bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting WNT/β-Catenin via Modulating EZH2 Function: A New Chapter in the Treatment of β-Catenin Mutant Hepatocellular Carcinoma?
Authors: Hung Man Hsin , Wang Xin Wei
Published: September 2023

In a recent study, Rialdi and colleagues identified a specific vulnerability in β-catenin mutant hepatocellular carcinoma (HCC) via EZH2-mediated suppression of WNT signaling and revealed the selective anti-HCC activity of WNTinib, a chemical derivative of regorafenib and sorafenib in targeting this vulnerability. Their discoveries highlight the role of EZH2 in modulating WNT signaling and suggest an implication of WNTinihb as a small-molecule inhibitor for the treatment of HCC with activated WNT/β-catenin.
Clinico-Genomic Profiling of Conventional and Dedifferentiated Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse Outcomes
Authors: Denu Ryan A. , Yang Richard K. , Lazar Alexander J. , Patel Shalin S. , Lewis Valerae O. , Roszik Jason , Livingston J. Andrew , Wang Wei-Lien , Shaw Kenna R. , Ratan Ravin , Zarzour Maria A. , Bird Justin , Raza Shaan , Akdemir Kadir C. , Rodon Ahnert Jordi , Subbiah Vivek , Patel Shreyaskumar , Conley Anthony P.
Published: September 2023

Purpose:

Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes.

Experimental Design:

We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas.

Results:

IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1–3 conventional chondrosarcoma. There was no difference in survival based on IDH mutation in univariate and multivariate analyses. TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses. TP53 mutation was also associated with higher risk of recurrence following curative-intent surgery and worse survival among patients that presented with de novo metastatic disease.

Conclusions:

IDH mutations are prevalent in chondrosarcoma though were not associated with survival outcomes in this cohort. TP53 mutations were the next most common alteration and were associated with worse outcomes.
A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor Regression in Preclinical Mesothelioma Models
Authors: Hillen Hanne , Candi Aurélie , Vanderhoydonck Bart , Kowalczyk Weronika , Sansores-Garcia Leticia , Kesikiadou Elena C. , Van Huffel Leen , Spiessens Lore , Nijs Marnik , Soons Erik , Haeck Wanda , Klaassen Hugo , Smets Wim , Spieser Stéphane A. , Marchand Arnaud , Chaltin Patrick , Ciesielski Fabrice , Debaene Francois , Chen Lei , Kamal Adeela , Gwaltney Stephen L. , Versele Matthias , Halder Georg A.
Published: September 2023

The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1–4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.
Supplementary Materials and Methods from HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer
Authors: Olson Devra , Taylor Janelle , Willis Kelsi , Hensley Kelly , Allred Sean , Zaval Margo , Farr Lauren , Thurman Robert , Jain Nishi , Hein Renee , Ulrich Michelle , Peterson Scott , Kulukian Anita
Published: September 2023

Supplementary Methods
Figure S3 from HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer
Authors: Olson Devra , Taylor Janelle , Willis Kelsi , Hensley Kelly , Allred Sean , Zaval Margo , Farr Lauren , Thurman Robert , Jain Nishi , Hein Renee , Ulrich Michelle , Peterson Scott , Kulukian Anita
Published: September 2023

HER2 in tucatinib-treated cells is targeted to the lysosome after a period of delay
Figure S1 from HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer
Authors: Olson Devra , Taylor Janelle , Willis Kelsi , Hensley Kelly , Allred Sean , Zaval Margo , Farr Lauren , Thurman Robert , Jain Nishi , Hein Renee , Ulrich Michelle , Peterson Scott , Kulukian Anita
Published: September 2023

Isobologram analysis of tucatinib with non-targeting IgG1-DM1 shows reduced synergy compared to T-DM1.
FIGURE 6 from HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer
Authors: Olson Devra , Taylor Janelle , Willis Kelsi , Hensley Kelly , Allred Sean , Zaval Margo , Farr Lauren , Thurman Robert , Jain Nishi , Hein Renee , Ulrich Michelle , Peterson Scott , Kulukian Anita
Published: September 2023

The combined suppression of HER2 signaling by tucatinib and T-DM1 is associated with reduced tumor growth. A, ELISAs quantifying phosphorylation of signaling components downstream of HER2 in BT-474 cells (as percentage phosphorylated protein vs. untreated cells with SEMs). B, IHC images of pHER2, pHER3, pAKT, and pMEK staining of the BT-474 xenograft tumor model. Inlay images represent HER2-stained tumor boundaries. C, HALO-based quantification of histologic analysis of HER2 and phospho-epitopes downstream of HER2 in the BT-474 tumor model. IHC images (D) and HALO-based quantification (E) of proliferation marker Ki67 in the BT-474 tumor model (7 days after dosing, 1–2 hours after final dose). Inlay images represent HER2-stained tumor boundaries. F, HALO-based quantification of histologic analysis of caspase-3 in the BT-474 tumor model. Results are representative of at least 2 independent experiments.
FIGURE 4 from HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer
Authors: Olson Devra , Taylor Janelle , Willis Kelsi , Hensley Kelly , Allred Sean , Zaval Margo , Farr Lauren , Thurman Robert , Jain Nishi , Hein Renee , Ulrich Michelle , Peterson Scott , Kulukian Anita
Published: September 2023

