bluuebunny/crossref_metadata_2025 huggingface dataset:
Reciprocal tumor‐platelet interaction through the EPHB1‐EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma
Authors: Yao Lin‐Li , Qin Wei‐Ting , Hu Li‐Peng , Shi Tie‐Zhu , Yu Yang Jian , Li Qing , Nie Hui‐Zhen , Li Jun , Wang Xu , Zhu Lei , Liu De‐Jun , Zhang Yan‐Li , Jiang Shu‐Heng , Zhang Zhi‐Gang , Yang Xiao‐Mei , Li Dong‐Xue , Zhang Xue‐Li
Published: December 2024

Background

The interaction between the metastatic microenvironment and tumor cells plays an important role in metastatic tumor formation. Platelets play pivotal roles in hematogenous cancer metastasis through tumor cell‐platelet interaction in blood vessels. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy distinguished by its notable tendency to metastasize to the liver. However, the role of platelet in the liver metastatic niche of PDAC remains elusive. This study aimed to elucidate the role of platelets and their interactions with tumor cells in the liver metastatic niche of PDAC.

Methods

An mCherry niche‐labeling system was established to identify cells in the liver metastatic niche of PDAC. Platelet depletion in a liver metastasis mouse model was used to observe the function of platelets in PDAC liver metastasis. Gain‐of‐function and loss‐of‐function of erythropoietin‐producing hepatocellular receptor B1 (Ephb1), tumor cell‐platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (Tph1)‐knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.

Results

The mCherry metastatic niche‐labeling system revealed the presence of activated platelets in the liver metastatic niche of PDAC patients. Platelet depletion decreased liver metastatic tumor growth in mice. Mechanistically, tumor cell‐expressed EPHB1 and platelet‐expressed Ephrin B1 (EFNB1) mediated contact‐dependent activation of platelets via reverse signaling‐mediated AKT signaling activation, and in turn, activated platelet‐released 5‐HT, further enhancing tumor growth.

Conclusion

We revealed the crosstalk between platelets and tumor cells in the liver metastatic niche of PDAC. Reciprocal tumor‐platelet interaction mediated by the EPHB1‐EFNB1 reverse signaling promoted metastatic PDAC outgrowth via 5‐HT in the liver. Interfering the tumor‐platelet interaction by targeting the EPHB1‐EFNB1 axis may represent a promising therapeutic intervention for PDAC liver metastasis.
A Monitoring Tool for the Evaluation of Program Outcomes in Engineering Education
Authors: Yorulmaz Muhammet , Keçeci Barış , Tansel İç Yusuf , Gülşen Mehmet , Dengiz Berna
Published: December 2024

During the evaluation process, organizations that accredit engineering programs determine whether a program meets a list of predetermined criteria. One criterion on the list is Program Outcomes (POs). The most common weakness statement is found in this criterion. First, we aim to develop a model that can support program evaluation during the accreditation process. Second, the proposed approach can be used as a feedback tool in the continuous improvement of teaching in engineering programs. The course instructor runs the first module, which predefined learning outcomes and the POs are linked together using an Excel‐based software for each activity performed in the course. The second module calculates the scores that reflect the achievement levels of the POs for the whole program. The scores from individual courses are simultaneously transferred to the Technique for Order Preference by Similarity to Ideal Solution module that determines the rating scores of the POs in the program. The proposed system shows which POs are at a satisfactory level and which are lagging behind and need attention. It helps the course administrators to manage the course material proactively. The proposed system is a powerful tool for monitoring and tracking POs, and it is the primary tool used by program administrators to improve the program continuously. It is particularly useful in identifying the weak spots of the program. The successful implementation of the system in our department since 2012 makes us confident that the system could be adopted by other engineering programs.
Cerebrospinal Fluid Flow Cytometry in Pediatric Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study in China
Authors: Tu Songji , Zhang Kunlong , Liu Chenzhu , Wang Ningling , Chu Jinhua , Yang Linhai , Xie Zhiwei , Hang Lingling , Li Jun , Yang Wenyu , Zhu Xiaofan
Published: December 2024

Objective

The central nervous system (CNS) is a frequent site of relapse in childhood acute lymphoblastic leukemia (ALL). This study aims to investigate the utility of cerebrospinal fluid (CSF) flow cytometry in detecting CNS infiltration and relapse.

Methods

Flow cytometry was used to detect CSF leukemia cells, and patients were categorized into the CSF Flow+ and CSF Flow− groups. The primary outcome was the cumulative incidence of relapse (CIR) in the CSF Flow+ and CSF Flow− groups.

Results

A total of 1301 patients were enrolled, 159 patients (12.2%) showed positive CSF flow cytometry results. The CNS Flow+ patients exhibited significantly higher rates of any CNS relapse (22.5% vs. 0.2%, p < 0.01) and isolated CNS relapse (10.7% vs. 0%, p < 0.01) compared to CNS Flow− patients. Cox regression analysis revealed that risk factors for isolated CNS relapse included a positive result of D46 minimal residual disease (MRD) and CSF Flow+ at a non‐initial diagnosis. For any CNS relapse, the significant risk factors were CSF Flow+ at the initial diagnosis and CSF Flow+ at a non‐initial diagnosis.

