bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep phenotyping of oxidative stress in emergency room patients reveals homoarginine as a novel predictor of sepsis severity, length of hospital stay, and length of intensive care unit stay
Authors: Ng Mei Li , Kuan Win Sen , Pakkiri Leroy Sivappiragasam , Goh Eugene Chen Howe , Wu Lik Hang , Drum Chester Lee
Published: November 2022

Background

We aimed to determine primary markers of oxidative stress (OS) in ED patients which predict hospital length of stay (LoS), intensive care unit (ICU) LoS, and sepsis severity.

Materials and methods

This prospective, single center observational study was conducted in adult patients recruited from the ED who were diagnosed with either sepsis, infection without sepsis, or non-infectious, age-matched controls. 290 patients were admitted to the hospital and 24 patients had direct admission to the ICU. A panel of 269 OS and related metabolic markers were profiled for each cohort. Clinical outcomes were direct ICU admission, hospital LoS, ICU LoS, and post-hoc, adjudicated sepsis severity scoring. Bonferroni correction was used for pairwise comparisons. Principal component regression was used for dimensionality reduction and selection of plasma metabolites associated with sepsis. Multivariable negative binomial regression was applied to predict admission, hospital, and ICU LoS.

Results

Homoarginine (hArg) was the top discriminator of sepsis severity [sepsis vs. control: ROC-AUC = 0.86 (95% CI 0.81–0.91)], [sepsis vs. infection: ROC-AUC = 0.73 (95% CI 0.68–0.78)]. The 25th percentile of hArg [odds ratio (OR) = 8.57 (95% CI 1.05–70.06)] was associated with hospital LoS [IRR = 2.54 (95% CI 1.83–3.52)] and ICU LOS [IRR = 18.73 (95% CI 4.32–81.27)]. In prediction of outcomes, hArg had superior performance compared to arginine (Arg) [hArg ROC-AUC = 0.77 (95% CI 0.67–0.88) vs. Arg ROC-AUC = 0.66 (95% CI 0.55–0.78)], and dimethylarginines [SDMA ROC-AUC 0.68 (95% CI 0.55–0.79) and ADMA ROC-AUC = 0.68 (95% CI 0.56–0.79)]. Ratio of hArg and Arg/NO metabolic markers and creatinine clearance provided modest improvements in clinical prediction.

Conclusion

Homoarginine is associated with sepsis severity and predicts hospital and ICU LoS, making it a useful biomarker in guiding treatment decisions for ED patients.
Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor
Authors: Yagai Tomoki , Nakamura Takahisa
Published: November 2022

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic disorders that 20-30% of the world population suffers from. The feature of NAFLD is excess lipid accumulation in the liver, exacerbating multiple metabolic syndromes such as hyperlipidemia, hypercholesterolemia, hypertension, and type 2 diabetes. Approximately 20-30% of NAFLD cases progress to more severe chronic hepatitis, known as non-alcoholic steatohepatitis (NASH), showing deterioration of hepatic functions and liver fibrosis followed by cirrhosis and cancer. Previous studies uncovered that several metabolic regulators had roles in disease progression as key factors. Peroxisome proliferator-activated receptor alpha (PPARα) has been identified as one of the main players in hepatic lipid homeostasis. PPARα is abundantly expressed in hepatocytes, and is a ligand-dependent nuclear receptor belonging to the NR1C nuclear receptor subfamily, orchestrating lipid/glucose metabolism, inflammation, cell proliferation, and carcinogenesis. PPARα agonists are expected to be novel prescription drugs for NASH treatment, and some of them (e.g., Lanifibranor) are currently under clinical trials. These potential novel drugs are developed based on the knowledge of PPARα-activating target genes related to NAFLD and NASH. Intriguingly, PPARα is known to suppress the expression of subsets of target genes under agonist treatment; however, the mechanisms of PPARα-mediated gene suppression and functions of these genes are not well understood. In this review, we summarize and discuss the mechanisms of target gene repression by PPARα and the roles of repressed target genes on hepatic lipid metabolism, fibrosis and carcinogenesis related to NALFD and NASH, and provide future perspectives for PPARα pharmaceutical potentials.
Signaling pathway intervention in premature ovarian failure
Authors: Bai Xuefeng , Wang Shaowei
Published: November 2022

