bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma
Authors: Khan Sabbir , Martinez-Ledesma Emmanuel , Dong Jianwen , Mahalingam Rajasekaran , Park Soon Young , Piao Yuji , Koul Dimpy , Balasubramaniyan Veerakumar , de Groot John F , Yung W K Alfred 
Published: October 2023

Abstract

Background
Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%–50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma.

Methods
Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation.

Results
Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (β-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%–30% of mice being long-term survivors.

Conclusions
Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.
Discovery of microRNAs in Pyrus stigma exudates opens new research avenues in Horticulture
Authors: Ambastha Vivek , Nevo Yuval , Matityhu Ifat , Honys David , Leshem Yehoram 
Published: October 2023

Abstract
In many plant species, flower stigma secretions are important in early stages of sexual reproduction. Previous chemical analysis and proteomic characterization of these exudates provided insights into their biological function. Nevertheless, the presence of nucleic acids in the stigma exudates has not been previously reported. Here, we studied the stigma exudates of Pyrus communis, Pyrus pyrifolia, and Pyrus syriaca and showed them to harbor extracellular RNAs of various sizes. RNA sequencing revealed, for the first time, the presence of known Rosaceae mature microRNAs (miRs), also abundant in the stigma source tissue. Predicted targets of the exudate miRs in the Arabidopsis thaliana genome include genes involved in various biological processes. Several of these genes are pollen transcribed, suggesting possible involvement of exudate miRs in transcriptional regulation of the pollen. Moreover, extracellular miRs can potentially act across kingdoms and target genes of stigma interacting organisms/microorganisms, thus opening novel applicative avenues in Horticulture.
In vivo transfection of cytokine genes into tumor cells using a synthetic vehicle promotes antitumor immune responses in a visceral tumor model
Authors: Watanabe Shunichi , Takagi Ayaka , Yuba Eiji , Kojima Chie , Dei Nanako , Matsumoto Akikazu , Tanikawa Jun , Kawamura Tetsuya , De Silva Nadeeka H. , Izawa Takeshi , Akazawa Takashi , Kanegi Ryoji , Hatoya Shingo , Inaba Toshio , Sugiura Kikuya 
Published: October 2023

AbstractThe tumor microenvironment (TME) strongly affects the clinical outcomes of immunotherapy. This study aimed to activate the antitumor immune response by manipulating the TME by transfecting genes encoding relevant cytokines into tumor cells using a synthetic vehicle, which is designed to target tumor cells and promote the expression of transfected genes. Lung tumors were formed by injecting CT26.WT intravenously into BALB/c mice. Upon intravenous injection of the green fluorescent protein‐coding plasmid encapsulated in the vehicle, 14.2% tumor‐specific expression was observed. Transfection of the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and CD40 ligand (L)‐plasmid combination and interferon gamma (IFNγ) and CD40L‐plasmid combination showed 45.5% and 54.5% complete remission (CR), respectively, on day 60; alternate treatments with both the plasmid combinations elicited 66.7% CR, while the control animals died within 48 days. Immune status analysis revealed that the density of dendritic cells significantly increased in tumors, particularly after GM‐CSF‐ and CD40L‐gene transfection, while that of regulatory T cells significantly decreased. The proportion of activated killer cells and antitumoral macrophages significantly increased, specifically after IFNγ and CD40L transfection. Furthermore, the level of the immune escape molecule programmed death ligand‐1 decreased in tumors after transfecting these cytokine genes. As a result, tumor cell‐specific transfection of these cytokine genes by the synthetic vehicle significantly promotes antitumor immune responses in the TME, a key aim for visceral tumor therapy.
Color Does Matter
Authors: Carter Brigit M. , Newberry Desi , Leonard Christina 
Published: October 2023

Background:
The observation of color is an integral part of the nursing assessment. However, the current understanding of individual skin qualities and pigmentation has not yet been integrated thoroughly into foundational assessment courses, clinical education, simulation, and textbooks.

