bluuebunny/crossref_metadata_2025 huggingface dataset:
TERRA G‐quadruplex stabilization behind the anti‐multiple myeloma activity: Novel insights about resveratrol pleiotropic effects
Authors: Rocca Roberta , Ascrizzi Serena , Citriniti Emanuele Liborio , Scionti Francesca , Juli Giada , Di Martino Maria Teresa , Caracciolo Daniele , Artese Anna , Tagliaferri Pierosandro , Tassone Pierfrancesco , Grillone Katia , Alcaro Stefano
Published: June 2024

Resveratrol (RSV) is a nutraceutical compound belonging to the nonflavonoid polyphenol family, whose antioxidants, anti‐inflammatory, and antitumoral properties have been widely investigated. The ability of RSV to provide beneficial effects for neurological, cardiovascular, and cancer disorders rekindled the interest to explore the molecular mechanisms behind its pleiotropic effects, which are due to the modulation of coding and noncoding genes involved in many key biological pathways. With a computational approach, including docking studies and thermodynamics calculations followed by 200‐ns‐long molecular dynamics and a clustering analysis, we hypothesized the stabilizing binding between RSV and G4 structures of telomeric repeat‐containing RNA (TERRA), which is a tumor‐suppressive long noncoding RNAs (lncRNA) involved in the regulation of telomere maintenance. In vitro studies performed on cellular models of multiple myeloma (MM) strengthened our hypothesis by highlighting that the antiproliferative and apoptotic effect induced by the treatment with RSV is associated with an increase of TERRA transcript and with upregulation of telomeric heterochromatin markers, such as H3K27Me3 and H4K20Me3, and of the hallmark of apoptosis, cleaved‐poly(ADP‐ribose) polymerase‐1. Our results propose innovative insights underlying the multifaceted role of RSV in MM, by pointing out the role of this natural compound in an lncRNA‐mediated regulation to counteract cellular immortality.
An alpha 5‐GABAA receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero
Authors: Souza Adriana Jesus , Freitas Ícaro Silva , Sharmin Dishary , Cook James M. , Guimarães Francisco S. , Gomes Felipe V.
Published: June 2024

Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5‐containing GABAA receptors (α5‐GABAARs) SH‐053‐2′F‐R‐CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH‐053‐2′F‐R‐CH3 could attenuate these changes. SH‐053‐2′F‐R‐CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self‐grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH‐053‐2′F‐R‐CH3 attenuated the impairments in sociability and cognitive function in male VPA‐exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA‐exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH‐053‐2′F‐R‐CH3. Despite sex differences, our findings indicate that α5‐GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.
Identification of a novel anti‐ROR1 nanobody through phage display and its biochemical characterization
Authors: Kang Li , Dong Yingkui , Wang Wanxue , Li Zehua , Wang Yizhuo , Yan Li , Yin Cunlong , Zhang XiaoHui , Dai Han , Wu Bo , Zhao Hongxin , Wang Junfeng
Published: June 2024

In this study, we aimed to develop nanobodies targeting receptor tyrosine kinase‐like orphan receptor 1 (ROR1) for cancer diagnosis and therapy. We immunized alpacas with ROR1, extracted RNA from their blood, and converted it to complementary DNA (cDNA) to amplify the VHH (variable domain of heavy‐chain antibodies) sequence. This sequence was used to construct a phage library with a capacity of 8 ×108. Screening identified a high‐affinity nanobody, HCAbs1, which binds effectively to ROR1. ELISA and surface plasmon resonance analyses revealed HCAbs1's binding affinities to ROR1 at 4.42 and 12.9 nM, respectively. Functional tests showed HCAbs1 could reduce extracellular signal‐regulated kinase (ERK) phosphorylation levels induced by Wnt5a in ROR1‐transfected cells. Our findings highlight the potential of HCAbs1 nanobodies in diagnosing and treating cancers through targeting ROR1.
Anwendung von mathematischer Optimierung für eine effiziente energetische Sanierungsplanung
Authors: Medgenberg Justus , Makowski Andreas , Langner Normen
Published: June 2024

Die energetische Bestandssanierung hat für die Dekarbonisierung des Gebäudesektors eine entscheidende Funktion. Um Ressourcen bestmöglich einzusetzen, ist die ganzheitliche Quantifizierung und Optimierung von Sanierungsentscheidungen sinnvoll. Die Anwendung von mathematischen Optimierungsverfahren bietet Potenzial, das bisher vor allem im deutschsprachigen Raum kaum genutzt wird. Vorgestellt wird eine neue Methodik, die mittels eines mathematischen Ersatzmodells die Optimierung variabler Zielfunktionen erlaubt. Das Modell wird anhand von punktuellen Gebäudesimulationen kalibriert. Die Stärke der vorgestellten Methode liegt in der Analyse einer sehr großen Zahl von Sanierungskombinationen bei minimalem Rechenaufwand. Die Anwendbarkeit auf reale Objekte wird anhand von zwei unterschiedlichen exemplarischen Wohngebäudetypen demonstriert. Resultierende Sanierungsstrategien aus der Analyse werden beispielhaft für drei verschiedene Zielfunktionen mit Investitions‐ und Betriebskosten sowie CO2‐Ausstoß bei unterschiedlichen Restriktionen dargestellt. Derzeit ist die vorgestellte Methode für die Bewertung und Optimierung des Heizwärmebedarfs von Wohngebäuden anwendbar. Es sind verschiedene Erweiterungen der Methodik angedacht.
Sustainable development in listed districts: CO2 neutral World Heritage Speicherstadt Hamburg
Authors: Teichmann Lena , Resta Laura Fernández , Hein Helen , Dinga Güren Tan , Ramadan Zaher , Bögle Anette , Mondino Daniel , Garrecht Harald
Published: June 2024

