bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiorgan Involvement of Dormant Uveal Melanoma Micrometastases in Postmortem Tissue From Patients Without Coexisting Macrometastases
Authors: Gill Viktor T , Norrman Emelie , Sabazade Shiva , Karim Ali , Lardner Emma , Stålhammar Gustav 
Published: April 2023

Abstract

Objectives
Almost half of all patients diagnosed with uveal melanoma will die of metastatic disease. This has been attributed to early seeding of micrometastases. We investigate the presence, density, organ involvement, and characteristics of micrometastases of uveal melanoma in tissue obtained at autopsy of patients with and without coexisting macrometastases.

Methods
Patients diagnosed with primary uveal melanoma at a national referral center between 1960 and 2020 (n = 4,282) were cross-referenced with autopsy registers at nearby hospitals. Eleven patients were included. Formalin-fixed, paraffin-embedded tissue samples obtained during autopsy were examined with routine histology, immunohistochemistry, and immunomagnetic separation.

Results
Micrometastases were detected in 5 of 5 patients with and in 5 of 6 patients without coexisting macrometastases. Micrometastases were identified in several sites, including lungs, kidneys, myocardium, and bone marrow. Their highest density per mm2 of tissue was seen in the liver. Of 11 examined patients, 2 had at least 1 BAP-1–positive metastasis. All micrometastases had immune cell infiltrates and no or very low proliferative activity.

Conclusions
We demonstrate multiorgan involvement of apparently dormant micrometastases in patients with uveal melanoma. This suggests that micrometastases are present in nearly all patients diagnosed with primary uveal melanoma, regardless of coexisting macrometastases.
Residency application content and considerations based on residency director review of a fictitious CV: What really matters?
Authors: Pate Adam N , Mills Alex R , Fleming Joshua W , Phan Ha K , Street Margaret , Pitcock James J 
Published: April 2023

Abstract

Purpose
This research was conducted to evaluate the influence of a pharmacy residency candidate’s prior work or research experience on the potential for selection for an interview. Additionally, residency program directors (RPDs) were asked to evaluate the importance of letters of intent and recommendation, rank the importance of typical curriculum vitae (CV) items along with general preferences, and provide advice for a standout CV.

Methods
This cross-sectional, survey-based study recruited RPDs to review a work-focused or research-focused fictitious residency candidate CV and complete a 33-question survey regarding interest in interviewing the fictitious candidate and their general perceptions of significant factors in interview candidate selection.

Results
A total of 456 RPDs responded to the survey, with 229 respondents assigned to evaluate the work-focused CV and 227 assigned to review the research-focused CV. Among RPDs who provided CV evaluations, 81.2% (147/181) of those who reviewed the research-focused CV and 78.3% (137/175) of those who reviewed the work-focused CV gave a positive evaluation (P &gt; 0.05). Work experience and extracurricular activities were considered the most important CV sections, and high-quality advanced pharmacy practice experience (APPE) rotations and pharmacy work experience were perceived to have the highest correlation with success in residency.

Conclusion
This work supports the importance of candidates creating a well-rounded CV in preparing themselves for residency. Pharmacy-related work experience and high-quality APPE rotations seem to be key in an RPD’s opinions of predicted success in a residency program. The CV remains a vital document in the residency candidate review process, and it deserves a high degree of effort in ensuring it adequately reflects professional experiences.
nestedcv: an R package for fast implementation of nested cross-validation with embedded feature selection designed for transcriptomics and high-dimensional data
Authors: Lewis Myles J , Spiliopoulou Athina , Goldmann Katriona , Pitzalis Costantino , McKeigue Paul , Barnes Michael R 
Published: April 2023

AbstractMotivationAlthough machine learning models are commonly used in medical research, many analyses implement a simple partition into training data and hold-out test data, with cross-validation (CV) for tuning of model hyperparameters. Nested CV with embedded feature selection is especially suited to biomedical data where the sample size is frequently limited, but the number of predictors may be significantly larger (P ≫ n).ResultsThe nestedcv R package implements fully nested k × l-fold CV for lasso and elastic-net regularized linear models via the glmnet package and supports a large array of other machine learning models via the caret framework. Inner CV is used to tune models and outer CV is used to determine model performance without bias. Fast filter functions for feature selection are provided and the package ensures that filters are nested within the outer CV loop to avoid information leakage from performance test sets. Measurement of performance by outer CV is also used to implement Bayesian linear and logistic regression models using the horseshoe prior over parameters to encourage a sparse model and determine unbiased model accuracy.Availability and implementationThe R package nestedcv is available from CRAN: https://CRAN.R-project.org/package=nestedcv.
Structure-aware protein self-supervised learning
Authors: Chen Can (Sam) , Zhou Jingbo , Wang Fan , Liu Xue , Dou Dejing 
Published: April 2023

Abstract

Motivation
Protein representation learning methods have shown great potential to many downstream tasks in biological applications. A few recent studies have demonstrated that the self-supervised learning is a promising solution to addressing insufficient labels of proteins, which is a major obstacle to effective protein representation learning. However, existing protein representation learning is usually pretrained on protein sequences without considering the important protein structural information.