Evidence Acquisition:
Literature is scarce regarding racial groups, skin color, and physical assessment for patients across the lifespan, but even more so for the neonatal population. Historically, many nursing textbooks did not provide visual pictures or observational assessment strategies for the assessment of the Black, Indigenous, and people of color (BIPOC) population. This is improving in some nursing textbooks; however, the descriptors of and visual differences and anticipated assessment findings for the BIPOC population are not comprehensive.

Results:
Evidence-based assessment findings, which may occur in newborns with varying skin tones/pigmentations, are presented.

Implications for Practice and Research:
The most essential step to having an accurate assessment is acknowledging the importance of color awareness. Color blindness, while thought to support inclusivity, only contributes to exclusion of one of the most important components of a person's being—their color.
Variables Associated With Resolution and Persistence of Ovarian Cysts
Authors: Lasher Anne , Harris Lauren E. , Solomon Angelica L. , Harbin Laura M. , Raby Lauren , Dietrich Charles S. , Kryscio Richard J. , van Nagell John R. , Pavlik Edward J. 
Published: October 2023

OBJECTIVE:
To estimate surveillance intervals of incident ovarian cysts, and describe variables associated with cyst resolution times.

METHODS:
The UK-OCST (University of Kentucky Ovarian Cancer Screening Trial) was a prospective cohort that enrolled 47,762 individuals over 30 years, including 2,638 individuals with incident cysts. Cyst diameter and structure and patient age, body mass index, use of hormone therapy (HT), family history of ovarian cancer, and menopausal status were examined as variables associated with cyst resolution using t tests, χ2 test, Kaplan Meier, and Cox multiple regression.

RESULTS:
Of 2,638 individuals with incident cysts, 1,667 experienced resolution (63.2%) within 1.2 years, and 971 experienced persistence (36.8%). Within 1 year, unilocular and septated cysts had similar resolution rates (35.4% and 36.7%, respectively, P>.05), but time to resolution was shorter for unilocular cysts compared with septated cysts (mean 1.89 years vs 2.58 years, respectively, P<.001). Both unilocular and septated cysts smaller than 3 cm resolved faster than cysts larger than 6 cm (P<.001). Variables associated with percent resolution included being of younger age, premenopausal status (but not for synchronous bilateral cysts), and those reporting a family history of ovarian cancer (P<.05). Variables associated with a faster cyst resolution rate included being older than age 70 years and not using hormone therapy. Body mass index and family history were not associated with cyst resolution time.

CONCLUSION:
Different surveillance times may be appropriate depending on cyst structure and size and patient age and HT use.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT04473833.
Correlation between Microperimetry and Imaging in Extensive Macular Atrophy with Pseudodrusen-like appearance (EMAP).
Authors: Romano Francesco , Boon Camiel J F , Invernizzi Alessandro , Bosello Francesca , Casati Stefano , Zaffalon Chiara , Riva Ester , Bertoni Alice Ingrid , Agarwal Aniruddha , Kalra Gagan , Cozzi Mariano , Staurenghi Giovanni , Salvetti Anna Paola 
Published: October 2023

ABSTRACT

PURPOSE:
To determine the correlation between microperimetry and imaging findings in extensive macular atrophy with pseudodrusen-like appearance (EMAP).

MTHODS:
This cross-sectional, observational study included 44 consecutive EMAP patients (88 eyes) and 30 healthy subjects (60 eyes). Both groups underwent visual acuity assessment, mesopic and scotopic microperimetry, fundus photography, autofluorescence, optical coherence tomography (OCT) and OCT angiography. Retinal sensitivity (RS) was also subdivided in macular (0-4°) and para-macular areas (8-10°). Scotopic sensitivity loss was defined as the difference between scotopic and mesopic sensitivities for each tested point. Eyes with EMAP were further classified into the 3 stages described by Romano et al: 19 eyes in stage 1, 31 in stage 2, 38 in stage 3.