To achieve Germany's 2045 goal of climate‐neutral building stock, the integration of renewable energies in retrofitting is necessary. The project ‘CO2‐neutrales Welterbe Speicherstadt Hamburg’ situated in the historic warehouse district, focuses on the sustainable heat supply in listed buildings. The project consists of two main approaches: a practical approach combining historically sensitive components for heat supply to create a comprehensive energy retrofitting concept with renewable energies in the listed area, and a methodological approach using Building Information Management (BIM) to integrate various simulation models and centralize outcomes efficiently. This enables a holistic and energy‐efficient retrofit, addressing flow‐specific, thermal, and ecological aspects, thereby marking a significant step toward achieving a CO2 neutral listed building stock.
Evaluation of bacteriophages for the alleviation of potential bacterial contamination risks in developmental engineering
Authors: Xiang Yu , Bao Xujin , Sun Tao
Published: June 2024

This research aimed to address the potential bacterial contamination risks in developmental engineering (DE) using bacteriophages. To compare and contrast the exemplar Escherichia coli T4 and M13 bacteriophages, human dermal fibroblasts cultivated on culture plates, natural cellulosic scaffolds, and poly(methyl methacrylate) (PMMA) particles were utilized as two‐dimensional (2D) cell, three‐dimensional (3D) tissue, and modular tissue culture models, respectively. When directly introduced into these distinct culture systems, both phages survived, exhibited no significant effects on the cultured cells or tissues, yet displayed their potentials to alleviate the infections caused by corresponding bacterial host cells. Apart from direct addition into the culture medium, both phages were also coated on PMMA, polystyrene, poly(lactic acid) particles with different diameters (5, 10, 30, and 100 µm) and cellulosic scaffolds. The coated phages endured the coating processes and demonstrated their viabilities in plaque assays. Further testing indicated that the phages coated on the PMMA particles tolerated multiple deliberate rinses and centrifugations, but not thermal treatment at 60–80°C. In summary, T4 and M13 bacteriophages not only manifested their antibacterial functions in diverse 2D cell, 3D tissue, and modular tissue culture systems, but also demonstrated their potentials of coating modular scaffolds to alleviate the bacterial contamination risks in DE.
Synergetic light and cytokinin treatments mitigate the recombinant protein yield depression induced by high‐density cultivation of hydroponically‐grown Nicotiana benthamiana
Authors: Bilotta Stefano , Éthier Gilbert , Laliberté Ann‐Catherine , Goulet Marie‐Claire , Martel Michèle , Michaud Dominique , Pepin Steeve
Published: June 2024

Plant molecular farming is currently operating a transition from soil‐based cultures toward hydroponic systems. In this study, we designed a whole‐plant NFT (nutrient film technique) platform for the transient expression of influenza virus‐like particles harboring hemagglutinin H1 proteins in Nicotiana benthamiana. In particular, we examined the effects of plant density during the post‐infiltration expression phase on plant growth and H1 yield in relation to the daily light integral (DLI) received by the crop and the exogenous application of 6‐BAP cytokinin (CK). We expected from previous work that high DLI and CK treatments would stimulate the development of highly productive leaves on axillary (secondary) stems and thereby improve the H1 yield at the whole‐plant scale. Increasing plant density from 35.7 to 61 plants m–2 during the post‐infiltration phase significantly decreased the proportion of axillary leaf biomass by 30% and H1 yield per plant by 39%, resulting in no additional yield gain on a whole‐crop area basis. Adding CK to the recirculated nutrient solution decreased the harvested leaf biomass by 31% and did not enhance the relative proportion of S leaves of the plants as previously reported with foliar CK application. There was a 36% increase in H1 yield when doubling the DLI from 14 to 28 mol m–2 s–1, and up to 71% yield gain when combining such an increase in DLI with the hydroponic CK treatment. Contrary to our expectations, leaves located on the main stem, particularly those from the upper half of the plant (i.e., eighth leaf and above), contributed about 80% of total H1 yield. Our study highlights the significantly different phenotype (~30% less secondary leaf biomass) and divergent responses to light and CK treatments of NFT‐grown N. benthamiana plants compared to previous studies conducted on potted plants.
Engineering strategies to mitigate toxicities associated with CAR‐T cell therapy
Authors: Wolter Tyler , Wang Yixin , Hu Quanyin
Published: June 2024

Chimeric antigen receptor (CAR) T cell therapy is a form of adoptive cell therapy that has revolutionized the field of cancer immunotherapy. Owing to the unprecedented efficacy seen in the treatment of blood cancers, the FDA has now approved multiple CAR T cell products for the treatment of various hematologic malignancies. Despite the clinical success seen in hematologic malignancies, CAR T cell therapies have demonstrated only modest efficacy in the treatment of solid tumors. Thus, great efforts are underway to increase the treatment efficacy in solid tumors and further enhance the treatment of hematologic malignancies. However, irrespective of advancements in efficacy, there are still unmet needs for patients receiving CAR T cell therapies. CAR T cell therapies carry significant risks of potentially fatal toxicities, and few of these toxicities were predicted in the animal models used to advance these therapies to the clinic. Therefore, significant advancements are needed to help reduce the incidence and severity of these toxicities to ultimately enhance patient safety and quality of life. This review will provide a brief overview of some of the major toxicities associated with CAR T cell therapies and will discuss the various engineering strategies used to mitigate such toxicities in preclinical models and clinical studies.
Effects of medicalization on case outcomes in transgender employment discrimination court decisions
Authors: Bender‐Baird Kyla , Stevenson Margaret C.
Published: June 2024