Conclusions

CSF flow cytometry may have clinical utility in detecting CNS infiltration among pediatric ALL patients. It could contribute to more effective risk stratification and treatment adjustments and potentially reduce the risk of CNS relapse.
The Evidence Effect: How Fact Boxes Shift Perceptions of Lung Cancer Screening in Austrian Medical Practice
Authors: Amelunxen Carolina , Bielecki Michel , Wegwarth Odette , Funk Georg‐Christian
Published: December 2024

Background

Recent results from the Dutch NELSON study have rekindled debates about the benefit‐to‐harm ratio of lung cancer screening and the comprehension of this by physicians.

Methods

This research surveyed the perception and understanding of 136 Austrian physicians regarding the advantages and risks of lung cancer screening, examining the impact of educational data visualization tools, including fact box and icon array. Physicians participated in an online survey about their understanding before and after exposure to either a fact box alone or combined with an icon array.

Results

The findings indicated that the fact box significantly enhanced physicians' grasp of the screening's benefits and harms, making them up to 13 times more likely to adjust their estimates within a predefined range. Notably, the intervention was more effective among physicians who initially did not recommend CT screening. However, the addition of the icon array did not offer significant improvement. Postintervention, physicians showcased better comprehension and an improved ability to offer patient‐centered advice, which may bolster adherence to lung cancer screening protocols.

Outlook

Despite its insights, the study's cross‐sectional nature and the unique cultural context underline the need for more research. Further exploration should focus on different settings and assess the real‐world implications on clinical practice and patient outcomes.
Dual‐Phase Enhanced CT‐Derived Radiomics Nomogram for Progression‐Free Survival Prediction in Stage IV Lung Adenocarcinoma
Authors: Sun Haitao , Peng Zhaohui , Chen Guoyue , Dai Zhengjun , Yao Jian , Zhou Peng
Published: December 2024

Purpose

The objective is to establish a radiomics nomogram (Rad‐nomogram) using dual‐phase enhanced computed tomography (DPE‐CT) for the prediction of progression‐free survival (PFS) in patients diagnosed with stage IV lung adenocarcinoma (ADC).

Methods

From DPE‐CT scans, radiomic characteristics were retrieved from 133 patients diagnosed with stage IV lung ADC. Clinical data were analyzed using univariate and multivariate Cox regression analyses. The radiomics signature was combined with clinical features employing multivariate Cox analysis in order to develop a Rad‐nomogram. The predictive efficiency of the nomogram was evaluated using survival studies, such as Kaplan–Meier curves and Harrell's C‐index. The benefits and clinical utility of various models were compared using the net reclassification index (NRI), decision curve analysis (DCA), and integrated discrimination improvement (IDI).

Results

In the test cohort, the C‐indexes for the clinical, artery, and vein phase CT models were 0.675, 0.691, and 0.678, respectively. The dual‐phase achieved a C‐index of 0.731, exceeding the CT model, while the developed nomogram reached a C‐index of 0.783. The Kaplan–Meier survival study classified patients into low‐risk and high‐risk groups related to PFS using the Rad‐nomogram (p < 0.05). The Rad‐nomogram demonstrated a greater net advantage when compared with clinical and Rad models, as indicated by positive values of the NRI and IDI (ranging from 11.6% to 52.6%, p < 0.05).

Conclusion

The Rad‐nomogram, employing DPE‐CT scans, offers a promising approach to predict PFS in individuals diagnosed with stage IV lung ADC.
Mitoxantrone‐Based Novel Conditioning Regimen Leads to Great Survival Benefit in Peripheral T‐Cell Lymphoma Compared to BEAM Regimen
Authors: Zuo Xinyu , Qian Wensi , Wu Min , Xie Yanhui , Ma Jiexian
Published: December 2024

Background

Peripheral T‐cell lymphomas (PTCL) frequently result in relapsed or refractory diseases. Upfront autologous hematopoietic stem cell transplantation (ASCT) using the BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen is recommended. However, relapses are common in PTCL, highlighting a critical need for improved survival outcomes in these patients.

Objective

Anthracycline drugs are essential in treating PTCL. We compared the efficacy and tolerability of a high‐dose mitoxantrone‐based conditioning regimen [mitoxantrone, cyclophosphamide, and etoposide (MCE)] to the BEAM regimen in upfront ASCT for newly diagnosed PTCL patients who achieved complete or partial remission after induction therapy.

Study Design

A retrospective study was conducted to analyze the treatment response, progression‐free survival (PFS), overall survival (OS), hematologic engraftment time, and adverse events of 64 patients between two regimens, who achieved complete or partial remission after induction chemotherapy. Twenty‐eight patients received the MCE regimen, while 36 patients were treated with the BEAM regimen.

Results

There were no significant differences in clinical characteristics or the incidence of adverse events between the two groups. However, the median OS significantly favored the MCE group at 102.4 (95% CI, 87.0–117.8) months compared to 62.6 (95% CI, 50.8–74.5) months in the BEAM group (p = 0.023). Similarly, the median PFS was longer in the MCE group at 87.8 (95% CI, 65.8–109.8) months versus 42.5 (95% CI, 30.0–55.0) months in the BEAM group (p = 0.031).

