bluuebunny/crossref_metadata_2025_split huggingface dataset:
The multifaceted role of vitreous hyalocytes: Orchestrating inflammation, angiomodulation and erythrophagocytosis in proliferative diabetic retinopathy
Authors: Boneva Stefaniya K. , Wolf Julian , Jung Malte , Prinz Gabriele , Chui Toco Y. P. , Jauch Jacqueline , Drougard Anne , Pospisilik J. Andrew , Schlecht Anja , Bucher Felicitas , Rosen Richard B. , Agostini Hansjürgen , Schlunck Günther , Lange Clemens A. K. 
Published: November 2024

Abstract
Background
Despite great advances in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. While resident vitreous macrophages called hyalocytes have been implicated in the pathophysiology of vitreoretinal proliferative disease previously, little is known about their exact role in PDR. In this study, we address molecular and cellular alterations in the vitreous of PDR patients as a means towards assessing the potential contribution of hyalocytes to disease pathogenesis.

Results
A total of 55 patients were included in this study encompassing RNA-Sequencing analysis of hyalocytes isolated from the vitreous of PDR and control patients, multiplex immunoassay and ELISA analyses of vitreous samples from PDR and control patients, as well as isolation and immunohistochemical staining of cultured porcine hyalocytes. Transcriptional analysis revealed an enhanced inflammatory response of hyalocytes contributing to the cytokine pool within the vitreous of PDR patients by expressing interleukin-6, among others. Further, increased angiopoietin-2 expression indicated that hyalocytes from PDR patients undergo a proangiogenic shift and may thus mediate the formation of retinal neovascularizations, the hallmark of PDR. Finally, RNA-Sequencing revealed an upregulation of factors known from hemoglobin catabolism in hyalocytes from PDR patients. By immunohistochemistry, cultured porcine hyalocytes exposed to red blood cells were shown to engulf and phagocytose these, which reveals hyalocytes’ potential to dispose of erythrocytes. Thus, our data suggest a potential role for vitreous macrophages in erythrophagocytosis and, thereby, clearance of vitreous hemorrhage, a severe complication of PDR.

Conclusion
Our results strongly indicate a critical role for vitreous hyalocytes in key pathophysiological processes of proliferative diabetic retinopathy: inflammation, angiomodulation and erythrophagocytosis. Immunomodulation of hyalocytes may thus prove an essential novel therapeutic approach in diabetic vitreoretinal disease.
A rotenone organotypic whole hemisphere slice model of mitochondrial abnormalities in the neonatal brain
Authors: Butler Brendan , Renney Malcolm , Bennett Kristin , Charpentier Gisele , Nance Elizabeth 
Published: November 2024

AbstractMitochondrial abnormalities underscore a variety of neurologic injuries and diseases and are well-studied in adult populations. Clinical studies identify critical roles of mitochondria in a wide range of developmental brain injuries, but models that capture mitochondrial abnormalities in systems representative of the neonatal brain environment are lacking. Here, we develop an organotypic whole-hemisphere (OWH) brain slice model of mitochondrial dysfunction in the neonatal brain. We extended the utility of complex I inhibitor rotenone (ROT), canonically used in models of adult neurodegenerative diseases, to inflict mitochondrial damage in OWH slices from term-equivalent rats. We quantified whole-slice health over 6 days of exposure for a range of doses represented in ROT literature. We identified 50 nM ROT as a suitable exposure level for OWH slices to inflict injury without compromising viability. At the selected exposure level, we confirmed exposure- and time-dependent mitochondrial responses showing differences in mitochondrial fluorescence and nuclear localization using MitoTracker imaging in live OWH slices and dysregulated mitochondrial markers via RT-qPCR screening. We leveraged the regional structures present in OWH slices to quantify cell density and cell death in the cortex and the midbrain regions, observing higher susceptibilities to damage in the midbrain as a function of exposure and culture time. We supplemented these findings with analysis of microglia and mature neurons showing time-, region-, and exposure-dependent differences in microglial responses. We demonstrated changes in tissue microstructure as a function of region, culture time, and exposure level using live-video epifluorescence microscopy of extracellularly diffusing nanoparticle probes in live OWH slices. Our results highlight severity-, time-, and region-dependent responses and establish a complimentary model system of mitochondrial abnormalities for high-throughput or live-tissue experimental needs.
Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates
Authors: Lalagkas Panagiotis N. , Melamed Rachel D. 
Published: November 2024

Abstract

Background
Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing.

Methods
We compile breast cancer’s predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer.

Results
We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher’s exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing.