Premature ovarian failure (POF) is a multifactorial disease that refers to the occurrence of secondary amenorrhea, estrogen decrease, and gonadotropin increase in women under the age of 40. The prevalence of POF is increasing year by year, and the existing instances can be categorized as primary or secondary cases. This disease has adverse effects on both the physiology and psychology of women. Hormone replacement therapy is the recommended treatment for POF, and a multidisciplinary strategy is required to enhance the quality of life of patients. According to recent studies, the primary mechanism of POF is the depletion of ovarian reserve function as a result of increased primordial follicular activation or primordial follicular insufficiency. Therefore, understanding the processes of primordial follicle activation and associated pathways and exploring effective interventions are important for the treatment of POF.
Engaging patients and citizens in digital health technology development through the virtual space
Authors: Barony Sanchez Romina Helena , Bergeron-Drolet Laurie-Ann , Sasseville Maxime , Gagnon Marie-Pierre
Published: November 2022

Digital technologies are increasingly empowering individuals to take charge of their health and improve their well-being. However, there are disparities in access related to demographic, economic, and sociocultural factors that result in exclusion from the use of digital technologies for different groups of the population. The development of digital technology in health is a powerful lever for improving care and services, but also brings risks for certain users in vulnerable situations. Increased digital health inequalities are associated with limited digital literacy, lack of interest, and low levels of self-efficacy in using technology. In the context of the COVID-19 pandemic and post-pandemic healthcare systems, the leap to digital is essential. To foster responsible innovation and optimal use of digital health by all, including vulnerable groups, we propose that patient and citizen engagement must be an essential component of the research strategy. Patient partners will define expectations and establish research priorities using their experiential knowledge, while benefiting from rich exposure to the research process to increase their self-efficacy and digital literacy. We will support this proposition with an operationalised example aiming to implement a Virtual Community of Patients and Citizens Partners (COMVIP), a digital tool co-created with patients and public experts, as active team members in research. Founded on the principles of equity, diversity and inclusion, this base of citizen expertise will assemble individuals from different backgrounds and literacy levels living in vulnerable situations to acquire knowledge, and share their experiences, while contributing actively in the co-development of innovative strategies and health technology assessment.
Quorum sensing in human gut and food microbiomes: Significance and potential for therapeutic targeting
Authors: Falà A. Kate , Álvarez-Ordóñez Avelino , Filloux Alain , Gahan Cormac G. M. , Cotter Paul D.
Published: November 2022

Human gut and food microbiomes interact during digestion. The outcome of these interactions influences the taxonomical composition and functional capacity of the resident human gut microbiome, with potential consequential impacts on health and disease. Microbe-microbe interactions between the resident and introduced microbiomes, which likely influence host colonisation, are orchestrated by environmental conditions, elements of the food matrix, host-associated factors as well as social cues from other microorganisms. Quorum sensing is one example of a social cue that allows bacterial communities to regulate genetic expression based on their respective population density and has emerged as an attractive target for therapeutic intervention. By interfering with bacterial quorum sensing, for instance, enzymatic degradation of signalling molecules (quorum quenching) or the application of quorum sensing inhibitory compounds, it may be possible to modulate the microbial composition of communities of interest without incurring negative effects associated with traditional antimicrobial approaches. In this review, we summarise and critically discuss the literature relating to quorum sensing from the perspective of the interactions between the food and human gut microbiome, providing a general overview of the current understanding of the prevalence and influence of quorum sensing in this context, and assessing the potential for therapeutic targeting of quorum sensing mechanisms.
Octocorals in the Gulf of Aqaba exhibit high photosymbiont fidelity
Authors: Liberman Ronen , Benayahu Yehuda , Huchon Dorothée
Published: November 2022