RESULTS:
Mesopic and scotopic RS were significantly reduced in EMAP patients compared with controls, particularly in the macular area (all p<0.001). Mesopic RS progressively declined in more advanced EMAP stages (all p<0.01), but no scotopic differences were observed between stages 2 and 3 (p=0.08). Remarkably, scotopic sensitivity loss was significantly higher in stage 1 (p<0.05).
On multivariate analysis, mesopic dysfunction was associated with larger atrophic areas (p<0.01), foveal involvement (p=0.03) and fibrosis (p=0.02). Conversely, no independent variable was associated with a reduced scotopic RS (all p>0.05).

CONCLUSIONS:
Our findings highlight that EMAP patients suffer from a severe cone- and rod-mediated dysfunction on microperimetry. The predominant rod impairment in the early cases (stage 1) emphasizes the importance of dark-adapted scotopic microperimetry as clinical endpoint and suggests a defective transportation across the RPE-Bruch’s membrane complex in its pathogenesis.
Genetic testing in the evaluation of recipient candidates and living kidney donors
Authors: Lee Brian K. , Thomas Christie P. 
Published: October 2023

Purpose of review
The aim of this study is to provide an overview of the role of genetic testing in the evaluation of kidney transplant candidates and living donors who may be at risk for heritable kidney disease. We focus our discussion on monogenic diseases, excluding renal diseases that have complex polygenic influences. Adoption of new technologies such as next-generation sequencing (NGS) with comprehensive gene panels has greatly enabled access to genetic testing recently; yet transplant professionals rarely receive adequate training in clinical genetics. In addition to a broad discussion of genetic testing, we hope to illustrate the thought processes and resources used in clinical genetic evaluation of recipient candidates and donors.

Recent findings
Targeted renal genetic panels, whole exome and genome sequencing have greatly expanded our ability to test for pathogenic variants. Testing methods, analytic tools and the subsequent interpretation by the testing laboratory and treating physician impacts patient management and clinicians may lack the resources to practice in this new era of genomic medicine.

Summary
The expansion of genomics into transplant medicine can provide improved diagnosis in transplant candidates and potentially disease prediction in living donors. Transplant professionals need to be familiar with emerging trends, promises and limitations of NGS-based testing.
Correlation of the apparent diffusion coefficient with the standardized uptake value in meningioma of the skull plane using [68]Ga-DOTATOC PET/MRI
Authors: Milosevic Aleksandar , Styczen Hanna , Haubold Johannes , Kessler Lukas , Grueneisen Johannes , Li Yan , Weber Manuel , Fendler Wolfgang P. , Morawitz Janna , Damman Philipp , Wrede Karsten , Kebir Sied , Glas Martin , Guberina Maja , Blau Tobias , Schaarschmidt Benedikt M , Deuschl Cornelius 
Published: October 2023

Purpose
To evaluate a correlation between an MRI-specific marker for cellular density [apparent diffusion coefficient (ADC)] and the expression of Somatostatin Receptors (SSTR) in patients with meningioma of the skull plane and orbital space.

Methods

68Ga-DOTATOC PET/MR imaging was performed in 60 Patients with suspected or diagnosed meningiomas of the skull base and eye socket. Analysis of ADC values succeeded in 32 patients. ADC values (ADCmean and ADCmin) were analyzed using a polygonal region of interest. Tracer-uptake of target lesions was assessed according to corresponding maximal (SUVmax) and mean (SUVmean) values. Correlations between assessed parameters were evaluated using the Pearson correlation coefficient.

Results
One out of 32 patients (3%) was diagnosed with lymphoma by histopathological examination and therefore excluded from further analysis. Median ADCmean amounted to 822 × 10-5 mm²/s-1 (95% CI: 570–1497) and median ADCmin was 493 × 10-5 mm2/s-1 (95% CI: 162–783). There were no significant correlations between SUVmax and ADCmin (r = 0.60; P = 0.76) or ADCmean (r = -0.52; P = 0.79), respectively. However, Pearson’s test showed a weak, inverse but insignificant correlation between ADCmean and SUVmean (r = −0.33; P = 0.07).