Conclusions
Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.
Physics-informed two-tier neural network for non-linear model order reduction
Authors: Hong Yankun , Bansal Harshit , Veroy Karen 
Published: November 2024

AbstractIn recent years, machine learning (ML) has had a great impact in the area of non-intrusive, non-linear model order reduction (MOR). However, the offline training phase often still entails high computational costs since it requires numerous, expensive, full-order solutions as the training data. Furthermore, in state-of-the-art methods, neural networks trained by a small amount of training data cannot be expected to generalize sufficiently well, and the training phase often ignores the underlying physical information when it is applied with MOR. Moreover, state-of-the-art MOR techniques that ensure an efficient online stage, such as hyper reduction techniques, are either intrusive or entail high offline computational costs. To resolve these challenges, inspired by recent developments in physics-informed and physics-reinforced neural networks, we propose a non-intrusive, physics-informed, two-tier deep network (TTDN) method. The proposed network, in which the first tier achieves the regression of the unknown quantity of interest and the second tier rebuilds the physical constitutive law between the unknown quantities of interest and derived quantities, is trained using pretraining and semi-supervised learning strategies. To illustrate the efficiency of the proposed approach, we perform numerical experiments on challenging non-linear and non-affine problems, including multi-scale mechanics problems.
Reduction of oxidative damage caused by Fusarium falciforme and Fusarium foetens in schefflera plants using chitosan nanoparticles loaded with l-proline or indole butyric acid
Authors: Imara Doaa A. , Ghebrial Eman W. R. , EL-Abeid Sozan E. , Hussein Eman M. A. , Elsayed Mona I. E. , Yousef Rania S. 
Published: November 2024

Abstract
Background
Root rot, wilt diseases, and rooting processes have been the major factors that constrain schefflera production. This study focuses on the impact of innovative applications of eco-friendly materials like chitosan nanoparticles loaded with l-proline or indole butyric acid to replace traditional chemical fungicides in controlling root rot and wilt diseases, as well as the vegetative propagation success of leafy stem schefflera cuttings.

Results
Fusarium foeten (strain 1) and Fusarium falciforme (strains 2 and 4) were first identified as root rot and wilt pathogens of schefflera in Egypt based on morphological features and confirmed with molecular analyses. Fusarium foetens (strain 1) and F. falciforme (strain 2) have the most aggressive action, as the infection percentages significantly increased in the pathogenicity test. The disease incidence reached 38.88 and 44.44%, respectively, whereas the disease severity was 18.51 and 26.84%, respectively. Chitosan nanoparticles at a concentration of 25 mg/L were the most effective dose, leading to a significant reduction in disease incidence to 25.00%, disease severity to 4.17%, and playing a vital role in activating plant defense, which correlates well with improved growth characteristics. The novel strategy of L-proline loaded on chitosan nanoparticles (LP-CSNPs) application occupied the first rank at protective influence against root rot and wilt disease-induced oxidative stress, signaling a defensive function that was freelance verified. L-proline loaded on chitosan nanoparticles (LP-CSNPs) at 0.125–0.25 g/L had a significant impact on reducing the incidence and severity of root rot and wilt diseases, as well as improving photosynthetic pigments and free radical scavenging activities, which included strengthening plant defense and further validating the findings from the biochemical trait analysis. The TT biplot graph was an influential statistical tool to study the impacts of treatments on schefflera production and its attributes and to discover the interrelationships among them.

Conclusions
Applying LP-CSNPs is one of the best techniques to manage schefflera root rot and wilt diseases, since it can be utilized as a growth stimulator and defense activator with sustainable increased efficiency.

Graphical Abstract
The development of a C5.0 machine learning model in a limited data set to predict early mortality in patients with ARDS undergoing an initial session of prone positioning
Authors: Hannon David M. , Syed Jaffar David Abbas , McNicholas Bairbre , Madden Michael , Laffey John G. 
Published: November 2024

Abstract
Background
Acute Respiratory Distress Syndrome (ARDS) has a high morbidity and mortality. One therapy that can decrease mortality is ventilation in the prone position (PP). Patients undergoing PP are amongst the sickest, and there is a need for early identification of patients at particularly high risk of death. These patients may benefit from an in-depth review of treatment or consideration of rescue therapies. We report the development of a machine learning model trained to predict early mortality in patients undergoing prone positioning as part of the management of their ARDS.

Methods
Prospectively collected clinical data were analysed retrospectively from a single tertiary ICU. The records of patients who underwent an initial session of prone positioning whilst receiving invasive mechanical ventilation were identified (n = 131). The decision to perform prone positioning was based on the criteria in the PROSEVA study. A C5.0 classifier algorithm with adaptive boosting was trained on data gathered before, during, and after initial proning. Data was split between training (85% of data) and testing (15% of data). Hyperparameter tuning was achieved through a grid-search using a maximal entropy configuration. Predictions for 7-day mortality after initial proning session were made on the training and testing data.