Results
In this work, we propose a novel structure-aware protein self-supervised learning method to effectively capture structural information of proteins. In particular, a graph neural network model is pretrained to preserve the protein structural information with self-supervised tasks from a pairwise residue distance perspective and a dihedral angle perspective, respectively. Furthermore, we propose to leverage the available protein language model pretrained on protein sequences to enhance the self-supervised learning. Specifically, we identify the relation between the sequential information in the protein language model and the structural information in the specially designed graph neural network model via a novel pseudo bi-level optimization scheme. We conduct experiments on three downstream tasks: the binary classification into membrane/non-membrane proteins, the location classification into 10 cellular compartments, and the enzyme-catalyzed reaction classification into 384 EC numbers, and these experiments verify the effectiveness of our proposed method.

Availability and implementation
The Alphafold2 database is available in https://alphafold.ebi.ac.uk/. The PDB files are available in https://www.rcsb.org/. The downstream tasks are available in https://github.com/phermosilla/IEConv\_proteins/tree/master/Datasets. The code of the proposed method is available in https://github.com/GGchen1997/STEPS_Bioinformatics.
Basal ganglia functional connectivity network analysis does not support the ‘noisy signal’ hypothesis of Parkinson’s disease
Authors: Williams David 
Published: April 2023

Abstract
The ‘noisy signal’ hypothesis of basal ganglia dysfunction in Parkinson’s disease (PD) suggests that major motor symptoms of the disorder are caused by the development of abnormal basal ganglia activity patterns resulting in the propagation of ‘noisy’ signals to target systems. While such abnormal activity patterns might be useful biomarkers for the development of therapeutic interventions, correlation between specific changes in activity and PD symptoms has been inconsistently demonstrated, and raises questions concerning the accuracy of the hypothesis. Here, we tested this hypothesis by considering three nodes of the basal ganglia network, the subthalamus, globus pallidus interna, and cortex during self-paced and cued movements in patients with PD. Interactions between these regions were analyzed using measures that assess both linear and non-linear relationships. Marked changes in the network are observed with dopamine state. Specifically, we detected functional disconnection of the basal ganglia from the cortex and higher network variability in untreated PD, but various patterns of directed functional connectivity with lower network variability in treated PD. When we examine the system output, significant correlation is observed between variability in the cortico-basal ganglia network and muscle activity variability but only in the treated state. Rather than supporting a role of the basal ganglia in the transmission of noisy signals in patients with PD, these findings suggest that cortico-basal ganglia network interactions by fault or design, in the treated Parkinsonian state, are actually associated with improved cortical network output variability.
Cancer-associated fibroblasts-derived exosome-mediated transfer of miR-345-5p promotes the progression of colorectal cancer by targeting CDKN1A
Authors: Shi Weikun , Liu Yuxin , Qiu Xiaoyuan , Yang Ling , Lin Guole 
Published: April 2023

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-induced death in the world. Cancer-associated fibroblasts (CAFs) released exosomes that contributed to cancer progression. This research was carried out to study the influence of CRC-associated fibroblasts-derived exosomes on the phenotype of CRC cells and the underlying mechanism. CAFs-derived exosomes (CAFs-exo) and normal fibroblasts (NFs)-derived exosomes (NFs-exo) were recognized by transmission electronic microscopy, nanoparticle tracking analysis and western blot analysis. Cell counting kit-8, flow cytometry analysis, colony formation assay, Transwell, qRT-PCR, immunofluorescence, immunohistochemistry staining and xenografts model were carried out to proceed with function studies in vitro and in vivo. The results showed that CAFs-exo induced cell proliferation, migration and invasion, while NFs-exo did not influence the tumor biological properties of CRC cells. Using qRT-PCR, miR-345-5p was observed to be a notably up-regulated miRNA in CAFs-exo compared to NFs-exo. CAFs-exo could mediate the transfer of miR-345-5p to CRC cells, and downregulation of miR-345-5p in CAFs notably reversed the pro-tumoral effect of CAFs-exo on CRC cells. Based on online prediction database, CDKN1A was proved as a direct downstream target of miR-345-5p in CRC cells, which was lowly expressed and negatively associated with miR-345-5p in CRC tumors. Furthermore, miR-345-5p upregulation-mediated tumor biological behaviors were abrogated by exogenous CDKN1A. In CRC cells-beared tumor xenograft, CAFs-exo administration promoted tumor growth and decreased CDKN1A expression, whereas miR-345-5p inhibition reversed these effects. The present study revealed that by interacting with CDKN1A, CAF-derived exosomal miR-345-5p promotes CRC progression and metastasis.
Inhibition of lung adenocarcinoma by combinations of sulfasalazine (SAS) and disulfiram-copper (DSF-Cu) in cell line models and mice
Authors: Bagherpoor Alireza Jian , Shameem Mohammad , Luo Xianghua , Seelig Davis , Kassie Fekadu 
Published: April 2023