Conclusion

ASCT with the mitoxantrone‐based conditioning regimen is tolerable and appears to significantly improve the prognosis of PTCL patients, offering a promising alternative to the current standard of care.
A Community Perspective on Boxing, Well‐being and Young People
Authors: Ryan Aoife , John Mary , Hanna Paul
Published: December 2024

Communities possess various resources, such as sporting organisations, that establish positive relationships with young people whom statutory services may struggle to engage. Boxing has been shown to attract individuals from diverse cultural and socio‐economic backgrounds, offering proven benefits in areas such as physical health and engagement. When taking into consideration mental and physical well‐being, there is limited knowledge regarding the overall well‐being benefits of boxing for young people. This study adopts an ethnographic approach within an Inner London community boxing gym to investigate the well‐being benefits of boxing for young people. Qualitative interviews, field notes and observations were employed with young people, staff and volunteers. The community identified that boxing provided young people with a changed sense of self, engaged them in a recursive learning process and instilled a sense of belonging, like that of a new family. These factors can all be associated with well‐being. The study highlights the significance of community‐based resources, such as boxing gyms, in providing support for improving well‐being for a diverse cohort of young people. Please refer to the Supplementary Material section to find this article's Community and Social Impact Statement
Seaweed‐Derived Bioactive Compounds: Potent Modulators in Breast Cancer Therapy
Authors: Behera Maheswari , Singh Lakshmi , Pradhan Biswajita , Behera Kanhu Charan
Published: December 2024

Cancer remains a major global health concern, with breast cancer being particularly challenging. To address this, new therapeutic strategies are being explored, including natural alternatives. Seaweeds, rich in bioactive compounds, have gained attention for their therapeutic potential. Traditionally valued for their nutritional content, seaweed‐derived compounds such as polysaccharides, polyphenols, sterols, vitamins, minerals, and carotenoids have shown anticancer properties. These compounds can modulate key cellular processes like apoptosis, angiogenesis, and inflammation—crucial in cancer progression. Their antioxidant, anti‐inflammatory, and immunomodulatory effects make them promising candidates for complementary cancer therapies. Key bioactive components like fucoidans, laminarins, phlorotannins, and carotenoids exhibit antiproliferative, proapoptotic, antiangiogenic, and antimetastatic properties. Recent studies focus on the ability of these compounds to induce apoptosis in cancer cells. This review highlights the chemical constituents of various seaweed species with antitumor activity, their mechanisms of action, and the potential for integration into cancer treatments. It also addresses challenges in clinical applications and outlines future research directions for leveraging these marine resources in breast cancer therapy.
Costus igneus: A Versatile Herbal Remedy for Multiple Health Conditions
Authors: Yadav Megha , Sahu Bhaskar , Sahu Mukesh
Published: December 2024

Costus igneus, commonly known as the insulin plant, is a potent medicinal herb with a wide range of pharmacological activities. Traditionally used in diabetes management, recent studies have highlighted its antidiabetic, antioxidant, antimicrobial, hepatoprotective, and kidney stone‐inhibitor properties. Phytochemical analyses reveal the presence of saponins, flavonoids, alkaloids, steroids, and terpenoids, which contribute to its therapeutic effects. In various in vitro and in vivo models, C. igneus demonstrated significant hypoglycemic activity. The plant exhibits strong antioxidant activity, as evidenced by FRAP, DPPH, and ABTS assays, with notable radical scavenging and reducing power. Other miscellaneous pharmacological activities include anti‐inflammatory, anti‐arthritic, cytotoxicity, and hypotensive effects. These findings support C. igneus as a safe and cost‐effective herbal remedy for managing diabetes and other ailments, highlighting its potential for future therapeutic applications and the development of herbal formulations.
Therapeutic targeting of cGAS–STING pathway in lung cancer
Authors: Wang Jinli , Xing Lumin
Published: December 2024

The presence of DNA in the cytosol triggers a protective response from the innate immune system. Cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS–STING) is an essential cytosolic DNA sensor that triggers a potent innate immune response. As a result of this signaling cascade reaction, type I interferon and other immune mediators activate an immune response. The cGAS–STING pathway has great anticancer immunity‐boosting potential since it produces type I interferons. The detection of double‐stranded DNA (dsDNA) in response to various stimuli initiates a protective host's cGAS–STING signals. So, it is clear that a substantial relationship is expected between cancer biotherapy and the functioning of the cGAS–STING pathway. Several STING agonists with promising outcomes have been created for preclinical cancer therapy research. Notably, immunotherapy has dramatically extended patient survival and radically altered the course of lung cancer treatment, particularly in more advanced instances. However, this method is still ineffective for a large number of lung cancer patients. cGAS–STING can overcome resistance and boost anticancer immunity by stimulating the activity of many pro‐inflammatory mediators, augmenting dendritic cell cross‐presentation, and initiating a tumor‐specific CD8+ T cell response. This review aims to present the most recent results on the functionality of the cGAS–STING pathway in cancer progression and its potential as an immunotherapy target, with a focus on lung cancer.
DRIM modulates Src activation and regulates angiogenic functions in vascular endothelial cells
Authors: Tong Jia , Dong Xuefei , Martin Tracey A. , Yang Yiming , Dong Bo , Jiang Wen G.
Published: December 2024