Results
The model demonstrated good performance in predicting 7-day mortality (AUROC: 0.89 training, 0.78 testing). Seven variables were used for prediction. Sensitivity was 0.80 and specificity was 0.67 on the testing data set. Patients predicted to survive had 13.3% mortality, while those predicted to die had 66.67% mortality. Among patients in whom the model predicted patient would survive to day 7 based on their response, mortality at day 7 was 13.3%. Conversely, if the model predicted the patient would not survive to day 7, mortality was 66.67%.

Conclusions
This proof-of-concept study shows that with a limited data set, a C5.0 classifier can predict 7-day mortality from a number of variables, including the response to initial proning, and identify a cohort at significantly higher risk of death. This can help identify patients failing conventional therapies who may benefit from a thorough review of their management, including consideration of rescue treatments, such as extracorporeal membrane oxygenation.
This study shows the potential of a machine learning model to identify ARDS patients at high risk of early mortality following PP. This information can guide clinicians in tailoring treatment strategies and considering rescue therapies. Further validation in larger cohorts is needed.
Effectiveness and safety of mineralocorticoid receptor antagonists in heart failure patients with and without diabetes: a systematic review and meta-analysis
Authors: Adji Arga Setyo , Widjaja Jordan Steven , de Liyis Bryan Gervais 
Published: November 2024

Abstract
Background
Mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcomes in various populations of heart failure (HF) patients. However, the impact of concomitant diseases, such as diabetes mellitus (DM), on these outcomes remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of MRAs in heart failure patients with and without diabetes mellitus.

Methods
A systematic search was conducted on PubMed, Scopus, and Google Scholar databases up to April 30, 2024. Data analysis was performed using a random-effects model to account for variability across studies, and statistical analysis was carried out using Review Manager 5.4. Efficacy and safety parameters were evaluated in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.

Results
The meta-analysis included a total of 21,832 subjects from ten studies. The pooled results demonstrated that MRAs, compared to placebo, significantly reduced all-cause mortality in HF patients with and without DM (RR: 0.85; 95%CI 0.75–0.96; p = 0.009). A similar effect was observed in HF patients without DM (RR: 0.83; 95%CI 0.71–0.97; p = 0.02), while no significant effect was detected in the DM subgroup (RR: 0.87; 95%CI 0.69–1.11; p = 0.27). Both treatments had comparable effects on cardiovascular mortality in HF patients with and without DM (RR: 0.88; 95%CI 0.82–0.94; p = 0.0002), in HF patients with DM (RR: 0.90; 95%CI 0.81–1.01; p = 0.08), and in the non-DM subgroup (RR: 0.86; 95%CI 0.79–0.94; p = 0.0009). MRAs significantly reduced the risk of cardiovascular mortality in HF patients with and without DM (RR: 0.82; 95%CI 0.72–0.94; p = 0.005) and in HF patients with DM (RR: 0.79; 95%CI 0.63–0.98; p = 0.03), but no significant effect was observed in the non-DM subgroup (RR: 0.85; 95%CI 0.69–1.05; p = 0.13). Furthermore, compared to placebo, MRAs were associated with an increased risk of hyperkalemia (> 5.5 mEq/L) in HF patients with and without DM (RR: 1.63; 95%CI 1.18–2.24; p = 0.003), particularly in HF patients with DM (RR: 1.44; 95%CI 0.97–2.13; p = 0.07) and in the non-DM subgroup (RR: 1.87; 95%CI 1.34–2.61; p = 0.0002).

Conclusion
MRAs are effective in reducing all-cause mortality, cardiovascular death, and cardiovascular mortality in heart failure patients. However, the use of MRAs is associated with an increased risk of hyperkalemia, necessitating careful monitoring, particularly in patients with diabetes mellitus.
Usage of the National Cancer Institute Cancer Research Data Commons by Researchers: A Scoping Review of the Literature
Authors: Chen Zhaoyi , Kim Erika , Davidsen Tanja , Barnholtz-Sloan Jill S. 
Published: November 2024

PURPOSE
Over the past decade, significant surges in cancer data of all types have happened. To promote sharing and use of these rich data, the National Cancer Institute's Cancer Research Data Commons (CRDC) was developed as a cloud-based infrastructure that provides a large, comprehensive, and expanding collection of cancer data with tools for analysis. We conducted this scoping review of articles to provide an overview of how CRDC resources are being used by cancer researchers.

METHODS
A thorough literature search was conducted to identify all relevant publications. We included publications that directly cited CRDC resources to specifically examine the impact and contributions of CRDC by itself. We summarized the distributions and trends of how CRDC components were used by the research community and discussed current research gaps and future opportunities.