Some attorneys and legal scholars argue that medicalizing transgender plaintiffs (i.e., introducing plaintiff diagnoses and/or medical procedures) in discrimination cases will enhance favorable plaintiff outcomes. Research and theory linking biological essentialism (i.e., believing social groups reflect biologically‐rooted, stable categories) to prejudice, however, suggests that medicalizing transgender plaintiffs might not help them win cases and might instead backfire and harm their case outcomes. To test these competing hypotheses, we coded all published cases involving alleged transgender discrimination (N = 124) from 1974 to 2021. Importantly, we addressed limitations of existing research that narrowly defined transgender plaintiff medicalization exclusively via diagnosis by documenting various other forms of medicalization beyond diagnosis. Contrary to legal scholars' claims and attorney intuitions, medicalization did not predict favorable outcomes for transgender plaintiffs. In fact, various forms of medicalization beyond diagnosis predicted negative plaintiff case outcomes. We discuss the implications of this research for informing scientific theory and legal practice.
Characterization of cancer survivors clustered by subjective and objective cognitive function scores
Authors: Goto Taichi , Saligan Leorey N. , Juneau Paul , Gonsalves Stephen G. , Rio Carielle Joy , Graves Letitia Y. , Von Ah Diane
Published: June 2024

Background

Cancer‐related cognitive impairment (CRCI) is a prevalent condition that significantly impacts the quality of life of individuals who receive cancer treatment. Clinical management of CRCI presents challenges due to the absence of a standardized assessment. This study identified clinically relevant phenotypic clusters of CRCI based on subjective and objective cognitive function scores.

Methods

In this cross‐sectional study, participants were clustered using the VARCLUS™ based on subjective cognitive impairment assessed through the PROMIS® version 1.0 short‐form subscales of cognitive abilities and cognitive concerns and the CANTAB Cambridge Cognition® scores, which included measures of visuospatial working memory capacity, visual episodic memory, new learning, working memory, executive function, and sustained attention. Each cluster's characteristics were described using demographics, physical and psychosocial factors (physical function, affect, optimism, and social support), and psychoneurological symptoms (anxiety, depression, fatigue, neuropathic pain, and sleep disturbance).

Results

We obtained five clusters from a total of 414 participants, where 99% were female, and 93% were self‐reported white. Clusters 4 and 5 showed the highest PROMIS® cognitive abilities and the lowest measures of cognitive concern, while Clusters 1 and 2 showed the lowest cognitive abilities and the highest cognitive concerns. Clusters 4 and 5 had higher education, income, employment, and higher scores in physical function, positive affect, optimism, and social support. Additionally, individuals in these clusters were less prone to experience severe cancer‐related psychoneurological symptoms.

Conclusion

Our clustering approach, combining subjective and objective cognitive function information, shows promise in identifying phenotypes that hold clinical relevance for categorizing patient presentation of CRCI and facilitating individualized management strategies.
Real world, multicentre patterns of treatment and survival in metastatic renal cell carcinoma with the UK Renal Oncology Collaborative (UK ROC): Is it time to look favourably on first‐line immunotherapy containing combinations in all IMDC groups?
Authors: McGrane John , Frazer Ricky , Challapalli Amarnath , Ratnayake Gihan , Boh Zhaung , Clayton Alison , Chau Caroline , Sharma Anand , Elgendy Manal , Charnley Natalie , Mohamed Wael , Kingdon Sarah , Protheroe Andrew , Lydon Anna , Halstead Anna , Ford Vicky , Muazzam Iqtedar , Lee Dawn , Melendez‐Torres G. J. , Bahl Amit
Published: June 2024

Introduction

Clinical trials show improved progression‐free survival (PFS) and overall survival (OS) in first‐line metastatic renal cell carcinoma (mRCC) patients with immunotherapy containing systemic anti‐cancer therapies (SACT). However, in the favourable international metastatic renal cell cancer database consortium (IMDC) group there is no trial evidence for OS benefit despite clear PFS improvement when comparing anti‐VEGF tyrosine kinase inhibitor (TKI) monotherapy and (immunotherapy and TKI) IO/TKI combinations.

Objective

To assess the impact of first‐line SACT choice on the clinical outcomes of PFS and OS in mRCC. To evaluate this impact of initial SACT for allcomers and the favourable IMDC group.

Methods

A multicentre retrospective review of patients who started SACT for mRCC (01/01/2018–30/06/2021) at 17 UK NHS trusts. Patient demographics and IMDC group were analysed. Survival data were compared using Kaplan–Meier curves, and the statistical significance of differences in outcome between the groups was assessed with the log‐rank test. Univariable and multivariable Cox proportional hazard modelling estimate the hazard ratios (HRs) for survival outcomes associated with IMDC and treatment subtype.

Results

One thousand three hundred and nineteen patients were identified with a median age of 64. 294 (22.3%), 695 (52.7%) and 321 (24.3%) were IMDC group favourable, intermediate and poor, respectively. 311 (23.6%), 197 (14.9%) and 778 (59%) patients received checkpoint inhibitor and anti‐CTLA4 monoclonal antibody (IO/IO), IO/TKI and TKI first‐line SACT across all IMDC groups. Significant PFS improvement favouring IO/TKI versus TKI was demonstrated in allcomers HR = 0.61. In the favourable risk group, Log rank testing demonstrated a significant benefit for IO/TKI over TKI for PFS (HR = 0.60, 95% CI [0.39, 0.91]) and OS (HR = 0.42, 95% CI [0.18, 0.99]).