Tucatinib mediates increased internalization and catabolism of T-DM1. A, Schematic of constant exposure internalization assays with Fabfluor-labeled trastuzumab. B, Fluorescence intensity of SK-BR-3 cells in internalization assays imaged over time. C, AUC of fluorescence intensity in internalization assays calculated at 35 hours. Results in panels B and C are representative of at least 2 independent experiments. D, Schematic of T-DM1 catabolism analysis. E, LC/MS-MS analysis of the predominant intracellular catabolite of T-DM1, Lys-MCC-DM1, in BT-474 cells after treatment in the presence or absence of either tucatinib or neratinib. F, LC/MS-MS analysis of the sum of all T-DM1 catabolites, both in intracellular and extracellular fractions. Data in panels E and F shown as mean ± SEM. AUC, area under the curve.
FIGURE 3 from HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer
Authors: Olson Devra , Taylor Janelle , Willis Kelsi , Hensley Kelly , Allred Sean , Zaval Margo , Farr Lauren , Thurman Robert , Jain Nishi , Hein Renee , Ulrich Michelle , Peterson Scott , Kulukian Anita
Published: September 2023

Tucatinib alters the internalization dynamics of HER2-targeted antibodies. A, Schematic of pulsed internalization assay with AF488 fluorescently-labeled trastuzumab. B, Images of SK-BR-3 cells in pulsed internalization assays incubated with AF488 fluorescently-labeled trastuzumab and/or treated with tucatinib or neratinib. Inlay images show counterstaining (Hoechst) to signify distribution of cells. C, Magnified images of tucatinib-treated cells in internalization assays, counterstained with lysosomal marker LAMP1. Chloroquine, which inhibits lysosomal function (49), was added to show more intense colocalization when lysosomal degradation is impaired. These results are representative of at least 2 independent experiments.
Bivalirudin Versus Heparin During PCI in NSTEMI: Individual Patient Data Meta-Analysis of Large Randomized Trials
Authors: Bikdeli Behnood , Erlinge David , Valgimigli Marco , Kastrati Adnan , Han Yaling , Steg Philippe Gabriel , Stables Rod H. , Mehran Roxana , James Stefan K. , Frigoli Enrico , Goldstein Patrick , Li Yi , Shahzad Adeel , Schüpke Stefanie , Mehdipoor Ghazaleh , Chen Shmuel , Redfors Björn , Crowley Aaron , Zhou Zhipeng , Stone Gregg W.
Published: September 2023

BACKGROUND:

The benefit:risk profile of bivalirudin versus heparin anticoagulation in patients with non–ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) is uncertain. Study-level meta-analyses lack granularity to provide conclusive answers. We sought to compare the outcomes of bivalirudin and heparin in patients with non–ST-segment–elevation myocardial infarction undergoing PCI.

METHODS:

We performed an individual patient data meta-analysis of patients with non–ST-segment–elevation myocardial infarction in all 5 trials that randomized ≥1000 patients with any myocardial infarction undergoing PCI to bivalirudin versus heparin (MATRIX [Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox], VALIDATE-SWEDEHEART [Bivalirudin Versus Heparin in ST-Segment and Non–ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies Registry Trial], ISAR-REACT 4 [Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4], ACUITY [Acute Catheterization and Urgent Intervention Triage Strategy], and BRIGHT [Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin Trial]). The primary effectiveness and safety end points were 30-day all-cause mortality and serious bleeding.

RESULTS:

A total of 12 155 patients were randomized: 6040 to bivalirudin (52.3% with a post-PCI bivalirudin infusion), and 6115 to heparin (53.2% with planned glycoprotein IIb/IIIa inhibitor use). Thirty-day mortality was not significantly different between bivalirudin and heparin (1.2% versus 1.1%; adjusted odds ratio, 1.24 [95% CI, 0.86–1.79];
P
=0.25). Cardiac mortality, reinfarction, and stent thrombosis rates were also not significantly different. Bivalirudin reduced serious bleeding (both access site–related and non—access site–related) compared with heparin (3.3% versus 5.5%; adjusted odds ratio, 0.59; 95% CI, 0.48–0.72;
P
<0.0001). Outcomes were consistent regardless of use of a post-PCI bivalirudin infusion or routine lycoprotein IIb/IIIa inhibitor use with heparin and during 1-year follow-up.