Symbiotic associations, widespread in terrestrial and marine ecosystems, are of considerable ecological importance. Many tropical coral species are holobionts, formed by the obligate association between a cnidarian host and endosymbiotic dinoflagellates of the family Symbiodiniaceae. The latter are abundant on coral reefs from very shallow water down to the upper mesophotic zone (30–70 m). The research on scleractinians has revealed that the photosymbiont lineages present in the cnidarian host play an important role in the coral’s ability to thrive under different environmental conditions, such as light regime and temperature. However, little is known regarding octocoral photosymbionts, and in particular regarding those found deeper than 30 m. Here, we used ribosomal (ITS2) and chloroplast (23S) markers to uncover, for the first time, the dominant Symbiodiniaceae taxa present in 19 mesophotic octocoral species (30–70 m depth) from the Gulf of Aqaba/Eilat (northern Red Sea). In addition, using high-throughput sequencing of the ITS2 region we characterized both the dominant and the rare Symbiodiniaceae lineages found in several species across depth. The phylogenetic analyses of both markers were in agreement and revealed that most of the studied mesophotic octocorals host the genus Cladocopium. Litophyton spp. and Klyxum utinomii were exceptions, as they harbored Symbiodinium and Durusdinium photosymbionts, respectively. While the dominant algal lineage of each coral species did not vary across depth, the endosymbiont community structure significantly differed between host species, as well as between different depths for some host species. The findings from this study contribute to the growing global-catalogue of Cnidaria-Symbiodiniaceae associations. Unravelling the Symbiodiniaceae composition in octocoral holobionts across environmental gradients, depth in particular, may enable a better understanding of how specialized those associations are, and to what extent coral holobionts are able to modify their photosymbionts.
From immune equilibrium to immunodynamics
Authors: Chen Xiaoping
Published: November 2022

Objective

The immunology field has long been short of a universally applicable theoretical model that can quantitatively describe the immune response, and the theory of immune equilibrium (balance) is usually limited to the interpretation of the philosophical significance of immune phenomena. Therefore, it is necessary to establish a new immunological theory, namely, immunodynamic theory, to reanalyze the immune response.

Methods

By quantifying the immune dynamic equilibrium as the ratio of positive and negative immune power, the immune dynamic equilibrium equation was established. Then, the area under the curve of the positive and negative immune power was assumed to be equal in the whole process of immune response (regardless of correct or not), and through thought experiments based on this key hypothesis, a series of new concepts and expressions were derived, to establish a series of immunodynamic equations.

Results

New concepts of immune force and immune braking force and their expression equations, namely, the theoretical equations of immunodynamics, were derived through thought experiments, and the theoretical curves of immunodynamics were obtained according to these equations. Via the equivalent transformation of the theoretical equations and practical calculation of functional data, and by the methods of curve comparison and fitting, some practical equations of immunodynamics were established, and these practical equations were used to solve theoretical and practical problems that are related to the immunotherapy of infectious diseases and cancers.

Conclusion

The traditional theory of immune equilibrium has been mathematized and transformed from a philosophical category into a new concrete scientific theory, namely the theory of immunodynamics, which solves the dilemma that the traditional theory cannot guide individualized medical practice for a long time. This new theory may develop into one of the core theories of immunology in the future.
Four new species and three new records of helicosporous hyphomycetes from China and their multi-gene phylogenies
Authors: Lu Yong-Zhong , Ma Jian , Xiao Xing-Juan , Zhang Li-Juan , Xiao Yuan-Pin , Kang Ji-Chuan
Published: November 2022

Helicosporous hyphomycetes have the potential to produce a variety of bioactive compounds. However, the strain resources of this fungal group are relatively scarce, which limits their further exploitation and utilization. In this study, based on phylogenetic analyses of combined ITS, LSU, RPB2, and TEF1α sequence data and the morphology from 11 isolates, we introduce four new species of helicosporous hyphomycetes, viz. Helicoma wuzhishanense, Helicosporium hainanense, H. viridisporum, and Neohelicomyces hainanensis, as well as three new records, viz. Helicoma guttulatum, H. longisporum, and Helicosporium sexuale. Detailed morphological comparisons of the four new species that distinguish them are provided.
Reviewing the state of the art of probiotics as clinical modalities for brain–gut–microbiota axis associated disorders
Authors: Wiegers Cato , Veerman Mariët A. , Brummer Robert Jan , Larsen Olaf F. A.
Published: November 2022