RESULTS
In terms of CRDC resources used by the research community, encouraging trends in utilization were observed, suggesting that CRDC has become an important building block for fostering a wide range of cancer research. We also noted a few areas where current applications are rather lacking and provided insights on how improvements can be made by CRDC and research community.

CONCLUSION
CRDC, as the foundation of a National Cancer Data Ecosystem, will continue empowering the research community to effectively leverage cancer-related data, uncover novel strategies, and address the needs of patients with cancer, ultimately combatting this disease more effectively.
Uncovering Hypercalcemia of Malignancy Following Parathyroidectomy for Hyperparathyroidism
Authors: Nessa Lutfor , Enabi Joud , Gonuguntla Samhitha , Modi Bosky , Faheem Maida , Reddy Anand 
Published: November 2024

Abstract
Hypercalcemia is a common complication of malignancy, often attributed to elevated PTH-related protein levels mimicking the effects of PTH and promoting bone resorption. We present the case of a 67-year-old Hispanic female with a history of hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic kidney disease, who initially underwent parathyroidectomy for suspected primary hyperparathyroidism resulting from persistent hypercalcemia. Despite surgery, the patient continued to experience hypercalcemia and was subsequently diagnosed with diffuse large B-cell lymphoma with hypercalcemia as a rare but life-threatening complication. This case highlights the importance of considering malignancy as a potential cause of hypercalcemia, particularly in the context of hematologic malignancies such as diffuse large B-cell lymphoma. Prompt recognition and management are crucial to prevent severe complications associated with hypercalcemia. A multidisciplinary approach involving oncologists, endocrinologists, and supportive care teams is essential for effective management in such cases.
Calcitriol-Mediated Hypercalcemia Due to Liver Metastases in a Patient With Primary Pancreatic Neuroendocrine Tumor
Authors: Wolf Katherine I , Crysler Oxana V , Fontana Robert , Saberi Sima 
Published: November 2024

Abstract
Hypercalcemia is most commonly associated with primary hyperparathyroidism or malignancy in the setting of elevated parathyroid hormone-related protein or bone metastases. Calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia is rare and typically associated with granulomatous conditions; however, other solid-organ etiologies have been reported. Here, we detail the case of a 62-year-old man with metastatic pancreatic neuroendocrine tumor (pNET) with hypercalcemia refractory to traditional bisphosphonate therapy in the setting of vastly elevated 1,25-dihydroxyvitamin D. Only after initiation of chemotherapy with capecitabine and temozolomide did his serum calcium consistently improve and 1,25-dihydroxyvitamin D begin to decrease. There are fewer than 5 reported cases of a pNET resulting in calcitriol-mediated hypercalcemia. Prompt initiation of treatment for the underlying condition can result in a significant improvement in serum calcium or 1,25-dihydroxyvitamin D. Multiple reports have also demonstrated success with high-dose steroid administration in patients with other solid-organ etiologies of calcitriol-mediated hypercalcemia, but this has not yet been reviewed in the pNET population.
Pro-Con Debate: Air or Saline for Loss-of-Resistance Technique of Interlaminar Epidural Access with Fluoroscopy-Guided Pain Medicine Procedures
Authors: Hao David , Bonner Kirk , Burnham Taylor , Stojanovic Milan P. 
Published: November 2024

In this Pro-Con commentary article, the Pro side advocates that using the loss of resistance (LOR) to air technique for interlaminar epidural access is safe as the risk of pneumocephalus is exceptionally low. They note that case reports detailing complications typically utilize at least 1 mL of air, frequently exceeding this amount. Even a 1-mL dosage surpasses the requirement, particularly when fluoroscopy is applied in the context of chronic pain management. The proponents also suggest a modified technique, where a syringe containing a drop of saline or contrast acts as a visual cue, minimizing air injection into the epidural space to a negligible quantity. Moreover, they emphasize that air facilitates the identification of any fluid as an indicator of unintended intrathecal access.
The Con perspective argues against the utilization of air for epidural access and advocates for the use of LOR with saline instead. This stance is supported by evidence pointing to a greater occurrence of adverse events, such as postdural puncture headache (PDPH) and pneumocephalus, associated with LOR to air compared to LOR with saline. They also argue that saline’s physical properties enhance tactile feedback, potentially contributing to its increased safety.
Both saline and air have been used for many years for epidural access via the interlaminar approach. Although both are generally accepted in practice, neither has been formally established as the standard of care. It would benefit the medical community to further delineate the pros and cons of each medium, enabling practitioners to make more informed decisions. This Pro-Con debate will provide 2 perspectives (Table) on the evidence and rationales for the use of air or saline for the LOR technique in interlaminar epidural access with fluoroscopy.