CONCLUSIONS:

In patients with non–ST-segment–elevation myocardial infarction undergoing PCI, procedural anticoagulation with bivalirudin and heparin did not result in significantly different rates of mortality or ischemic events, including stent thrombosis and reinfarction. Bivalirudin reduced serious bleeding compared with heparin arising both from the access site and nonaccess sites.
A new combination in Mucuna (Leguminosae-Phaseoleae) of Florae Fluminensis
Authors: MENEZES HELEN F. DE , PASTORE JOSÉ FLORIANO B.
Published: September 2023

The name Dolichos pungens, described in Vellozo’s Florae Fluminensis, is here revised and transferred to the genus Mucuna, as M. pungens. Expeditions were conducted to the probable original locality of Dolichos pungens in Paraty, a municipality in the state of Rio de Janeiro, Brazil, accompanied by the revision of herbarium specimens. A comprehensively species description, distribution map, and taxonomic notes are provided. A lectotype has been designated for Dolichos pungens.
Dothiorella saprophytica sp. nov.: a new Dothiorella sexual morph from Thailand
Authors: FARIAS ANTONIO ROBERTO GOMES DE , LOUANGPHAN JOHNNY , AFSHARI NAGHMEH
Published: September 2023

Dothiorella has cosmopolitan species and a wide range of hosts as endophytes, saprobes, and pathogens. Many species have been introduced solely based on their host association, resulting in misidentification. This study describes a novel species, Dothiorella saprophytica sp. nov., a sexual morph of Dothiorella, from Chiang Mai, Thailand using multi-locus phylogeny (ITS + tef1-α + β-tub) and morphological characters. Detailed morphology and multi-locus phylogeny are provided to give more insights into the diversity and taxonomy of this genus. Dothiorella saprophytica is characterized by its sexual morph with pseudothecial and immersed ascomata, peridium textura angularis, hyaline, thin-walled, unbranched, and septate pseudoparaphyses, clavate and bitunicate asci, and ovoid to sub-clavate, 0–1-septate ascospores. Introducing new fungal species, such as D. saprophytica sp. nov., adds to our understanding of biodiversity and the ecology of fungi and provides opportunities for further research.
The Nearctic species of Asindulum Latreille and Macrorrhyncha Winnertz (Diptera: Keroplatidae)
Authors: FITZGERALD SCOTT J.
Published: September 2023

The genera Asindulum Latreille and Macrorrhyncha Winnertz are revised for the Nearctic Region with six species recognized, four in Asindulum and two in Macrorrhyncha: Asindulum coxale Loew generic combination reinstated, A. flavidum n. sp., A. mexicanum n. sp., A. montanum Röder, Macrorrhyncha borealis n. sp., and M. vockerothi n. sp. Asindulum tenuipes Walker should be excluded from future keroplatid works as it belongs to the family Blephariceridae and previous Nearctic records of the Palearctic species Macrorrhyncha flava Winnertz are discussed and concluded to be based on misidentifications. Nearctic taxa are imaged and a key to the species of Asindulum and the Nearctic species of Macrorrhyncha is provided. The two Palearctic species of Asindulum, A. nigrum Latreille and A. theodori Matile, are briefly addressed in the text and the male terminalia of the first species imaged to allow for comparison with the very similar Nearctic species A. coxale.
A new species of Eucalantica Busck (Lepidoptera, Yponomeutidae) poses potential concerns on blueberry industry in Mexico
Authors: RUIZ-GALVAN ISABEL , SOHN JAE-CHEON
Published: September 2023

A new species of Eucalantica, E. nestori n. sp. is reported on the basis of 13 type specimens collected from blueberry farms in Atzingo and Xoxonacatla, Puebla, Mexico. Habitus and genital features of the species are described and illustrated. Larval feeding habit of E. nestori n. sp. is demonstrated from field observations. Damage of the larvae was observed from the leaves, flowers and shoots of blueberries. Agricultural concerns involving E. nestori n. sp. are discussed.
Examining the Spatial Proximity of Vulnerable Communities to Cooling Centers across the Texas Triangle Megaregion
Authors: Dumlao Angelina , Debbage Neil
Published: September 2023