Conclusion
The presented data displays no relevant correlations between increased SSTR expression and cellularity in patients with meningioma of the skull base. SSTR-PET and DWI thus may offer complementary information on tumor characteristics of meningioma.
Closing the Fluid Gap: Improving Isotonic Maintenance Intravenous Fluid Use in a Community Hospital Network
Authors: Mittal Shraddha , Knerr Sheila , Prasto Julianne , Hunt Jessica , Mattern Carolyn , Chang Tsae , Marchese Ronald , Jessee Morgan , Marlowe Lauren , Haupt Josh 
Published: October 2023

Introduction:
The American Academy of Pediatrics recommends using isotonic intravenous fluids (IVF) for maintenance needs to decrease the risk of hyponatremia. We conducted a quality improvement project to increase the use of isotonic maintenance IVF in pediatric patients admitted to three sites in a community hospital network to >85% within 12 months.

Methods:
We used improvement methodology to identify causes of continued hypotonic fluid use, which involved provider behavior and systems factors. We implemented interventions to address these factors including: (1) education; (2) clinical decision support; and (3) stocking automated medication dispensing systems with isotonic IVF. We compared isotonic IVF use before and after interventions in all admitted patients aged 28 days to 18 years who received maintenance IVFs at the rate of at least 10 mL/hour. We excluded admissions of patients with active chronic medical conditions like diabetic ketoacidosis. Balancing measures were the occurrence of adverse events from hypo- or hypernatremia. Data were analyzed using Laney P′ statistical process control charts.

Results:
Isotonic IVF use among patients requiring maintenance fluids at all three sites surpassed the goal of >85% within 12 months. There were no reports of hypo- or hypernatremia or other adverse outcomes related to the use of isotonic IVF.

Conclusion:
A combination of interventions aimed at provider behavior and systems factors was critical to successfully adopting the American Academy of Pediatrics guideline regarding the use of maintenance isotonic IVF in hospitalized children.
Stratification of Stage II Colon Cancer Using Recurrence Prediction Value
Authors: Mizuno Shodai , Shigeta Kohei , Kato Yujin , Okui Jun , Morita Satoru , Sonal Swati , Goldstone Robert , Berger David , Al-Masri Rama , Al-Masri Mahmoud , Tajima Yuki , Kikuchi Hiroto , Hirata Akira , Nakadai Jumpei , Baba Hideo , Sugiura Kiyoaki , Hoshino Go , Seo Yuki , Makino Akitsugu , Suzumura Hirofumi , Suzuki Yoshiyuki , Adachi Yoko , Shimada Takehiro , Kondo Takayuki , Matsui Shimpei , Seishima Ryo , Okabayashi Koji , Kitagawa Yuko , Kunitake Hiroko 
Published: October 2023

Objective:
To create a recurrence prediction value (RPV) of high-risk factor and identify the patients with high risk of cancer recurrence.

Background:
There are several high-risk factors known to lead to poor outcomes. Weighting each high-risk factor based on their association with increased risk of cancer recurrence can provide a more precise understanding of risk of recurrence.

Methods:
We performed a multi-institutional international retrospective analysis of patients with stage II colon cancer patients who underwent surgery from 2010 to 2020. Patient data from a multi-institutional database were used as the Training data, and data from a completely separate international database from 2 countries were used as the Validation data. The primary endpoint was recurrence-free survival.

Results:
A total of 739 patients were included from Training data. To validate the feasibility of RPV, 467 patients were included from Validation data. Training data patients were divided into RPV low (n=564) and RPV high (n=175). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low [hazard ratio (HR) 2.628; 95% confidence interval (CI) 1.887–3.660; P<0.001). Validation data patients were divided into 2 groups (RPV low, n=420) and RPV high (n=47). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (HR 3.053; 95% CI 1.962–4.750; P<0.001).

Conclusions:
RPV can identify stage II colon cancer patients with high risk of cancer recurrence worldwide.
Emergency vascular repairs in trauma: Predictors of poor prognosis and a novel scoring system
Authors: Boyev Artem , Sutton Gabrielle , Rosenblad Harris , Eisenberg Michael , Mills Alexander , Miller Charles C. , McNutt Michelle K. 
Published: October 2023

BACKGROUND
Vascular injuries comprise 1% to 4% of all trauma patients, and there are no widely used risk-stratification tools. We sought to establish predictors of revascularization failures and compare outcomes of trauma and vascular surgeons.