Downregulated in Metastasis Protein (DRIM) was discovered in malignant epithelial cells and was thought to be mainly a nucleus protein affecting cancer cells. Recent single‐cell sequencing analysis suggests that DRIM is abundantly expressed in vascular endothelial cells. There has been no knowledge of the role of DRIM in the endothelium. In the present study, using protein fraction method and cell imaging, we identified that the DRIM protein was abundantly present in both nucleus and the cytoskeletal fractions of human vascular endothelial cells. Knockdown of DRIM in the endothelial cells significantly affected growth, migration, and angiogenic tubule formation. Proteomics analyses revealed that Src was an important direct target protein of DRIM, a finding further confirmed by protein interaction assay. Silencing DRIM activated the tyrosine 419 site phosphorylation of Src kinase in endothelial cells, thereby affecting the downstream proteins of Src including p‐FAK and p‐STAT3, and exerting biological effects. To conclude, our results provide evidence of DRIM being a nuclear and cytoskeletal‐associated protein, having a novel key role of the protein in vascular endothelial cells.
Hydrogen Release From Ammonia: Size and Support Effects in Heterogeneous Transition Metal Catalysis
Authors: Wang Jihao , Chen Shilong , Behrens Malte
Published: December 2024

Ammonia, industrially produced by the Haber–Bosch process, can serve as a promising renewable energy carrier based on its high hydrogen content and energy density as well as its full‐fledged infrastructure worldwide for transportation. Renewable hydrogen will be converted firstly in ammonia synthesis, stored and/or transported bound in ammonia, and released on demand by ammonia decomposition. So far, the most active catalysts for the decomposition reaction are Ru‐based due to its optimal nitrogen binding energy compared to other transition metals. However, due to the high cost of Ru, the development of alternative catalysts for ammonia decomposition is attractive, especially non‐noble transition metals such as Fe, Ni, or Co. For supported metal catalysts, size and support effects play important roles in the catalytic reaction, resulting in a change of their geometric and/or electronic properties. In this review, we first discuss and comment on representative existing studies of the size and support effects of Ru, Fe, Ni, and Co catalysts in ammonia decomposition from an experimental and theoretical view, suggesting possible reasons for geometrical and electronic effects. Afterward, we will summarize the available catalytic data in the literature in the form of TOFH2 and reaction rate of each supported transition‐metal catalyst with different supports as a function of the particle size, attempting to identify an optimum particle size and a trend for the different supports. Finally, we will discuss the challenges and perspectives of future‐oriented research on the size and support effect in ammonia decomposition.
Propane Dehydrogenation Over Silicalite‐1 Supported PtMn Catalyst with Low Pt Loading
Authors: Wang Wenxin , Hu Huimin , Song Jiaxin , Fan Xiaoqiang , Yu Xuehua , Kong Lian , Xiao Xia , Xie Zean , Zhao Zhen
Published: December 2024

Pt‐based catalysts have been widely studied for propane dehydrogenation (PDH) because of their high activity and environmental sustainability. However, as a precious metal, the development of catalysts with high stability and low Pt content is of great significance. In this study, a series of silicalite‐1 (S‐1) supported PtMn (0.1PtxMn/S‐1) catalysts with low Pt loading amount (0.1 wt%) was prepared. The effects of different Mn loadings on the physicochemical properties and catalytic performance in the PDH reaction were studied. The addition of an appropriate amount of Mn regulated the dispersion of Pt particles and increased the number of active sites of the catalyst, enhancing the catalytic performance of PDH even at a low Pt loading. The initial propane conversion was 46.1% over 0.1Pt0.3Mn/S‐1 catalyst, and the deactivation rate constant was the lowest of 0.01 h−1. This may be because of an appropriate Mn loading was beneficial for enhancing the interaction between the metal and the support, forming MnOx is attached to the S‐1 surface, while the surface of MnOx stabilized the PtMn alloy, thereby improving the catalytic performance for PDH.
Chemoenzymatic Cascade Synthesis of Metal‐Chelating α‐Amino Acids
Authors: Young Sophie H. , Andon James S. , Lim Jooyeon , Franke Mareena C. , Weix Daniel J. , Wang Tina , Buller Andrew R.
Published: December 2024

Metal‐chelating noncanonical amino acids (ncAAs) are uniquely functional building blocks for proteins, peptide catalysts, and small molecule sensors. However, catalytic asymmetric approaches to synthesizing these molecules are hindered by their functional group variability and intrinsic propensity to ligate metals. In particular, bipyridyl‐l‐alanine (BpyAla) is a highly sought ncAA, but its complex, inefficient syntheses have limited utility. Here, we develop a chemoenzymatic approach to efficiently construct BpyAla. Three enzymes that can be produced in high titer together react to convert Gly and an aldehyde into the corresponding β‐hydroxy ncAA, which is subsequently deoxygenated. We explore approaches to synthesizing biaryl aldehydes and show how the three‐enzymatic cascade can access a range of α‐amino acids with bulky side chains, including a variety of metal‐chelating amino acids. We show that newly accessible BpyAla analogues are compatible with existing amber suppression technology, which will enable future merging of traditional synthetic and biosynthetic approaches to tuning metal reactivity.
Photocatalyzed Dehydration of 1‐Aryl‐1,2‐Ethanediols to Methyl Ketones Driven by Eosin Y Fragmentation Products
Authors: Taskinen Elina K. , Kolb Daniel , Morgenstern Martin , König Burkhard
Published: December 2024

