following single oral doses in dogs, rats, and mice up to 250, 400, 1000 mg/kg, respectively, and in NHP up to 180 mg/kg administered three times daily for 10 days. UV-4-related findings were generally seen at higher doses after 7- or 14-day exposure. The most common clinical pathology findings (increase in aspartate aminotransferase and decreased platelet count) were consistently found across species and each appeared dose related. The kidney, mesenteric lymph nodes, stomach including gastrointestinal tract, and thymus were identified as target organs in mice, rats, and dogs. In 14-day repeat-dose toxicology studies in mice and dogs conducted in compliance with Good Laboratory Practice regulations, the dog was considered to be the most sensitive species to UV-4 exposure based on the treatment-related adverse effects noted in the identified target organs. The results of these studies demonstrate the safety profile of UV-4 hydrochloride and supported the selection of starting and maximal doses for a single ascending dose first-in-human clinical study.
The role of familiarity with the experimenter on cognitive performance, metacognition, pro-social behaviors, and the well-being of adults with moderate to severe intellectual disabilities
Authors: Igier Suzanne , Valérie Pennequin 
Published: April 2022

Background Few studies have evaluated the explanatory factors of poor performance and the effects of context in adults with intellectual disabilities. The aim of this study is to assess the role of a familiar experimenter on their cognitive performance, well-being, metacognitive experiences, and social behaviors. Method Participants with moderate to severe intellectual disability were recruited into two groups, one with a familiar and one with an unfamiliar experimenter. They carried out a categorization task. Before and after they reported their metacognitive experiences and level of well-being. The experimenter observed their pro-social behavior. Results Performance and some social behaviors were better when the participant knew the experimenter. However, he did not affect the level of well-being. The participants’ metacognitive experiences were poor, whether or not they knew the experimenter. Conclusions The familiarity of the experimenter plays a determining role, both on the participants’ performance, and on their compliance with certain pro-social behavior.