The rise in prevalence of mental and neurological disorders is causing a high burden on society, however adequate interventions are not always available. The brain–gut–microbiota axis (BGMA) may provide a new angle for the development of clinical modalities. Due to the intricate bi-directional signaling between the brain and the gut, it may be helpful to look into interventions that target the gut, such as probiotics. Therefore, this review aimed to investigate the state of the art of probiotics and their potential as clinical modalities for BGMA-associated indications by gaining insight into patents and clinical trials that have been applied for and executed since 1999. A total of 565 patents and 390 clinical trials were found, focusing on probiotic applications for 83 indications. Since the start of the 21st century, the highest numbers of patents and clinical trials were related to primary neuropsychological, affective (depression, anxiety) and cognitive disorders, neurodegenerative and/or inflammatory brain disorders (Alzheimer’s disease, Parkinson’s disease, amongst others), and gastrointestinal disorders (irritable bowel syndrome). The locations where the most patents and clinical trials were registered included China, the United States, and Iran. From 1999 to ~2013 a slight growth could be seen in the numbers of patents and clinical trials, followed by an almost exponential growth from ~2013 onwards. Overall, the developments of the state of the art were in accordance with previous research, however it appeared that clinical trials showed a slightly slower growth compared to patents, which may have implications for the future implementation of probiotics as clinical modalities for BGMA-associated indications.
An anchored experimental design and meta-analysis approach to address batch effects in large-scale metabolomics
Authors: Shaver Amanda O. , Garcia Brianna M. , Gouveia Goncalo J. , Morse Alison M. , Liu Zihao , Asef Carter K. , Borges Ricardo M. , Leach Franklin E. , Andersen Erik C. , Amster I. Jonathan , Fernández Facundo M. , Edison Arthur S. , McIntyre Lauren M.
Published: November 2022

Untargeted metabolomics studies are unbiased but identifying the same feature across studies is complicated by environmental variation, batch effects, and instrument variability. Ideally, several studies that assay the same set of metabolic features would be used to select recurring features to pursue for identification. Here, we developed an anchored experimental design. This generalizable approach enabled us to integrate three genetic studies consisting of 14 test strains of Caenorhabditis elegans prior to the compound identification process. An anchor strain, PD1074, was included in every sample collection, resulting in a large set of biological replicates of a genetically identical strain that anchored each study. This enables us to estimate treatment effects within each batch and apply straightforward meta-analytic approaches to combine treatment effects across batches without the need for estimation of batch effects and complex normalization strategies. We collected 104 test samples for three genetic studies across six batches to produce five analytical datasets from two complementary technologies commonly used in untargeted metabolomics. Here, we use the model system C. elegans to demonstrate that an augmented design combined with experimental blocks and other metabolomic QC approaches can be used to anchor studies and enable comparisons of stable spectral features across time without the need for compound identification. This approach is generalizable to systems where the same genotype can be assayed in multiple environments and provides biologically relevant features for downstream compound identification efforts. All methods are included in the newest release of the publicly available SECIMTools based on the open-source Galaxy platform.
The longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in older adults
Authors: Hausman Hanna K. , Dai Yunfeng , O’Shea Andrew , Dominguez Vanessa , Fillingim Matthew , Calfee Kristin , Carballo Daniela , Hernandez Cindy , Perryman Sean , Kraft Jessica N. , Evangelista Nicole D. , Van Etten Emily J. , Smith Samantha G. , Bharadwaj Pradyumna K. , Song Hyun , Porges Eric , DeKosky Steven T. , Hishaw Georg A. , Marsiske Michael , Cohen Ronald , Alexander Gene E. , Wu Samuel S. , Woods Adam J.
Published: November 2022

Background: Older adults are at a greater risk for contracting and experiencing severe illness from COVID-19 and may be further affected by pandemic-related precautions (e.g., social distancing and isolation in quarantine). However, the longitudinal impact of the COVID-19 pandemic on older adults is unclear. The current study examines changes in health behaviors, psychosocial factors, and cognitive functioning in a large sample of older adults using a pre-pandemic baseline and longitudinal follow-up throughout 9 months of the COVID-19 pandemic.