Abstract
Sulfasalazine (SAS) is a repurposed antitumor drug which inhibits the proliferation and survival of cancer cells by inhibiting the xCT cellular antioxidant system. Recent clinical studies have shown that, due to poor bioavailability, the antitumor effects of SAS monotherapy are minimal. Therefore, we hypothesized that DSF, another repurposed drug that has demonstrated anticancer effects, or its complex with copper (DSF-copper, DSF-Cu) could potentiate the antilung cancer effects of SAS. Exposure of non-small cell lung cancer cells to therapeutically achievable concentrations of SAS-induced low-to-moderate cytotoxic effects (20–40% reduction in cell viability) and, unexpectedly, induced the antioxidant protein NRF2 and its downstream effectors xCT and ALDH1A1. However, combinations of SAS and DSF-Cu, but not SAS and DSF, induced a significantly higher cytotoxic effect (64–88% reduction in cell viability), apoptosis and generation of mitochondrial reactive oxygen species as compared with SAS or DSF-Cu alone. Moreover, DSF-Cu abrogated SAS-induced NRF2, xCT and ALDH1A1 expression. In a mouse model of lung tumor, SAS + DSF-Cu showed a higher efficacy than the individual drugs in reducing the number and size of tumors as well as the incidence and multiplicity of lung adenocarcinoma. Taken together, our findings indicate that the observed antilung cancer effects of SAS plus DSF-Cu are mediated, at least in part, via impairment of reactive oxygen species defense and ­enhancement of oxidative stress and provide evidence for the preventive/therapeutic potential of this combinatorial approach against lung cancer.
High exposure to tacrolimus is associated with spontaneous remission of recurrent membranous nephropathy after kidney transplantation
Authors: Buxeda Anna , Caravaca-Fontán Fernando , Vigara Luis Alberto , Pérez-Canga José Luis , Calatayud Emma , Coloma Ana , Mazuecos Auxiliadora , Rodrigo Emilio , Sancho Asunción , Melilli Edoardo , Praga Manuel , Pérez-Sáez María José , Pascual Julio 
Published: April 2023

ABSTRACT

Introduction
We aimed to characterize the incidence and clinical presentation of membranous nephropathy (MN) after kidney transplantation (KT), and to assess allograft outcomes according to proteinuria rates and immunosuppression management.

Methods
Multicenter retrospective cohort study including patients from six Spanish centers who received a KT between 1991–2019. Demographic, clinical, and histological data were collected from recipients with biopsy-proven MN as primary kidney disease (n = 71) or MN diagnosed de novo after KT (n = 4).

Results
Up to 25.4% of patients with biopsy-proven MN as primary kidney disease recurred after a median time of 18.1 months posttransplant, without a clear impact on graft survival. Proteinuria at 3-months post-KT was a predictor for MN recurrence (rMN, HR 4.28; P = 0.008). Patients who lost their grafts had higher proteinuria during follow-up [1.0 (0.5–2.5) vs 0.3 (0.1–0.5) g/24 h], but only eGFR after recurrence treatment predicted poorer graft survival (eGFR &lt; 30 ml/min: RR = 6.8). We did not observe an association between maintenance immunosuppression and recurrence diagnosis. Spontaneous remission after rMN was associated with a higher exposure to tacrolimus before recurrence (trough concentration/dose ratio: 2.86 vs 1.18; P = 0.028). Up to 94.4% of KT recipients received one or several treatments after recurrence onset: 22.2% rituximab, 38.9% increased corticosteroid dose, and 66.7% ACEi/ARBs. Only 21 patients had proper antiPLA2R immunological monitoring.

Conclusions
One-fourth of patients with biopsy-proven MN as primary kidney disease recurred after KT, without a clear impact on graft survival. Spontaneous remission after rMN was associated with a higher exposure to tacrolimus before recurrence.
The circadian protein BMAL1 supports endothelial cell cycle during angiogenesis
Authors: Astone Matteo , Oberkersch Roxana E , Tosi Giovanni , Biscontin Alberto , Santoro Massimo M 
Published: April 2023

Abstract

Aims
The circadian clock is an internal biological timer that co-ordinates physiology and gene expression with the 24-h solar day. Circadian clock perturbations have been associated to vascular dysfunctions in mammals, and a function of the circadian clock in angiogenesis has been suggested. However, the functional role of the circadian clock in endothelial cells (ECs) and in the regulation of angiogenesis is widely unexplored.