Herein, we report a mild photocatalytic redox‐neutral dehydration of aryl‐1,2‐ethanediols forming the respective methyl ketones. In the proposed mechanistic cycle an initial hydrogen atom abstraction (HAT) is followed by a 1,2‐spin center shift (SCS) as key steps. Interestingly, Eosin Y was found to act as a pre‐catalyst dissociating into a catalytically active mixture under irradiation. To the best of our knowledge, this exemplifies the first synthetic utilization of Eosin Y degradation products. As a result, our reaction can be realized with a single organic photocatalyst and releases water as a sole by‐product.
Continuous packed bed column removal of Cr6+, Cd2+, and Pb2+ ions from synthetic wastewater using polymeric ultra‐permeable and biodegradable ferromagnetic nanocomposite membrane
Authors: Suter Evans , Rutto Hilary , Omwoyo Wesley
Published: December 2024

Water purification techniques, including membrane technologies, ion exchange and adsorption, chemical/biochemical reduction, and electrochemical processes, have been developed to remove/recover metal ions species from polluted wastewater. This work assessed the efficiency of polymeric, biodegradable, ultra‐permeable and magnetic nanocomposite membrane (CNCs/N6@Fe3O4‐CT) in a continuous packed bed column for the removal of Cd(II), Cr(VI), and Pb(II) metal ions from synthetic wastewaters. The eco‐compatibility of CNCs/N6@Fe3O4‐CT was increased using chitosan biopolymer. Fe3O4 nanoparticles increased the surface area and improved the separation process. CNCs and N6 polymeric materials enhanced their strength, porosity, and additional binding sites. The CNCs/N6@Fe3O4‐CT nanocomposite membrane was employed as packing material in a fixed‐bed lab‐scale column (height 30 cm, diameter 1.5 cm) to constantly remove Cd(II), Cr(VI), and Pb(II) metal ions from synthetic wastewaters and actual hexavalent chromium tannery effluent. The studies were carried out with different initial metal ion concentrations (10, 20, and 30 mg/L), input flow rates (2, 4, and 6 mL/min), and solution pH values (2.0, 5.0, and 8.0). The obtained experimental data from the breakthrough curves was fitted to the traditional dynamic Thomas model, Yoon‐Nelson, and Bed Depth Service Time (BDST) model.
Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges
Authors: Francavilla Fabio , Intranuovo Francesca , La Spada Gabriella , Lacivita Enza , Catto Marco , Graps Elisabetta Anna , Altomare Cosimo Damiano
Published: December 2024

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so‐called long‐COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self‐sustaining process. Anti‐inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post‐COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules‐based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.
4‐Aza Cyclopentenone Prostaglandin Analogues: Synthesis and NF‐κB Inhibitory Activities
Authors: Doherty William , Conway Lorna , Leveau Brian , Giulia Nacca Francesca , Chiappa Lucia , Riccio Anna , Roberts Stanley M. , Gabriella Santoro M. , Evans Paul
Published: December 2024

Inspired by the cyclopentenone family of prostaglandins, a series of 4‐aza, cross‐conjugated cyclopentenones is described. Synthesised from N‐protected (4R)‐aza‐cyclopentenone 5, the exocyclic alkene was installed using a modified Baylis‐Hillman type aldol reaction, whereby carbon‐carbon bond formation is accompanied by dehydration. In this manner octanal and octenal, for example, can be introduced to mimic the ω‐group present in the natural prostaglandins. Similarly, a focused range of alternative substituents were introduced using different aldehydes and ketones. The presence of the tert‐butyloxycarbonyl (Boc) group on the 4‐amino‐cyclopentenone substituent enabled subsequent derivatisation and various electrophiles were successfully incorporated. The ability of the family of 4‐amino functionalised cross‐conjugated cyclopentenones to block activation of nuclear factor‐kappa B (NF‐κB) was studied and compared with the natural prostanoid, Δ12,14‐15‐deoxy‐PGJ2 (2). Thereafter, the synthesis of a series of thiol adducts from these compounds were prepared and similarly evaluated biologically. The adducts showed comparable and, on occasion, more potent inhibition of NF‐κB than their cyclopentenone precursors and generally demonstrated diminished cytotoxicity. For example, cross‐conjugated dieneone 12 inhibited the activation of NF‐κB with an IC50 value of 6.2 μM, whereas its endocyclic N‐Boc (27) and N‐acetyl (28) cysteine adducts blocked NF‐κB activity with values of 1.0 and 8.0 μM respectively.
FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose
Authors: Nallani Srikanth C. , Li Zhihua , Florian Jeffry , Xu Yun , Sabarinath Sreedharan , Brescia‐Oddo Tanya , Roca Rigoberto A. , Uppoor Ramana S. , Mehta Mehul U.
Published: December 2024