Conclusion

In this real‐world evidence cohort, we have shown OS and PFS benefit with IO/TKI versus TKI in the favourable IMDC risk group. This has not been previously reported from trial outcomes and would support use of front‐line IO/TKI in mRCC favourable risk patients.
Barriers, facilitators, and other factors associated with health behaviors in childhood, adolescent, and young adult cancer survivors: A systematic review
Authors: de Beijer Ismay A. E. , Bouwman Eline , Mulder Renée L. , Steensma Philippa , Brown Morven C. , Araújo‐Soares Vera , Balcerek Magdalena , Bardi Edit , Falck Winther Jeanette , Frederiksen Line Elmerdahl , van Gorp Marloes , Oberti Sara , van Kalsbeek Rebecca J. , Kepak Tomas , Kepakova Katerina , Gsell Hannah , Kienesberger Anita , van Litsenburg Raphaële , Mader Luzius , Michel Gisela , Muraca Monica , van den Oever Selina R. , van der Pal Helena J. H. , Roser Katharina , Skinner Roderick , Stolman Iridi , Uyttebroeck Anne , Kremer Leontien C. M. , Loonen Jacqueline , van Dalen Elvira C. , Pluijm Saskia M. F. ,   the PanCareFollowUp Consortium
Published: June 2024

Background

Healthy behaviors are paramount in preventing long‐term adverse health outcomes in childhood, adolescent, and young adult (CAYA) cancer survivors. We systematically reviewed and synthesized existing literature on barriers, facilitators, and other factors associated with health behaviors in this population.

Methods

MEDLINE and PsycInfo were searched for qualitative and quantitative studies including survivors aged 16–50 years at study, a cancer diagnosis ≤25 years and ≥2 years post diagnosis. Health behaviors included physical activity, smoking, diet, alcohol consumption, sun exposure, and a combination of these behaviors (defined as health behaviors in general).

Results

Barriers, facilitators, and other factors reported in ≥2 two studies were considered relevant. Out of 4529 studies, 27 were included (n = 31,905 participants). Physical activity was the most frequently examined behavior (n = 12 studies), followed by smoking (n = 7), diet (n = 7), alcohol (n = 4), sun exposure (n = 4), and health behavior in general (n = 4). Relevant barriers to physical activity were fatigue, lack of motivation, time constraints, and current smoking. Relevant facilitators were perceived health benefits and motivation. Influence of the social environment and poor mental health were associated with more smoking, while increased energy was associated with less smoking. No relevant barriers and facilitators were identified for diet, alcohol consumption, and sun exposure. Barriers to healthy behavior in general were unmet information needs and time constraints whereas lifestyle advice, information, and discussions with a healthcare professional facilitated healthy behavior in general. Concerning other factors, women were more likely to be physically inactive, but less likely to drink alcohol and more likely to comply with sun protection recommendations than men. Higher education was associated with more physical activity, and lower education with more smoking.

Conclusion

This knowledge can be used as a starting point to develop health behavior interventions, inform lifestyle coaches, and increase awareness among healthcare providers regarding which survivors are most at risk of unhealthy behaviors.
Targeted agents in patients with progressive glioblastoma—A systematic meta‐analysis of randomized clinical trials
Authors: Ippen Franziska Maria , Scherm Angelika , Kessler Tobias , Hau Peter , Agkatsev Sarina , Baurecht Hansjörg , Wick Wolfgang , Knüttel Helge , Leitzmann Michael F. , Seliger‐Behme Corinna
Published: June 2024

Background

Glioblastoma (GB) is the most common malignant primary brain tumor in adults and is associated with a poor prognosis. Current treatment guidelines outline the standard of care for patients with newly diagnosed GB; however, there is currently no well‐established consensus for the treatment of progressive GB. With this systematic meta‐analysis of recently published randomized controlled trials (RCTs), we aim to establish evidence on targeted agents in the treatment of patients with progressive GB.

Material and Methods

We conducted searches across the Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO‘s International Clinical Trials Registry Platform and Google Scholar, encompassing the time span from 1954 to 2022, aiming to identify RCTs evaluating targeted therapies in patients with progressive GB. In order to perform a random‐effects meta‐analysis, we extracted hazard ratios (HRs) of overall survival (OS) and progression‐free survival (PFS).

Results

We included 16 RCTs (n = 3025 patients) in the systematic meta‐analysis. Formally, regorafenib (RR 0.50; 95% CI 0.33–0.75), Depatux‐M + TMZ (RR 0.66; 95% CI 0.47–0.93) and rindopepimut + bevacizumab (RR 0.53; 95% CI 0.32–0.88) were associated with an improved OS compared to the control arm. The combination of bevacizumab + CCNU (RR = 0.49; 95% CI 0.35–0.69) and regorafenib (RR 0.65; 95% CI 0.44–0.95) were formally associated with improved PFS.