Methods and results
Here, we used both in vivo and in vitro approaches to demonstrate that ECs possess an endogenous molecular clock and show robust circadian oscillations of core clock genes. By impairing the EC-specific function of the circadian clock transcriptional activator basic helix-loop-helix ARNT like 1 (BMAL1) in vivo, we detect angiogenesis defects in mouse neonatal vascular tissues, as well as in adult tumour angiogenic settings. We then investigate the function of circadian clock machinery in cultured EC and show evidence that BMAL and circadian locomotor output cycles protein kaput knock-down impair EC cell cycle progression. By using an RNA- and chromatin immunoprecipitation sequencing genome-wide approaches, we identified that BMAL1 binds the promoters of CCNA1 and CDK1 genes and controls their expression in ECs.

Conclusion(s)
Our findings show that EC display a robust circadian clock and that BMAL1 regulates EC physiology in both developmental and pathological contexts. Genetic alteration of BMAL1 can affect angiogenesis in vivo and in vitro settings.
CHARGE syndrome-associated CHD7 acts at ISL1-regulated enhancers to modulate second heart field gene expression
Authors: Stathopoulou Athanasia , Wang Ping , Thellier Charlotte , Kelly Robert G , Zheng Deyou , Scambler Peter J 
Published: April 2023

Abstract

Aims
Haploinsufficiency of the chromo-domain protein CHD7 underlies most cases of CHARGE syndrome, a multisystem birth defect including congenital heart malformation. Context specific roles for CHD7 in various stem, progenitor, and differentiated cell lineages have been reported. Previously, we showed severe defects when Chd7 is absent from cardiopharyngeal mesoderm (CPM). Here, we investigate altered gene expression in the CPM and identify specific CHD7-bound target genes with known roles in the morphogenesis of affected structures.

Methods and results
We generated conditional KO of Chd7 in CPM and analysed cardiac progenitor cells using transcriptomic and epigenomic analyses, in vivo expression analysis, and bioinformatic comparisons with existing datasets. We show CHD7 is required for correct expression of several genes established as major players in cardiac development, especially within the second heart field (SHF). We identified CHD7 binding sites in cardiac progenitor cells and found strong association with histone marks suggestive of dynamically regulated enhancers during the mesodermal to cardiac progenitor transition of mESC differentiation. Moreover, CHD7 shares a subset of its target sites with ISL1, a pioneer transcription factor in the cardiogenic gene regulatory network, including one enhancer modulating Fgf10 expression in SHF progenitor cells vs. differentiating cardiomyocytes.

Conclusion
We show that CHD7 interacts with ISL1, binds ISL1-regulated cardiac enhancers, and modulates gene expression across the mesodermal heart fields during cardiac morphogenesis.
Of Rights and Riots: Indenture and (Mis)Rule in the Late Nineteenth-Century British Caribbean
Authors: Auerbach Sascha 
Published: April 2023

Abstract
This article builds on the work of Walter Rodney, Thomas Holt, Gad Heuman, Diana Paton, and others who have investigated the complexities of post-slavery societies in the Caribbean. It addresses the dynamics of resistance and the re-working of legal and cultural processes that took place in the half-century following emancipation. Whereas indenture plays a tertiary role in these previous analyses, it is the central concern of this article. Through a close examination of the 1872 killing of five indentured Indian workers on the Devonshire Castle plantation, I analyse how the institution of indenture restructured the interrelation of the colonial state, labour control and violence in British Guiana. I consider the killings not only in the context typically employed by Caribbean historians to examine race, labour and violence—that of slave rebellions and African-Caribbean revolts in the post-emancipation era—but also in relation to the 1857 Indian Rebellion and in the context of an Empire-wide narrative that justified violent state repression against colonised peoples. Although this is largely a microhistorical account, I hope to provide some useful avenues of analysis by which indenture (primarily approached until now through the lens of social history) can be more broadly engaged as an institution that catalysed a new relationship between the state and labour management, that fostered new (or, at least, revised) discourses of the role of violence in colonialism, and that generated new patterns of response and resistance among subalterns.
Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial
Authors: Tolomeo Paolo , Butt Jawad H , Kondo Toru , Campo Gianluca , Desai Akshay S , Jhund Pardeep S , Køber Lars , Lefkowitz Martin P , Rouleau Jean L , Solomon Scott D , Swedberg Karl , Vaduganathan Muthiah , Zile Michael R , Packer Milton , McMurray John J V 
Published: April 2023

Abstract

Aims
The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation.

Methods and results
CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (&lt;−10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (&gt;−10 and &lt;10 mL/min/1.73 m2), and Group 3 (&gt;10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was −0.7 (−6.4–4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C.

Conclusion
The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients.

Clinical Trial Registration
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.