A cool environment is critical for protecting vulnerable populations from the adverse health effects associated with exposure to extreme heat. Although cooling centers are commonly established to provide temporary heat relief to the public, there is limited research exploring the spatial distributions and accessibility of cooling centers across cities in Texas. The intent of this study was to examine the spatial characteristics of cooling center locations throughout the Texas Triangle megaregion and evaluate the proximity of cooling centers to vulnerable populations. Specifically, spatial clustering analysis was used to quantitatively characterize the spatial distributions of cooling centers in San Antonio, Houston, and Dallas, while spatial lag regression was conducted to evaluate the relationships between indicators of socioeconomic vulnerability and proximity to cooling centers. The findings indicated that cooling centers exhibited clustering at short distances, which suggested there were potential spatial redundancies. The distributions of the cooling centers also illustrated possible accessibility issues due to the concentration of the locations in urban cores. The spatial lag regression models highlighted several problematic relationships, as elderly and disabled populations were located at significantly greater distances from cooling centers in San Antonio and Dallas, respectively. However, numerous insignificant relationships were also observed, which suggested that cooling center locations did not consistently marginalize or favor vulnerable populations. Therefore, a higher degree of intentionality that explicitly considers cooling center proximity to the vulnerable populations they aim to serve might be beneficial as planners and emergency managers determine cooling center locations in response to extreme heat.
On problems and technology innovation implementation in micro, small and medium enterprises: An evidence from Indian Northern region using situation-actor-process-learning-action-performance framework
Authors: Singh Davinder
Published: September 2023

The paper aims to identify problems and technology innovation initiatives among micro, small and medium enterprises that effect their performance. The purpose of this paper is to assess the status of problems faced by micro, small and medium enterprises and study the technology innovation implementation (technology innovation initiative) dimensions through case studies conducted in selected manufacturing firms in the Northern region in India. This study proposes a two-stage approach. In the first stage, the author gathered responses with a well-structured questionnaire on problems and technology innovation initiatives affecting manufacturing performance using exploratory and confirmatory factor analyses. In the next stage, the validation of stage 1 findings was carried out to authenticate the proposition that technology innovation initiatives affect performance through case studies conducted in selected manufacturing firms situated in the Northern region of the country. For conducting case studies, the widely used flexible systems methodology, strengths, weaknesses, opportunities and threats and situation-actor-process-learning-action-performance analysis have been employed in the present study. The results from the study can act as an important guide for entrepreneur, practitioners and academicians. The results of the study show that effective implementation of technology innovation initiatives can contribute to enhance manufacturing performance of micro, small and medium enterprises in India. The research presents a better understanding of the problems that are hindering the successful implementation of technology innovation in micro, small and medium enterprises. Further, the two case studies provide valuable insights into technology innovation dimensions in two firms and highlight the methodology to be adopted by the companies towards their manufacturing performance enhancement. This study reveals the problems and technology innovation dimensions of micro, small and medium enterprises, their status and the impact of technology innovation initiatives on manufacturing performance of micro, small and medium enterprises. This, in turn, helps the stakeholder to comprehend the concept of technology innovation in a much simpler way.
Exploring the Drivers of Child Maltreatment Under- and Overreporting: A Qualitative Study
Authors: Perrigo Judith L. , Palmer Molina Abigail , Hurlburt Michael S. , Finno-Velasquez Megan
Published: September 2023

Child abuse and neglect (CAN) is a complex issue that is subject to both under- and overreporting; yet, research into the underlying neighborhood-level drivers of these practices remains limited. The current study gathered perspectives from 30 child protective service (CPS) workers and agency leaders in Southern California neighborhoods to identify perceptions of social and contextual neighborhood factors that might influence over- and underreporting of CAN. The data were analyzed using a grounded theory approach, which revealed five themes: (a) neighborhood conflict, (b) neighborhood fear and mistrust, (c) neighborhood norms, (d) poor CAN reporting knowledge, and (e) mandated reporters’ discretion. These themes highlight the potential impact of neighborhood contexts and social dynamics on CAN reporting practices, emphasizing the need for prevention and early intervention neighborhood-level initiatives that improve CPS relationships within their local community.
Histopathologic diagnosis and patient characteristics in cats with small intestinal obstructions secondary to trichobezoars
Authors: Pawenski Michael , Smola Christopher C , Dionne Trysta , Larson Melinda
Published: September 2023

Objectives

The aim of the present study was to describe the distribution of gastrointestinal histopathology findings associated with gastrointestinal obstructions secondary to trichobezoar formation in cats.

Methods

A total of 100 surgical gastrointestinal biopsies were obtained from 44 cats with gastrointestinal obstructions secondary to a trichobezoar. Medical records, including signalment, type and duration of clinical signs, surgical reports and histopathologic analysis, were reviewed for each cat.

Results

Biopsies taken near the site of the trichobezoar were more likely to show neutrophilic inflammation and mucosal erosion/ulceration compared with biopsies taken elsewhere in the small intestine. Lymphoplasmacytic and mixed lymphocytic and eosinophilic populations were the most common histopathologic findings from all biopsies followed by alimentary small cell lymphoma. Biopsy samples were more likely to represent a diagnosis of alimentary lymphoma in cats older than 10 years.