On May 22, 2023, the United States Food and Drug Administration approved the first nalmefene hydrochloride nasal spray for the emergency treatment of known or suspected opioid overdose in adults and pediatric patients 12 years of age and older. This approval of a new prescription nalmefene hydrochloride nasal spray adds to the available opioid reversal options for hospitals, communities, harm reduction groups, and emergency responders. Due to the life‐threatening nature of opioid overdose, conducting randomized, well‐controlled clinical efficacy trials in the target patient population is neither ethical nor feasible. Clinical investigations of nalmefene nasal spray consisted of two pharmacokinetic studies and one pharmacodynamic study. Approval of the new drug application was based on the scientific bridge established by the two pharmacokinetic studies to the Agency's previous efficacy and safety findings for the listed drug nalmefene hydrochloride injection. Additionally, the pharmacodynamic study conducted in an opioid‐induced respiratory depression model in healthy volunteers established the onset of action of nalmefene administered as a nasal spray. A high‐level summary of regulatory and scientific considerations during the development and approval of nalmefene nasal spray are presented.
Background Factors Contributing to Safety Warning Discordance in the Initial Labeling of New Drugs in Japan, the United States, and the European Union
Authors: Fukuda Koichi , Narukawa Mamoru
Published: December 2024

Drug labels summarize essential safety information for healthcare professionals and patients. However, studies have reported a discordance of safety information in drug labeling among countries/regions. We aimed to identify the characteristics of adverse events associated with discordant safety warnings during the initial labeling of new drugs approved at approximately the same time in Japan, the United States, and the European Union. Safety warning discordance/concordance between two countries/regions and the explanatory variables were assessed using multivariable logistic regression. The safety warning concordance rate was 71.0% (152/214) for the United States and the European Union, 59.5% (135/227) for Japan and the United States, and 64.3% (144/224) for Japan and the European Union. A significant association with discordant safety warnings was revealed for “adverse event rate” and “warning status in a similar drug” between the United States and the European Union; “adverse event rate,” “adverse event included in important medical event list,” and “warning status in a similar drug” between Japan and the United States; and “adverse event included in important medical event list” and “warning status in a similar drug” between Japan and the European Union. Clarifying and publicizing the reasons for safety warnings, along with an awareness of the factors associated with the discordance identified in this study, will help healthcare professionals, patients, marketing authorization holders, and regulatory authorities around the world share the background of country/region‐specific warnings, reducing the possibility of confusion among them due to the discrepancies.
Suboccipital Cisterna Magna Injection for Vehicle Delivery in Pigs Using Computed Tomography
Authors: Myers Luke S. , Christian Sarah , Fridley Jennifer , Dindot Scott V.
Published: December 2024

Gene therapies are being developed for several central nervous system (CNS) disorders. These therapies are primarily administered to the CNS via the cerebrospinal fluid (CSF), as the blood–brain barrier prevents the transport of large molecules to the brain. Currently, intrathecal injection is the most commonly used route of administration over cisterna magna injections in the clinic for gaining access to the CSF. However, studies in nonhuman primates (NHPs) have shown that administering gene therapies via suboccipital cisterna magna injection results in superior distribution and more cells being transduced in the brain compared to lumbar injection. It has also been reported that comparable CNS size is important when translating therapeutic dosages from animal studies to human trials. Therefore, we chose to develop a computed tomography (CT)‐guided cisterna magna injection protocol in pigs as they are anatomically closer in size to humans than nonhuman primates and rodents. Pigs are also a readily available and cost‐effective large animal model for preclinical studies compared to nonhuman NHPs. In this paper, we describe a method for CT‐guided suboccipital cisterna magna injections in pigs. We developed this protocol utilizing CT to confirm needle placement with three‐dimensional visualization. A CT‐guided injection minimizes procedural risk and can be performed without a contrast agent, which is required in magnetic resonance and fluoroscopy imaging. © 2024 Wiley Periodicals LLC.

Basic Protocol: Computed tomography–guided suboccipital cisterna magna injection in pigs to confirm needle placement prior to the administration of a test article or vehicle
Growth and Inelastic Light Scattering Studies on Sr2Nb2O7 Single Crystal
Authors: Suganya M. , Vijayakumar P. , Sivasubramanian V. , Ganesan K. , Sarguna R.M. , Gill Amirdha Sher , Ganesamoorthy S.
Published: December 2024

A crack‐free and high structural quality Sr2Nb2O7 single crystals are grown by the optical float zone method using optimized growth parameters. The Laue pattern confirms the single crystalline nature of the grown crystal. Temperature‐dependent Raman and Brillouin light scattering studies reveal a significant shift in phonon modes across normal to incommensurate phase transition (Tn‐in) which occurs ≈488 K. In the temperature range from 900 down to 500 K, two optical phonon modes ≈63 (B1 mode) and 54 cm−1 (A1 mode) are observed. The frequency of A1 mode strongly decreases with an increase in temperature above the Tn‐in while the frequency of this mode almost remains constant below the Tn‐in. In contrast, the frequency of B1 phonon mode is found to increase with temperature in the range of 500–900 K but it does not display a significant shift below the phase transition temperature. In addition, in the in‐commensurate phase (T< 488 K), a new optical phonon mode (M1) at ≈35 cm−1 also begins to appear and exhibits strong stiffening behavior with an increase in temperature in the range of 300–488 K. Moreover, the anomalous behavior of the acoustic phonon across Tn‐in are further probed using Brilliouin scattering. Longitudinal acoustic phonon mode at 41 GHz exhibits a strong change in slope near Tn‐in. In addition, the transverse acoustic modes at 28.6 and 22.4 GHz also exhibit strong anomalies with minimum frequency near Tn‐in. The inelastic light scattering studies provide valuable information on the phase transition.
The Roles of Surface Hydrogen and Hydroxyl in Alkaline Hydrogen Oxidation on Ni‐Based Electrocatalysts
Authors: Tian Xiaoyu , Liu Jiaxiang , Zhao Pengcheng , Li Xianping , Li Zhuo , Sheng Wenchao
Published: December 2024