Methods: One hundred and eighty-nine older adults (ages 65-89) were recruited from a multisite clinical trial to complete additional virtual assessments during the COVID-19 pandemic. Mixed effects models evaluated changes in health behaviors, psychosocial factors, and cognitive functioning during the pandemic compared to a pre-pandemic baseline and over the course of the pandemic (i.e., comparing the first and last COVID-19 timepoints).

Results: Compared to their pre-pandemic baseline, during the pandemic, older adults reported worsened sleep quality, perceived physical health and functioning, mental health, slight increases in depression and apathy symptoms, reduced social engagement/perceived social support, but demonstrated better performance on objective cognitive tasks of attention and working memory. Throughout the course of the pandemic, these older adults reported continued worsening of perceived physical health and function, fewer depression symptoms, and they demonstrated improved cognitive performance. It is important to note that changes on self-report mood measures and cognitive performance were relatively small regarding clinical significance. Education largely served as a protective factor, such that greater years of education was generally associated with better outcomes across domains.

Conclusions: The present study provides insights into the longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in a population disproportionately affected by the virus. Replicating this study design in a demographically representative older adult sample is warranted to further inform intervention strategies targeting older adults negatively impacted by the COVID-19 pandemic.
Regional brain dysfunction in insomnia after ischemic stroke: A resting-state fMRI study
Authors: Wang Hongzhuo , Huang Yunxuan , Li Mingrui , Yang Han , An Jie , Leng Xi , Xu Danghan , Qiu Shijun
Published: November 2022

Objective

This study aimed to explore the abnormality of local brain function in patients with post-stroke insomnia (PSI) based on fMRI and explore the possible neuropathological mechanisms of insomnia in patients with PSI in combination with the Pittsburgh sleep quality index (PSQI) score and provide an objective evaluation index for the follow-up study of acupuncture treatment of PSI.

Methods

A total of 27 patients with insomnia after stroke were enrolled, and the PSQI was used to evaluate their sleep status. Twenty-seven healthy participants who underwent physical examinations during the same period were selected as controls. Resting-state brain function images and structural images of the two groups of participants were collected, and the abnormal changes in the regional brain function in patients with PSI were analyzed using three methods: regional homogeneity (ReHo), the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF), and a correlation analysis with the PSQI scale score.

Results

Compared with the HCs, the ReHo values of the PSI group in the bilateral lingual gyrus, right cuneus, right precentral and postcentral gyri were significantly lower, and the ReHo values of the left supramarginal gyrus were significantly higher. In the PSI group, the ALFF values in the bilateral lingual gyrus were significantly decreased, whereas those in the bilateral middle temporal gyrus, right inferior temporal gyrus, right inferior frontal gyrus, right limbic lobe, right precuneus, left posterior cingulate gyrus, and left middle occipital gyrus were significantly increased. Compared with HCs, the fALFF values of the bilateral lingual gyrus, bilateral inferior occipital gyrus, and bilateral cuneus in the PSI group were significantly higher. The ReHo value of the left supramarginal gyrus in the PSI group was significantly negatively correlated with the total PSQI score.