Conclusions and relevance

Gastrointestinal biopsies taken at the time of surgery in cats with trichobezoar obstructions may represent an important diagnostic tool for further evaluation of potential feline chronic enteropathy. Biopsies taken at the site of the obstruction should be interpreted cautiously as the presence of a trichobezoar may induce an acute inflammatory reaction. The resultant histologic interpretation at this site may not represent the chronic state of the intestinal mucosa, supporting the utility of obtaining multiple biopsies orad and aborad to the obstruction.
Transnationalization of Educational Aspirations: Evidence from China
Authors: Nuhoglu Soysal Yasemin , Cebolla Boado Héctor
Published: September 2023

The international migration of students has garnered a lot of attention from researchers due to its growing popularity and significance. However, the current state of research in this field is limited. On one hand, there is a scarcity of high-quality, large-scale data, and existing studies primarily focus on students who are already abroad. On the other hand, the field predominantly revolves around Bourdieusian-inspired arguments that narrowly view international education as a strategic investment by parents and a means of perpetuating social advantage. This article addresses these limitations by utilizing nationally representative survey data from China, the largest single source of international students globally. Our findings challenge the existing literature by revealing that parental aspirations to send their children abroad are more widespread across diverse social backgrounds than previously suggested. Furthermore, we observe that exposure to transnational environments amplifies aspirations for international education across various parental backgrounds and mitigates differences in aspirations based on parental education levels. We argue that these empirical patterns reflect the global standardization and diffusion of models and ideals of self, of which international education has increasingly become a part within the context of the transnationalization of higher education itself.
The Art of Persuasion: A Sociocultural and Literary Comparison of Two Speeches of Reuben and Judah in Genesis, with Suggestions for Translating for Africans
Authors: Nyirenda Misheck
Published: September 2023

Two speeches in the book of Genesis, one by Reuben and the other by Judah, are made to secure the release of Benjamin from their father Jacob in Canaan. The first speech fails while the second succeeds. The aim of this article is to identify the sociocultural and literary reasons behind these outcomes. It also aims to suggest ways of translating these texts into African languages and for African audiences that do justice to the realities in the texts. Careful analysis of the words and rhetorical features of the speeches is conducted in the light of other narratives of Jacob, his wives, concubines, and offspring in the Hebrew Bible. This analysis informs the conclusions of the paper: Judah succeeded where Reuben had failed because of his personal standing in the clan and because of his precise use of facts and the persuasive power of his speeches.
Clearing and replacing tissue-resident myeloid cells with an anti-CD45 antibody–drug conjugate
Authors: Gustafsson Karin , Rhee Catherine , Frodermann Vanessa , Scadden Elizabeth W. , Li Dan , Iwamoto Yoshiko , Palchaudhuri Rahul , Hyzy Sharon L. , Boitano Anthony E. , Nahrendorf Matthias , Scadden David T.
Published: September 2023

Tissue-resident myeloid (TRM) cells in adults have highly variable lifespans, and may be derived from early embryonic yolk sac, fetal liver, or bone marrow. Some of these TRM cells are known pathogenic participants in congenital and acquired diseases. Myeloablative conditioning and hematopoietic stem cell transplantation can replace long-lived brain TRM cells, resulting in clinical improvements in metabolic storage diseases. With the advent of antibody–drug conjugate (ADC)-targeted cell killing as a cell-selective means of transplant conditioning, we assessed the impact of anti-CD45–ADC on TRM cells in multiple tissues. Replacement of TRM cells ranged from 40% to 95% efficiencies in liver, lung, and skin tissues, after a single anti-CD45–ADC dose and bone marrow hematopoietic cell transfer. Of note, the population size of TRM cells in tissues returned to pretreatment levels, suggesting a regulated control of TRM cell abundance. As expected, brain microglia were not affected, but brain monocytes and macrophages were 50% replaced. Anti-CD45–ADC and adoptive cell transfer were then tested in the chronic acquired condition, atherosclerosis exacerbated by Tet2 mutant clonal hematopoiesis. Plaque-resident myeloid cells were efficiently replaced with anti-CD45–ADC and wild-type bone marrow cells. Notably, this reduced existent atherosclerotic plaque burden. Overall, these results indicate that the anti-CD45–ADC clears both hematopoietic stem and TRM cells from their niches, enabling cell replacement to achieve disease modification in a resident myeloid cell–driven disease.
Improved production of andrimid in Erwinia persicina BST187 strain by fermentation optimization
Authors: Cheng Tingfeng , Ge Tongling , Zhao Lunqiang , Hou Yuyong , Xia Jianye , Zhao Lei
Published: September 2023

Background

Andrimid is reported to be a novel kind of polyketide-nonribosomal peptide hybrid product (PK-NRPs) that inhibits fatty acid biosynthesis in bacteria. Considering its great potential in biomedicine and biofarming, intensive studies have been conducted to increase the production of andrimid to overcome the excessive costs of chemosynthesis. In screening for species with broad-spectrum antibacterial activity, we detected andrimid in the fermentation products of Erwinia persicina BST187. To increase andrimid production, the BST187 fermentation medium formulation and fermentation conditions were optimized by using systematic design of experiments (One-Factor-At-A-Time, Plackett–Burman design, Response Surface Methodology).