METHODS
We performed a single-institution, case-control study of consecutive patients with traumatic arterial injuries who underwent open repair between 2016 and 2021. Multivariable logistic regression was used to investigate covariates impacting the primary composite outcome of repair failure/revision, amputation, or in-hospital mortality.

RESULTS
Among 165 patients, the median age was 34 years, 149 (90%) were male, and 99 (60%) suffered penetrating injury. Popliteal (46%) and superficial femoral (44%) arterial injuries were most common. Interposition graft/bypass was the most frequent repair (n = 107 [65%]). Revascularization failure was observed in 24 patients (15%). Compared with trauma surgeons, vascular surgeons more frequently repaired blunt injuries (66% vs. 20%, p < 0.001), anterior tibial (18% vs. 5%, p = 0.012), or tibioperoneal injuries (28% vs. 4%, p < 0.001), with a below-knee bypass (38% vs. 20%, p = 0.019). Revascularization failure occurred in 10% (9 of 93) of repairs by trauma surgeons and 21% (13 of 61) of repairs by vascular surgeons. Mangled Extremity Severity Score >8 (odds ratio, 15.6; 95% confidence interval, 4.4–55.9; p < 0.001) and concomitant laparotomy or orthopedic procedure (odds ratio, 6.7; 95% confidence interval, 1.6–28.6; p = 0.010) were independently associated with revascularization failure. A novel composite scoring system (UT Houston Score) was developed by combining Mangled Extremity Severity Score, concomitant procedure, mechanism of injury, and injury location. This score demonstrated a sensitivity of 100% with a score of 0 and a specificity of 95% with a score of >3.

CONCLUSION
After traumatic arterial injury, trauma surgeons repaired less-complex injuries but with fewer revascularization failures than vascular surgeons. The UT Houston Score may be used to risk stratify patients to determine who may benefit from vascular surgery consultation.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Independent Inheritance of Cognition and Bipolar Disorder in a Family Sample
Authors: D’Amico Alexander , Sung Heejong , Arbona-Lampaya Alejandro , Freifeld Ally , Hosey Katie , Garcia Joshua , Lacbawan Ley , Besançon Emily , Kassem Layla , Akula Nirmala , Knowles Emma E. M. , Dickinson Dwight , McMahon Francis J. 
Published: October 2023

AbstractBackgroundThe basis of cognitive deficits in people with bipolar disorder (BD) has not been elucidated. These deficits may be the result of the illness or its treatment, but could also reflect genetic risk factors that are shared between BD and cognition. We investigated this question using empirical genetic relationships within a sample of patients with BD and their unaffected relatives.MethodsParticipants with bipolar I, II, or schizoaffective disorder (“narrow” BD, n=69), related mood disorders (“broad” BD, n=135), and their clinically unaffected relatives (n=227) completed tests of matrix reasoning, trail making, digit-symbol coding, semantic short-term recall, and affect recognition (DANVA2). General cognitive function (g) was quantified via principal components analysis (PCA). Heritability and genetic correlations were estimated with SOLAR-Eclipse.ResultsParticipants with a “narrow” or “broad” BD diagnosis showed deficits in g, though affect recognition was not impaired. Cognitive performance was significantly heritable (h2= 0.322 for g, p<0.005). Coheritability between BD and cognition was small (coheritability for g & Narrow = 0.0184, for g & Broad = 0.0327) and healthy relatives of those with BD were cognitively unimpaired.ConclusionsIn this family sample, cognitive deficits were present in participants with BD, but social cognition, measured by affect recognition, was not impaired. Deficits were largely not explained by overlapping genetic determinants of mood and cognition. These findings support the view that cognition comprises separable social and non-social domains and that cognitive deficits in BD are largely the result of the illness or its treatment.