One important target for anion exchange membrane fuel cells (AEMFCs) is to enable the application of anode non‐precious metal hydrogen oxidation reaction (HOR) catalyst. Nickel presents a promising candidate for alkaline HOR; yet, its practical application is hampered by the intrinsically sluggish activity and poor stability. Herein, a series of Ni‐based metals (Ni5Mo, Ni25Co, Ni14W and Ni) are electrodeposited as model catalysts to systematically explore the alkaline HOR by considering the role of adsorbed hydroxyl (OHad). Spectroscopic studies together with density functional theory calculations shed light on the beneficial effect of transition metal M (M=Mo, Co, W) alloying/doping on HOR by introducing the charge transfer from M to Ni and down shifting Ni 3d band center. The HOR specific activities on Ni‐based catalysts reveal a volcano‐type relationship with the hydrogen binding energy (HBE). The strongly adsorbed OHad is proven to induce deactivation for Ni active sites, and the deactivation potential is OHad binding energy (OHBE) dependent. This study adds new insight into the HOR mechanism and stability of Ni‐based electrocatalysts, providing a new avenue for the rational design of highly efficient and robust alkaline HOR catalysts.
Developmental Trajectory of Autistic‐Like Behaviors in a Prenatal Valproic Acid Rat Model of Autism
Authors: Lian Bin , He Yihan , Dong Da , Quan Li , Feng Tingyong , Li Ming
Published: December 2024

Autism spectrum disorders (ASDs) are characterized by deficits in social functioning, stereotyped patterns of behaviors, narrowed interests, and elevated anxiety. Certain ASD symptoms can persist, whereas others may improve throughout the lifespan, but the specific patterns of changes have not been clearly delineated. Using a valproic acid (VPA) rat model of ASD, the present study took a developmental approach and examined how autistic‐like behaviors, including anxiety‐like behavior, object obsession, and social functioning deficits, manifested differently in three critical periods representing preadolescent (postnatal day [PND] 25), adolescent (PND 45), and adulthood life stage (PND 75) in a sex‐dependent manner. Starting on PNDs 25, 45, and 75, VPA‐ or saline‐exposed male and female offspring were tested in an elevated plus maze (EPM) and a newly validated composite social and object interaction and a triple recognition test (object, spatial, and social recognition). Across the three age groups, VPA‐exposed offspring did not exhibit enhanced anxiety‐like behavior in the EPM nor enhanced object interaction (“object obsession”) in the triple recognition test. However, both male and female preadolescent (PND 25) VPA‐exposed offspring showed a significantly increased latency to initiate social contact than the saline‐exposed controls, although their latencies to contact novel objects were comparable to those of the controls. Male preadolescent and adolescent VPA‐exposed offspring, to a lesser extent the female preadolescent offspring, exhibited significantly lower levels of social interaction. These social functioning deficits were absent in adult VPA offspring. Additionally, prenatal VPA exposure did not cause an impairment of object recognition, spatial recognition, or social recognition of a familiar conspecific. Unexpectedly, it enhanced social recognition of a novel conspecific, but only in adolescent female offspring. These findings suggest that this rat model based on prenatal VPA exposure is valid in capturing early social motivational and functioning deficits but is limited in its capacity to model increased object obsession and enhanced anxiety as seen in ASD, as well as the developmental trajectory of non‐social ASD symptoms. Recognizing these limitations is important as it informs us how to properly use this model to investigate the neurobiology of ASD and incentivizes us to develop better rodent models.
Maternal Sensitization in Virgin Female Rats: Behavioral Effects of Enriched Environment
Authors: Núñez‐Murrieta Mauricio A. , Rendón‐Candanedo Esmeralda , Angeles‐Torres Diana , Noguez Paula , Coria‐Avila Genaro A. , Bolado‐García Victoria E. , Corona‐Morales Aleph A.
Published: December 2024

In virgin female rats, the continuous presence of pups causes them to express typical maternal behaviors, a process known as maternal sensitization. Previous experience with pups accelerates maternal sensitization. It is also known that in primiparous rats, enriched environment (EE) increases the expression of maternal behaviors. Here, we investigated whether experience, other than pup exposure, affects the process of maternal sensitization and hypothesized that EE increases the expression of maternal behaviors and maternal motivation in virgin rats. Virgin adult females were housed in standard conditions or physical and social EE for 21 days. Then, females were exposed daily to pups until they expressed full maternal behaviors. Thereafter, females performed pup preference, pup motivation in a novel context, and resident‐intruder tests. We found that initial pup rejection was higher in EE rats, but eventually, both groups became maternally sensitized simultaneously. The frequency and duration of pup licking were higher in EE rats. In the other tests, EE rats exhibited more entries to the open arms, retrieved more pups toward the closed arms, and were more aggressive towards an intruder. We conclude that housing in a social EE modulates aspects of the pup‐induced maternal sensitization, particularly increasing pup licking and motivation in both familiar and novel circumstances.
Trajectories of Maternal Behavior, Infant's Respiratory Sinus Arrhythmia, and Emotional Recovery Following the Still Face Paradigm
Authors: Green Lindsey M. , Thompson Stephanie F. , Shimomaeda Lisa , Katz Lynn Fainsilber , Lengua Liliana J.
Published: December 2024