Conclusion

Patients with PSI have abnormal local activities in multiple brain regions, including the visual processing-related cortex, sensorimotor cortex, and some default-mode network (DMN) regions. Over-arousal of the DMN and over-sensitivity of the audiovisual stimuli in patients with PSI may be the main mechanisms of insomnia and can lead to a decline in cognitive function and abnormalities in emotion regulation simultaneously.
Repetitive bout of controlled soccer heading does not alter heart rate variability metrics: A preliminary investigation
Authors: Smirl Jonathan David , Peacock Dakota , Burma Joel Stephen , Wright Alexander D. , Bouliane Kevin J. , Dierijck Jill , van Donkelaar Paul
Published: November 2022

Objectives

There is elevated unease regarding how repetitive head impacts, such as those associated with soccer heading, contribute to alterations in brain function. This study examined the extent heart rate variability (HRV) and cardiac baroreceptor sensitivity (BRS) metrics are altered immediately following an acute bout of soccer heading.

Methods

Seven male elite soccer players (24.1 ± 1.5 years) completed 40 successful soccer headers in 20-min. The headers were performed under controlled circumstances using a soccer ball launcher located 25 meters away and using an initial ball velocity of 77.5 ± 3.7 km/h (heading condition). An accelerometer (xPatch) on the right mastoid process quantified linear/rotational head accelerations. Participants also completed sham (body contact) and control (non-contact) sessions. A three-lead ECG and finger photoplethysmography characterized short-term spontaneous HRV/cardiac BRS, before and after each condition. The SCAT3 indexed symptom scores pre-post exposures to all three conditions.

Results

During the heading condition, cumulative linear and rotational accelerations experienced were 1,574 ± 97.9 g and 313,761 ± 23,966 rad/s2, respectively. Heart rate trended toward an increase from pre- to post-heading (p = 0.063), however HRV metrics in the time-domain (ps > 0.260) and frequency-domain (ps > 0.327) as well as cardiac BRS (ps > 0.144) were not significantly changed following all three conditions. Following the heading condition, SCAT3 symptom severity increased (p = 0.030) with a trend for symptom score augmentation (p = 0.078) compared to control and sham.

Conclusion

Whereas, symptoms as measured by the SCAT3 were induced following an acute bout of controlled soccer heading, these preliminary findings indicate they were not accompanied by alterations to autonomic function. Ultimately, this demonstrates further research is needed to understand the physiological underpinnings of alterations in brain function occurring immediately after a bout of soccer heading and how these may, over time, contribute to long-term neurological impairments.
Emerging current trends and research focus related to pancreatic cancer metabolism: A bibliometric and visualized analysis
Authors: Shen Qian , Zhang Chuanlong , Jiang Xiaochen , Li Junchen , Liu Fudong , Zhang Xiyuan , En Ge’er , Pang Bo
Published: November 2022

Background

As a malignant digestive system tumor, pancreatic cancer has unique metabolic characteristics. In recent years, the study of pancreatic cancer metabolism is in full swing, which provides a new direction for the treatment of pancreatic cancer patients. However, there is no systematic report of pancreatic cancer metabolism. In this paper, bibliometrics and visualization methods were used to analyze the number of publications, countries/regions, authors, institutions, journals, co-cited references, and keywords of pancreatic cancer metabolism articles, to summarize the research trends and predict research hotspots.

Methods

We searched, screened and downloaded articles on pancreatic cancer metabolism through the Web of Science Core Collection (WoSCC). Using CiteSpace, VOSviewer and Bibliometrix Package to analyze publications, countries/regions, authors, institutions, journals, co-cited references, and keywords of pancreatic cancer metabolism to identify research trends and predict research hotspots.

Results

According to the inclusion and exclusion criteria, a total of 5,255 articles were retrieved during the period 1943-2022. The number of publications on pancreatic cancer metabolism is increasing year by year. The United States (n=1602, 30.49%), China (n=1074, 20.44%), and Italy (n=313, 5.96%) are the three countries with the largest number of publications and citations, and there is close cooperation between countries. LI J (n=55) is the most prolific author. FUDAN UNIV (n=348) is the most published institution. CANCERS (n=118), PLOS ONE (n=93), and CANCER RESEARCH (n=80) are the most popular journals in this field. “Nutriment-deficient environment”, “cancer chemoprevention” and “targeting cancer stem cell” are the main areas of focus. “immunotherapy”, “ferroptosis” and “targeted therapy” are hot keywords in recent years. Taking pancreatic cancer metabolism as an entry point to study the role of traditional Chinese medicine (TCM) mainly focuses on curcumin and resveratrol, lack of broader and deeper research on TCM.