Results

The results indicate that the actual andrimid production reached 140.3 ± 1.28 mg/L under the optimized conditions (trisodium citrate dihydrate-30 g/L, beef extract-17.1 g/L, MgCl2·6H2O-100 mM, inoculation amount-1%, initial pH-7.0, fermentation time-36 h, temperature-19.7℃), which is 20-fold greater than the initial condition without optimization (7.00 ± 0.40 mg/L), consistent with the improved antibacterial effect of the fermentation supernatant.

Conclusions

The present study provides valuable information for improving andrimid production via optimization of the fermentation process, which will be of great value in the future industrialization of andrimid production.
Dietary behaviour change intervention for managing sarcopenic obesity among community-dwelling older people: a pilot randomised controlled trial
Authors: Yin Yue-Heng , Liu Justina Yat Wa , Välimäki Maritta
Published: September 2023

Background

The effects of dietary intervention in managing sarcopenic obesity are controversial, and behavior change techniques are lacking in previous studies which are important for the success of dietary intervention. This study aimed to evaluate the feasibility and preliminary effects of a dietary behaviour change (DBC) intervention on managing sarcopenic obesity among community-dwelling older people in the community.

Methods

A two-armed, RCT was conducted. Sixty community-dwelling older adults (≥ 60 years old) with sarcopenic obesity were randomised into either the experimental group (n = 30), receiving a 15-week dietary intervention combined with behaviour change techniques guided by the Health Action Process Approach model, or the control group (n = 30), receiving regular health talks. Individual semi-structured interviews were conducted with 21 experimental group participants to determine the barriers and facilitators of dietary behaviour changes after the intervention.

Results

The feasibility of the DBC intervention was confirmed by an acceptable recruitment rate (57.14%) and a good retention rate (83.33%). Compared with the control group, the experimental group significantly reduced their body weight (p = 0.027, d = 1.22) and improved their dietary quality (p < 0.001, d = 1.31). A positive improvement in handgrip strength (from 15.37 ± 1.08 kg to 18.21 ± 1.68 kg), waist circumference (from 99.28 ± 1.32 cm to 98.42 ± 1.39 cm), and gait speed (from 0.91 ± 0.02 m/s to 0.99 ± 0.03 m/s) was observed only in the experimental group. However, the skeletal muscle mass index in the experimental group decreased. The interview indicated that behaviour change techniques enhanced the partcipants’ compliance with their dietary regimen, while cultural contextual factors (e.g., family dining style) led to some barriers.

Conclusion

The DBC intervention could reduce body weight, and has positive trends in managing handgrip strength, gait speed, and waist circumference. Interestingly, the subtle difference between the two groups in the change of muscle mass index warrants futures investigation. This study demonstrated the potential for employing dietary behaviour change interventions in community healthcare.

Trial registration

Registered retrospectively on ClinicalTrailas.gov (31/12/2020, NCT04690985).
Randomized, open-label phase II study of brigatinib and carboplatin plus pemetrexed and brigatinib alone for chemotherapy-naive patients with ALK-rearranged non-squamous non-small cell lung cancer: treatment rationale and protocol design of the B-DASH study (WJOG 14720 L)
Authors: Wakuda Kazushige , Kenmotsu Hirotsugu , Sato Yuki , Nakamura Atsushi , Akamatsu Hiroaki , Tachihara Motoko , Miura Satoru , Yokoyama Toshihide , Mori Keita , Nakagawa Kazuhiko , Yamamoto Nobuyuki
Published: September 2023

Background

The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L).

Methods

B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing.

Discussion

The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC.

Trial registration

jRCT identifier: jRCTs041210103.
Dietary branched-chain amino acids intake, glycemic markers, metabolic profile, and anthropometric features in a community-based sample of overweight and obese adults
Authors: Soleimani Ensiye , Rashnoo Fariborz , Farhangi Mahdieh Abbasalizad , Hosseini Babak , Jafarzadeh Faria , Shakarami Amir , Sadabadi Yoones
Published: September 2023

Background

Existing research provides conflicting evidence regarding the relationship between estimated branched-chain amino acid (BCAA) intake and metabolic, glycemic markers, and anthropometric characteristics. This research seeks to examine the association between estimated dietary BCAA consumption and glycemic, and metabolic markers, as well as anthropometric parameters in adults classified as overweight or obese.