Conclusions

The aim of this systematic meta‐analysis was to establish evidence for the use of targeted therapies in progressive GB. While some studies demonstrated benefits for OS and/or PFS, those results have to be interpreted with caution as most studies had major methodological weaknesses, including potential differences in sample size, trial design, or the initial distribution of prognostic factors.
Fully automated viability and toxicity screening—A reliable all‐in‐one attempt
Authors: Liedtke Victoria , Weiss Romano , Skifov Anastasia , Rödiger Stefan , Schenk Lysann
Published: June 2024

Background

The CRISPR/Cas9 technology is nowadays a common tool for genome editing to achieve new insights into, for example, diagnostics and therapeutics in cancer and genetic disorders. Cell proliferation and anticancer drug response studies are widely used to evaluate the impact of editing. However, these assays are often time‐consuming, expensive, and reproducibility is an issue. To overcome this, we developed a fast and cheap assay that combines a fully automated multispectral fluorescence microscopy platform with a nuclei staining and open‐source software analysis.

Methods

Here, we generated different LEDGF/p75 model cell lines to validate the effect on proliferation and chemosensitivity. Therefore, a fast protocol for an optimized all‐in‐one attempt for cytotoxicity screenings and proliferation analysis of adherent cells in a 96‐well plate format was established using differential staining with two fluorescent dyes (Hoechst 33342 and propidium iodide) for live/dead cell discrimination. Subsequently, an automated cell nuclei count and analysis were performed using bioimage informatics.

Results

With the new established assay technology, up to 50,000 cells/well can be detected and analyzed in a 96‐well plate, resulting in a fast and accurate verification of viability and proliferation with consistency of 98% compared to manual counting. Our screening revealed that LEDGF depletion using CRISPR/Cas9 showed a diminished proliferation and chemosensitivity independent of cell line origin. Moreover, LEDGF depletion caused a significant increase in 𝛾H2AX foci, indicating a substantial increase in DNA double strand breaks. LEDGF/p75 overexpression enhanced proliferation and chemoresistance underlining the role of LEDGF in DNA damage response.

Conclusion

Independent of cancer cell type, LEDGF/p75 is a central player in DNA damage repair and is implicated in chemoresistance. Moreover, our automated fluorescence biosensor technology allowed fast and reliable data acquisition without any fixation or additional washing steps. Additionally, data analysis was implemented using the modular open‐source software that can be adapted as needed.
Bioinformatics‐based identification of hepatocellular carcinoma‐associated hub genes and assessment of the restorative effect of tannic acid in rat liver exposed to monosodium glutamate
Authors: Tosun Hilal , Karadas Habibe , Ceylan Hamid
Published: June 2024

Background

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, occurring mostly in individuals with chronic liver disease, but biomarkers for therapeutic diagnosis and prognosis are lacking. This study aimed to investigate the possible effect of the common food additive monosodium glutamate (MSG) and tannic acid (TA), a phenolic compound, on the key molecular actors responsible for HCC development.

Methods

Eight HCC‐related public microarray datasets (GSE84005, GSE14520, GSE25097, GSE57958, GSE22058, GSE84402, GSE54238, and GSE36376) were extracted from the gene expression omnibus (GEO) database and analyzed to identify differentially expressed genes (DEGs). To make sense of the identified biological data and to identify hub genes, protein–protein interaction (PPI) network and enrichment analysis were performed. The mRNA expression profiles of the identified hub genes, expression changes in different stages of HCC, and their prognostic significances in HCC were determined using GEPIA, UALCAN, and Kaplan–Meier Plotter databases, respectively. Finally, mRNA expression changes of identified hub genes in the liver tissues of rats treated with MSG and TA were measured by the quantitative real‐time PCR (qPCR) method.

Results

Two up‐regulated (AURKA and CCNB2) and two down‐regulated (F9 and CYP2E1) genes were identified between the HCC tumor and adjacent non‐tumor liver tissue samples. qPCR results showed that the mRNA expression of up‐regulated DEGs involved in HCC development increased significantly in rat liver tissues exposed to MSG, while this increase was remarkably suppressed by TA treatment. It was observed that the mRNA expressions of down‐regulated DEGs involved in HCC development decreased markedly in the presence of MSG, while this decrease was alleviated with TA.

Conclusion

Our results provide new insights into pivotal molecular candidates that should be focused on in future in vivo and in vitro HCC research. Moreover, MSG may play a crucial role in HCC development and progression and TA may be used as a favorable restorative agent in HCC.
Phase II clinical trial of nab‐paclitaxel plus cisplatin plus gemcitabine (NABPLAGEM) in patients with untreated advanced pancreatic cancer
Authors: Jameson Gayle S. , Hosein Peter J. , Pierce Erin , Kamgar Mandana , Gordon Michael S. , Snyder Courtney , Roe Denise J. , Wertheim Betsy C. , Davey Marina , Barrett Michael T. , Von Hoff Daniel D. , Borazanci Erkut
Published: June 2024

Background

A previous phase IB/II study of nab‐paclitaxel + cisplatin + gemcitabine (NABPLAGEM) in 25 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) demonstrated favorable results. This phase II study was conducted to further evaluate the safety, efficacy, and impact on quality of life (QOL) of NABPLAGEM in a multi‐center setting.

Methods

Participants were ≥18 years; had measurable PDAC; Karnofsky performance status of ≥70%; life expectancy ≥12 weeks; <grade 2 pre‐existing peripheral neuropathy, and adequate hematologic, hepatic, and renal function. Study treatment included nab‐paclitaxel (125 mg/m2), cisplatin (25 mg/m2), and gemcitabine (1000 mg/m2), on Days 1 and 8 of a 21‐day cycle. The primary endpoint was 12‐month overall survival (OS).