The development of emotion regulation is integral to children's socioemotional adjustment. Respiratory sinus arrhythmia (RSA) reflects parasympathetic regulation of cardiac arousal and is thought to be an indicator of emotion regulation. However, it is unclear how RSA is associated with positive maternal behaviors and infant emotional recovery in real time over the course of a recovery period following a social stressor. Mothers and their 5‐ to 6‐month‐old infants (N = 143) completed the Still Face paradigm. Using a series of autoregressive latent trajectory models, the current study aimed to elucidate the associations among observed maternal warmth, infant RSA, and observed infant negative affect across a 5‐min observation. The hypotheses were that trajectories of maternal warmth would predict trajectories of infant RSA and negative affect, and that trajectories of RSA would be associated with the infants' observed negative affect. Change in maternal warmth was associated with infant negative affect and RSA at the end of the reunion and change in RSA was associated with ultimate levels of negative affect. The results provide partial support for our hypothesis that maternal warmth supports infant physiological, and in turn, emotional recovery.
Warm Parenting Throughout Adolescence Predicts Basal Parasympathetic Activity Among Mexican‐Origin Youths
Authors: Her Helena , Ugarte Elisa , Weissman David G. , Robins Richard W. , Guyer Amanda E. , Hastings Paul D.
Published: December 2024

Parenting that is warm and supportive has been consistently linked to better emotion regulation in children, but less is known about this association in adolescents. Adolescence is thought to be an important period for emotion regulation development given that it coincides with the emergence of mental health issues. Respiratory sinus arrhythmia (RSA) is a measure of parasympathetic regulation linked to emotion and behavior regulation. Despite the well‐documented links between parenting practices and emotion regulation, and between RSA and emotion regulation, few studies have focused on the association between positive parenting and adolescent RSA or included both mothers and fathers. The current study analyzed the influence of warm parenting throughout adolescence (ages 10–16) on basal RSA at age 17 in 229 Mexican‐origin youths. Latent‐growth curve models were used to analyze associations between maternal and paternal warmth and baseline RSA. Changes in maternal, but not paternal, warmth from age 10 to 16 were related to youths’ basal RSA at age 17. Specifically, youths who perceived increasing (or less decreasing) maternal warmth across adolescence had higher basal RSA. This finding suggests that positive maternal parenting experiences during adolescence “get under the skin” to enhance parasympathetic functioning that supports youths’ emotion regulation capacities.
Predictive Strength of Auditory Maturity Across Different Levels of Language Ability: An Exploratory Quantile Regression Study
Authors: Pham Theresa , Janes Alyssa , Kwok Elaine , Oram Janis
Published: December 2024

Auditory evoked potential‐age (AEP‐age) is proposed to index auditory maturation and has been found to predict language skills in children with and without a language disorder. However, reporting average effects using linear regression does not fully capitalize on the potential of AEP‐age to estimate individual differences in young children. This study used a quantile regression approach to examine the predictive utility of AEP‐age for 105 typical and neurodiverse 7–10‐year‐old children (61 males; 44 females; largely monolingual English) with varying language skills without creating subgroups. Although linear regression did not find an association between AEP‐age and language skills, the quantile model added specificity by revealing differential associations. AEP‐age was only related to language skills for children at around the median point of the language continuum, but, not for those at the lowest or highest end of the language distribution. Overall, the quantile regression methodology provides us with the flexibility of understanding how AEP‐age is related to different language abilities.
Differential Effects of Prenatal Buprenorphine and Methadone on Postnatal Growth and Gene Expression in the Nucleus Accumbens
Authors: Gildawie Kelsea R. , Budge Kerri E. , Vassoler Fair M. , Yen Elizabeth , Byrnes Elizabeth M.
Published: December 2024

Methadone and buprenorphine are commonly prescribed during pregnancy to maintain recovery and prevent symptoms of withdrawal in women with opioid use disorder. Infants prenatally exposed to medications for opioid use disorder (MOUD), however, commonly show signs of neonatal opioid withdrawal syndrome (NOWS), which can include feeding‐related issues like hyperphagia. To investigate the effects of prenatal MOUD exposure on feeding behavior, female Sprague‐Dawley rats were implanted with osmotic minipumps filled with methadone, buprenorphine, or saline and subsequently mated. On postnatal day (PND) 1, buprenorphine‐ and methadone‐exposed offspring weighed less than saline‐exposed subjects. Throughout early postnatal development (PND2, 7, and 12), this reduction in weight persisted in buprenorphine, but not methadone, offspring. RNAscope in situ hybridization was then used to measure expression of genes in the nucleus accumbens (NAc) previously associated with hyperphagia in NOWS infants, including proopiomelanocortin (Pomc), neuropeptide Y2 receptors (Npy2r), and dopamine type 2 receptors (Drd2). Distinct developmental expression patterns were noted across the postnatal period, with few effects of MOUD; however, significantly lower Pomc expression was observed in methadone‐exposed but not buprenorphine‐exposed offspring. These findings demonstrate differential effects of methadone and buprenorphine on offspring development and gene expression, highlighting differences in offspring outcomes associated with these two MOUDs.