Methods

In this cross-sectional analysis, we gathered data from 465 overweight and obese individuals aged between 18 and 37 years. To evaluate dietary data, we employed the food frequency questionnaire, and the BCAA content in foods was determined via the United States Department of Agriculture website. We utilized ELISA kits to measure fasting blood glucose (FBS) and lipid profile markers, and additionally calculated low-density lipoprotein (LDL) and insulin sensitivity markers. We assessed sociodemographic status, physical activity (PA), and anthropometric attributes through a method recognized as both valid and reliable. For statistical analysis, we conducted analyses of covariance (ANCOVA), making adjustments for variables including sex, PA, age, energy, and body mass index (BMI).

Results

Upon adjusting for confounders, those in the highest tertiles of BCAA intake exhibited an increase in weight, BMI, waist circumference (WC), waist-to-hip ratio (WHR), and fat-free mass (FFM). Conversely, they demonstrated reduced fat mass (FM) (%) and FM (kg) compared to their counterparts in the lowest tertiles (P < 0.05). Additionally, there was a noted association between greater estimated BCAA intake and reduced LDL levels. Nonetheless, our findings did not reveal a significant relationship between dietary BCAA and glycemic indices.

Conclusions

From our findings, an increased estimated intake of BCAA seems to correlate with diminished serum LDL concentrations. To gain a more comprehensive understanding of this association, it is imperative that further experimental and longitudinal studies be conducted.
Non-alcoholic fatty liver disease and compromised endothelial function in people with type 2 diabetes
Authors: Montazeri Zeinab , Hashemi-Madani Nahid , Iraji Hamed , Sohrabi Masoudreza , Alaei-Shahmiri Fariba , Emami Zahra , Babaei Mohammad Reza , Malek Mojtaba , Khamseh Mohammad E.
Published: September 2023

Introduction

Nonalcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM) and synergistically contributes to the development of atherosclerosis. Flow-mediated dilation (FMD) is a commonly used noninvasive test for assessing endothelial function. The main objective of this study was to explore FMD in patients with T2DM with and without NAFLD.

Methods

In this cross-sectional study, conducted on people with T2DM, NAFLD was defined as controlled attenuation parameter (CAP) score > 302 dB/m. Endothelial dysfunction was detected when arterial FMD of brachial artery was equal or less than 0.7%. Regression analyses were applied to assess factors associated with impaired FMD.

Result

A total of 147 patients (72 with NAFLD and 75 without NAFLD) were included in the final analysis. Patients with NAFLD were more likely to develop FMD ≤ 7% (77.8% vs. 58.7%, P = 0.01). In multivariate analysis, NAFLD (OR = 2.581, 95% CI (1.18–5.62), P = 0.017) and hypertension (HTN) (OR = 3.114, 95% CI (1.31–7.35), P = 0.010) were associated with an increased risk of impaired FMD. However, female sex was associated with a decreased risk of impaired FMD (OR = 0.371, 95% CI (0.15–0.87), P = 0.024).

Conclusion

NAFLD is associated with endothelial dysfunction in people with T2DM. This risk is comparable with the risk imposed by HTN, highlighting the importance of screening and management of NAFLD in these patients.
Long-acting family planning switching and associated factors among revisit women in Toke Kutaye district of West Shoa Zone, Oromia Region public health facilities, Ethiopia: a mixed methods study
Authors: Teshoma Fayera , Tefera Eden Girmaye , Girma Teka , Ragasa Misganu Teshoma , Yohannes Ephrem , Bulto Gizachew Abdissa , Wakgari Negash
Published: September 2023

Background

Switching from a long-acting family planning (LAFP) method to another could lead to an unintended pregnancy. However, the proportions of LAFP method switching and predictable factors are not well addressed. Therefore, the aim of this study was to determine the magnitude of LAFP method switching and associated factors among revisit women. The study also explored the reasons for the LAFP method switching among the revisited women.

Method

A mixed methods study was conducted among 377 reproductive age women attending public health facilities in Toke Kutaye district, West Shoa, Zone, Ethiopia, from 20 May 2021 to 28 July 2021. A systematic random sampling for quantitative and purposive sampling technique for qualitative study was used to select the study participants. A pretested structured questionnaire and in-depth interview were used to determine and explore long-acting family planning switching among revisit women. Data were analysed by Statistical Package for the Social Sciences (SPSS) version 21. Binary logistic regression was conducted to identify the dependent and independent variables at p-value < 0.05 along with 95% Confidence Interval (CI) and Adjusted Odds Ratio (AOR). The qualitative data were analysed using thematic analysis.