Results

A total of 42 patients were enrolled with a median age of 66.8 years, a majority were male (66.7%) and white (76.2%). Treatment‐related adverse events ≥grade 3 were: thrombocytopenia (64.3%), anemia (47.6%), and neutropenia (26.1%). OS at 12 months was 38.1%, with 12% of patients alive as of last contact (20–40+ months). In 37 evaluable participants responses included: partial response (40.5%), stable disease (43.2%), and progressive disease (16.2%), with overall response rate of 40.5% and DCR of 88.6%. Statistically significant improvement in QOL was reported during the first three cycles.

Conclusion

The primary objective of achieving a 12‐month survival comparable to the previous phase Ib/II NABPLAGEM PCRT 12‐001 was not achieved in this trial. NABPLAGEM has efficacy in advanced PDAC, demonstrating early disease control noted by improvement in patient symptoms, decrease in tumor volume and tumor markers within the first 9 weeks. The activity and tolerability make this a suitable regimen for further testing in the neoadjuvant setting.
Lymphocyte activation markers predict the therapeutic response to immune checkpoint inhibitors: A case–control study
Authors: Iwamoto Takuya , Fujimoto Hajime , Kobayashi Tetsu , Gabazza Esteban C.
Published: June 2024

Background

Reports on changes in circulating immune cells induced by immune checkpoint inhibitors (ICIs) and their association with therapeutic responses are limited. This study aimed to analyze the interaction between ICIs and circulating blood cells in real‐world practice and identify biomarkers associated with therapeutic efficacy.

Materials and Methods

Patients with non‐small cell lung cancer who received nivolumab, pembrolizumab, or atezolizumab monotherapy were eligible. Blood samples were collected before and 7–21, and 22–42 days after treatment, and changes in the number and characteristics of neutrophils and lymphocytes in the peripheral blood were analyzed. The efficacy of ICIs was evaluated based on the best overall response up to 3 months after treatment. The patients were divided into the following groups: patients with non‐progressive disease (non‐PD) and those with progressive disease (PD). Blood immunological factors related to treatment response were analyzed.

Results

There were 16 and 27 patients in the non‐PD and PD groups, respectively. The non‐PD group had significantly lower pretreatment CD56+ cell (CD56+ IFN‐γ+ cell), and neutrophil counts at 7–21 days after ICI administration than the PD group. Additionally, there was a significant increase in CD8+ IFN‐γ+, and CD8+CD28+ IFN‐γ+ T‐cell counts 7–21 days after ICI administration in the non‐PD group. CD8+CD28+IFN‐γ+ T‐cell count greater than 94.6 cells/μL at 7–21 days after ICI administration was highly predictive with an AUC greater than 0.8 in the ROC curve analysis.

Conclusions

Predictors of disease progression include a low activated CD56+ cell count, no increase in the neutrophil count before ICI therapy, and an increase of activated CD8+ cell count early after ICI administration. The findings will contribute to selecting patients with a favorable therapeutic response and early prediction of therapeutic response to ICI.
Quality‐of‐life comparison between intensity‐modulated proton therapy and volumetric‐modulated arc therapy in patients with nasopharyngeal carcinoma: Preliminary findings from real‐world data
Authors: Wu Ching‐Nung , Wang Yu‐Ming , Chen Wei‐Chih , Wang Jung‐Der , Li Shau‐Hsuan , Hwang Chung‐Feng , Lin Yun‐Hsuan , Luo Sheng‐Dean , Lin Chung‐Ying
Published: June 2024

Background

Limited data are available to examine the effects of intensity‐modulated proton therapy (IMPT) on patient‐reported outcomes in patients with nasopharyngeal carcinoma (NPC). Thus, we assessed whether patients receiving IMPT reported a better short‐term quality of life (QoL) than those receiving volumetric‐modulated arc therapy (VMAT).

Methods

We consecutively invited newly diagnosed NPC patients who had undergone standard treatment protocol within 2 years post‐radiotherapy at our institute between 2021 and 2023 to participate in the observational study. All participants completed the EuroQol five‐dimension, World Health Organization Quality‐of‐Life—Brief, Sinonasal Outcome Test 22, Eustachian Tube Dysfunction Questionnaire‐7, and Eating Assessment Tool‐10 (EAT‐10) questionnaires. QoL functions were estimated using a kernel‐smoothing method. A linear mixed model introducing the inverse probability of treatment weighting was constructed to estimate the effect of IMPT versus VMAT.

Results

We identified 94 patients who completed 120 QoL assessments. Participants receiving IMPT were younger and had higher levels of education and higher household income. QoL functions showed that post‐treatment EAT‐10 scores consistently appeared significantly lower for IMPT than VMAT. After adjusting for factors including age, gender, education, household income, and cancer stages, patients receiving IMPT consistently showed significantly better QoL scores in EAT‐10, indicative of a medium effect. Additionally, factors such as age, household income level, and treatment regimen might influence either generic or condition‐specific QoL.