Results

The magnitude of long-acting family planning method switching was 53.3%. Switching from an implant to other short-acting method was 39.8%, and switching from an intrauterine contraceptive device (IUCD) to other short-acting method was 13.5%. A formal education (AOR, 10.38, 95% CI: 3.48, 30.95), birth spacing (AOR, 5.52, 95% CI: 1.31, 23.33) and perceived infertility (AOR, 11.16, 95% CI: 5.55, 22.45) were factors associated with LAFP switching. The qualitative findings revealed that fear of side effects, lack of adequate information, religion, and misconceptions hinder users from maintaining the LAFP.

Conclusions

The study finds that the proportion of women switching from long-acting family planning was relatively higher than in other studies. The main reasons for LAFP switching were fear of side effects, lack of adequate information specific to LAFP and misconceptions. Therefore, the provision of quality contraceptive counselling by the service providers may mitigate the concern of IUD and implant switching. Furthermore, future prospective research at a larger sample size is needed.
Documentation practice and associated factors among nurses working in public hospitals in Wolaita Zone, Southern Ethiopia
Authors: Bolado Getachew Nigussie , Ayalew Tadele Lankrew , Feleke Mulualem Gete , Haile Kirubel Eshetu , Geta Temesgen
Published: September 2023

Background

Nursing documentation documents the everyday activities of nursing care that are planned and implemented on individual patients by nurses of different educational statuses. Documentation of nursing activities is the key source of clinical information to meet professional and legal requirements. Although nursing documentation is an important part of nursing practice, it is commonly undone by nurses working with patients for different reasons.

Objective

To assess the documentation practice and their associated factors among nurses working in public hospitals in the Wolaita Zone, Southern Ethiopia.

Methods

An institutional-based cross-sectional study was conducted among 402 nurses and a simple random sampling technique was used to select participants. Data were collected using a pretested structured self-administered questionnaire adapted from previous studies. Statistical Package for the Social Science version 26 was used for data entry and analysis. Independent variables with p-value < 0.25 from bivariable logistic regression were entered into the multivariable logistic regression method and significant associations were obtained at an adjusted odds ratio with a 95% confidence interval and p-value < 0.05.

Results

In this study, the good documentation practice among nurses was 42% [95% confidence interval (CI), 37.2–46.8]. There was a statistically significant relationship between documentation practice and age [adjusted odds ratio (AOR): 2.590 (95% CI: 1.4–4.79)], educational status [AOR: 2.248 (95% CI: 1.13–4.48)], hospital level [AOR: 4.185 (95% CI: 2.63–6.72)], work experience (2–5 years and > 5 years) [AOR: 4.066 (95% CI: 1.55–10.64)] and [AOR: 5.395 (95% CI: 1.97–14.81)] respectively and in-service training [AOR: 0.582 (95% CI: 0.366–0.923)].

Conclusion and recommendations

This study demonstrated that the good practice of documentation among nurses was found to be low. Age, educational status, working in comprehensive specialized hospitals, work experience, and having in-service training had significant associations with documentation practice. It is very important to plan and intervene with different strategies, such as providing training for young nurses, nurses with low educational status, nurses working in primary hospitals, and nurses with less than two years of work experience on documentation standards, to create positive attitudes and enhance their knowledge.
Integrative rare disease biomedical profile based network supporting drug repurposing or repositioning, a case study of glioblastoma
Authors: McGowan Erin , Sanjak Jaleal , Mathé Ewy A. , Zhu Qian
Published: September 2023

Background

Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing or repositioning candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data.

Methods

We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repurposing or repositioning candidates for GBM.

Results

We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM.

Conclusion

Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing or repositioning. Further validation will be conducted by using other different types of biomedical and clinical data and biological experiments. The findings could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.
Beckwith-Wiedemann syndrome and twinning: case report and brief review of literature
Authors: Elefante Pierandrea , Spedicati Beatrice , Faletra Flavio , Pignata Laura , Cerrato Flavia , Riccio Andrea , Barbi Egidio , Memo Luigi , Travan Laura
Published: September 2023

Background

Beckwith-Wiedemann syndrome (BWS, OMIM #130,650) is a pediatric overgrowth disorder involving a predisposition to tumor development. Although the clinical management of affected patients is well established, it is less clear how to handle with the cases of siblings of affected patients, since the prevalence of the condition in twins (1:1000) is ten times higher than in singletones (1:10000).

Case presentation

We report the case of a premature twin patient who during her follow-up develops a clinical phenotype compatible with BWS, genetically confirmed in blood. However, the methylation alteration characteristic of the condition was also found in the almost phenotypically normal sibling, making it challening her management.

Conclusion

Through our case report we highlight how the diagnosis of BWS can be made without any prenatal suspicion and we propose a review of the literature on how to manage siblings of affected patients in twinning situation.