Conclusions

Patients receiving IMPT demonstrated potentially improved eating‐related QoL compared to those receiving VMAT within a 2‐year post‐radiotherapy period. However, larger head‐to‐head comparison studies are warranted to confirm these findings.
Hepatoprotective Lignan Glycosides from the Leaves and Stems of Symplocos cochinchinensis (Lour.) S. Moore
Authors: Giang Le Thi , Park SeonJu , Lee Sion , Seo Yohan , Van Kiem Phan , Tai Bui Huu , Hang Nguyen Thi Minh , Thao Vu Mai , Van Cuong Pham , Ban Ninh Khac , Cuong Nguyen The , Nhiem Nguyen Xuan
Published: June 2024

This study investigates Symplocos cochinchinensis (Lour.) S. Moore leaves and stems, commonly known as Symplocos, a plant indigenous to Asia renowned for its traditional use in holistic medicine. A comprehensive phytochemical analysis of S. cochinchinensis led to the isolation of two new lignans, namely symplolignans A and B (1 and 2) along with eleven known lignan glucosides: nortrachelogenin 4‐O‐β‐D‐glucopyranoside (3), nortracheloside (4), matairesinol 4‐O‐β‐D‐glucopyranoside (5), lariciresinol 4′‐O‐β‐D‐glucopyranoside (6), balanophonin 4‐O‐β‐D‐glucopyranoside (7), dehydrodiconiferyl alcohol 4‐O‐β‐D‐glucopyranoside (8), dehydrodiconiferyl alcohol γ′‐O‐β‐D‐glucopyranoside (9), 3‐(β‐D‐glucopyranosyloxymethyl)‐2‐(4‐hydroxy‐3‐methoxyphenyl)‐5‐(3‐hydroxypropyl)‐7‐methoxy‐(2R,3S)‐dihydrobenzofura (10), and pinoresinol 4′‐O‐β‐D‐glucopyranoside (11). Their chemical structures were elucidated using 1D‐ and 2D‐NMR, mass spectrometry, and their spectroscopic data were compared with those reported in literatures. Furthermore, all compounds were evaluated for their hepatoprotective effects using the Resazurin reduction assay in HepG2 hepatocellular carcinoma cells. Compounds 1, 5, 7, and 8 exhibited notable hepatoprotective efficacy, with cell viability ranging from 105.0±2.6 to 109.2±3.3 at a concentration of 10 μM. This research highlights the therapeutic potential of these compounds and enhanced to the understanding of lignans and neolignans in liver cell proliferation.
Exploration of the Mechanisms of Bu‐Yang‐Huan‐Wu Decoction in the Treatment of Diabetic Peripheral Neuropathy by Integrating of Serum Pharmacochemistry and Network Pharmacology
Authors: Chen Peng‐Fei , Huang Guang‐Xiao , Gu Wen‐Ting , Zhuang Guo‐Dong , Chen Chong , Wang Shu‐Mei , Tang Dan
Published: June 2024

Diabetic peripheral neuropathy (DPN) is a significant and frequent complication of diabetes. Bu‐Yang‐Huan‐Wu Decoction (BHD) is a classic traditional Chinese herbal prescription that is commonly used in modern clinical practice for the effective treatment of DPN, but the underlying mechanism is not yet clearly defined. The chemical constituents of BHD were characterized by UPLC‐Q‐Orbitrap HR MS/MS, and a total of 101 chemical components were identified, including 30 components absorbed into blood. An interaction network of “compound‐target‐disease” interactions was constructed based on the compounds detected absorbed in blood and their corresponding targets of diabetic neuropathy acquired from disease gene databases, and the possible biological targets and potential signalling pathways of BHD were predicted via network pharmacology analysis. Subsequently, methylglyoxal‐induced (MGO‐induced) Schwann cells (SCs) were used to identify the active ingredients in blood components of BHD and verify the molecular mechanisms of BHD. Through network topological analysis, 30 shared targets strongly implicated in the anti‐DPN effects of BHD were identifed. Combined network pharmacology and in vitro cellular analysis, we found that the active ingredient of BHD may treat DPN by modulating the AGEs/RAGE pathway. This study provides valuable evidence for future mechanistic studies and potential therapeutic applications for patients with DPN.
Talaromyces marneffei: A challenging diagnosis in a kidney transplant patient
Authors: Luo Sulin , Yan Pengpeng , Wang Xingxia , Ren Xue , Sun Ke , Guo Luying , Lv Junhao , Su Xinhui , Zhao Kui , Chen Jianghua , Wang Rending
Published: June 2024

Key Clinical Message

In addition to post‐transplant lymphoproliferative disorders, it is necessary to be alert to the drug‐resistant bacteria or fungal infection, especially Talaromyces marneffei, in kidney transplant patients who have failed antibiotic treatment and whose PET‐CT indicates high metabolic mass in the transplanted kidney with a large number of other organs and lymph nodes.

Talaromyces marneffei (TM) is a rare pathogenic fungus that primarily affects individuals with compromised immune systems. Post‐transplant lymphoproliferative disorders (PTLD) are serious complications that can occur after solid organ and cell transplantation. Both TM infection and PTLD can invade the monocyte–macrophage system and often manifest as extranodal masses. This case report describes a kidney transplant patient who presented with symptoms of frequent, urgent, and painful urination over 6 months. Pulmonary CT scans revealed multiple nodules, and PET‐CT demonstrated enlarged lymph nodes in the lungs and the transplanted kidney. The clinical manifestations closely mimicked those of PTLD. The confirmation of TM was achieved through pathogen metagenomic next‐generation sequencing and renal biopsy. Unfortunately, despite receiving treatment with antifungal agents, anti‐infective therapy, the patient's condition did not respond favorably, ultimately resulting in their unfortunate demise due to COVID‐19.
Metagenomic next‐generation sequencing in the early diagnosis of leptospirosis infection presenting as acalculous cholecystitis and septic shock in a non‐epidemic area after typhoons: A case report
Authors: Han Xueying , Huang Bihan , Yang Lilei , Wu Jinglan , Zhang Haigang
Published: June 2024

Key Clinical Message

Leptospirosis is an important zoonosis worldwide. Due to nonspecific clinical manifestation and poor recognition in non‐epidemic area, there is often a delay in diagnosis and treatment. Early diagnosis from Metagenomic next‐generation sequencing test is crucial for timely intervention.

We presented a case of a 19‐year‐old male patient who developed leptospirosis infection characterized by acalculous cholecystitis and septic shock after typhoon events. Metagenomic next‐generation sequencing (mNGS) helped to early diagnose leptospirosis infection. Finally, the patient achieved full recovery following the antibiotic treatment in addition to supportive care and was discharged.
Radiofrequency ablation of osteoid osteoma at the base of the coracoid process: Report of two cases
Authors: Babaei Mohammad Reza , Gharepapagh Esmaeil , Alamdari Amir Honarmand , Jalili Javad , Mohammadi Amin , Karbasi Mahsa , Rezaei Sahar
Published: June 2024

Key Clinical Message

If you encounter an unexplained case of bone marrow edema in a young patient, consider the possibility of osteoid osteoma (OO). Even in the presence of a nidus near vital structures, RFA can safely be used to treat OO.
Post cataract surgery refractive surprise due to intraocular lens mislabeling
Authors: Shokoohi Rad Saeed , Ansari Astaneh Mohammad Reza , Kiarudi Mohammad Yaser , Ghavami Shahri Seyed Hossein , Heidarzadeh Hamid Reza
Published: June 2024

Key Clinical Message

If an intraocular lens (IOL) is incorrectly labeled, problems can arise for surgeons and patients. Precise biometry is important to accurately determine the IOL power and prevent the implantation of the wrong IOL. Labeling and verifying IOLs with accuracy is crucial to ensuring the best possible results of cataract surgery.

Mislabeling of IOLs can cause unpredictable problems for surgeons. However, we can prevent incorrect IOLs by using precise biometry to determine accurate IOL power and safely implant the correct IOL. A 50‐year‐old female with no medical or ocular history came to our clinic complaining of decreased vision in both eyes that had been ongoing for several months. After being diagnosed with cataracts, primary angle closure suspect, and high hyperopia, the patient underwent phacoemulsification surgery. A posterior chamber IOL was implanted, and visco‐goniosynechialysis was performed. During follow‐up appointments, it was discovered that the patient had an uncorrected visual acuity of 20/50 in her right eye, which was corrected to 20/20 with a + 7.00 D lens. Upon further evaluation, it was determined that the source of the error was due to a manufacturing mislabeling of the IOL power. The patient then underwent successful IOL exchange surgery, and her best‐corrected visual acuity became 20/20 with no significant refraction. This case highlights an uncommon source of refractive surprise after phacoemulsification surgery, successfully managed with IOL exchange surgery using the same IOL power from a different brand.
Cancrum oris and hemiparesis in a young female patient—a case report
Authors: Ngokwe Zilefac Brian , Gimel Nokam Kamdem Stephane , Ntep David Bienvenue Ntep , Kalla Ginette Claude Mireille , Messanga Charles Bengondo
Published: June 2024

Key Clinical Message

Noma is still around today and can be deadly if ignored. Prompt identification and comprehensive care are essential for averting permanent impairments and disfigurements.

Noma is a rapid developing orofacial gangrene and a disabling disease that primarily affects young children who live in dangerous conditions. Underlying diseases such as HIV/AIDS and malnutrition can enhance the likelihood of Noma's emergence. This is a case of a 9‐year‐old girl patient who arrived malnourished and with an ulcerating communicating right mandibular soft tissue lesion as well as right hemiparesis which had an acute onset. The patient was likewise HIV positive discovered upon admission, possibly as a result of vertical transmission, and was an ART (antiretroviral therapy) treatment naive patient. A holistic treatment plan was installed and a positive clinical response was observed. Early treatment is key in Noma management.
Exploring B‐site Doping in LaFeO3 Perovskites for Superior ORR Performance in Acidic and Alkaline Conditions
Authors: Nandikes Gopa , Pathak Pankaj , Singh Lakhveer
Published: June 2024

In recent times, perovskite oxides have recognized to be an ideal alternative to platinum‐based oxygen reduction reaction (ORR) electrocatalysts due to their excellent stability, cost‐effectiveness, and tailorable properties. Herein, an ABO3 type LaFeO3 perovskite was doped at its B‐site to form electrochemically active LaFeB′O6 (B′=Cr, Zn, Co) by one‐pot hydrothermal synthesis process. Due to the synergistic effects of increased surface area and electrochemically active sites, Cr‐doped LaFeO3 largely improves the mass transfer kinetics for ORR in both conditions, alkaline (0.1 M KOH) and acidic (0.5 M H2SO4) with a positive onset Eon of 0.80 and 0.81 V (vs Ag/AgCl). Similarly, a half‐wave (E1/2) potential of 0.68 and 0.63 V (vs Ag/AgCl), which was comparable to the commercial 20 % Pt/C. Moreover, the La‐based perovskites were able to catalyze ORR with an electron transfer number (n)>3.6 signifying the superior 4‐electron pathway. Doped and undoped LaFeO3 exhibited remarkable stability in the chronoamperometry studies with a relative current of 92–95 % sustained over 8 h. Additionally, the La‐based electrocatalysts was unaffected by the crossover effect of methanol in both acidic and basic conditions, contrary to the commercial 20 % Pt/C. The present work serves as a useful strategy to maximize the efficiency and reliability in perovskites for energy‐related electrocatalytic applications and for alternative fuel generation.