Conclusions

The number of publications on pancreatic cancer metabolism has generally increased, and scholars have generally paid more attention to this field. “immunotherapy”, “ferroptosis” and “targeted therapy” are the current research hotspots. The in-depth study of pancreatic cancer metabolism will provide new ideas for the treatment of pancreatic cancer.
Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
Authors: Howard David , James David , Garcia-Parra Jezabel , Pan-Castillo Belen , Worthington Jenny , Williams Nicole , Coombes Zoe , Rees Sophie Colleen , Lutchman-Singh Kerryn , Francis Lewis W. , Rees Paul , Margarit Lavinia , Conlan R. Steven , Gonzalez Deyarina
Published: November 2022

Background

Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC.

Aim

The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility.

Methods

The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study.

Results and conclusions

Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC.
Emerging roles of alternative RNA splicing in oral squamous cell carcinoma
Authors: Liu Miaomiao , Guo Jihua , Jia Rong
Published: November 2022

Alternative RNA splicing (ARS) is an essential and tightly regulated cellular process of post-transcriptional regulation of pre-mRNA. It produces multiple isoforms and may encode proteins with different or even opposite functions. The dysregulated ARS of pre-mRNA contributes to the development of many cancer types, including oral squamous cell carcinoma (OSCC), and may serve as a biomarker for the diagnosis and prognosis of OSCC and an attractive therapeutic target. ARS is mainly regulated by splicing factors, whose expression is also often dysregulated in OSCC and involved in tumorigenesis. This review focuses on the expression and roles of splicing factors in OSCC, the alternative RNA splicing events associated with OSCC, and recent advances in therapeutic approaches that target ARS.
Case report: an initially unresectable stage III pulmonary sarcomatoid carcinoma qith EGFR mutation achieving pathological complete response following neoadjuvant therapy with osimertinib plus chemotherapy
Authors: Liu Xiguang , Zheng Yating , Mai Shijie , Tong Yu , Yang Lili , Huang Mengli , Cai Ruijun
Published: November 2022

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) provide dramatic response to patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, the use of neoadjuvant therapy with EGFR-TKIs in EGFR-mutant NSCLC remains controversial, especially in pulmonary sarcomatoid carcinoma (PSC). One patient with initially unresectable stage III (cT4N0M0) PSC was found to carry EGFR mutation by the next generation sequencing. After neoadjuvant therapy with osimertinib plus chemotherapy, radical resection of the right upper lung lesion was achieved, and the pathological results reached pathological complete response (pCR). To the best of our knowledge, this is the first report of an EGFR-mutant patient with initially unresectable stage III PSC achieved pCR by neoadjuvant therapy with osimertinib plus chemotherapy. Therefore, neoadjuvant therapy with EGFR-TKIs may be a viable option for EGFR-mutant PSC patients.
Conditioning regimens for allogeneic hematopoietic cell transplantation in acute myeloid leukemia: Real-world data from the Japanese registry studies
Authors: Yanada Masamitsu , Harada Kaito , Shimomura Yoshimitsu , Arai Yasuyuki , Konuma Takaaki
Published: November 2022

Conditioning regimens play a crucial role in preventing relapse of acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). In early times, myeloablative conditioning was used exclusively, but it was associated with significant toxicity. However, the advent of reduced-intensity conditioning has allowed allogeneic HCT to be performed more safely, leading to an expansion of our choices for conditioning regimens. As the transplantation methods have become highly diversified, it is reasonable to determine an optimal conditioning regimen in consideration of patient-, disease-, and transplantation-related factors. In this context, large-scale registry-based studies provide real-world data to allow for a detailed evaluation of the utility of individual conditioning regimens in specific clinical settings. The Japanese Society for Transplantation and Cellular Therapy has been conducting a nationwide survey for HCT since 1993 that currently covers >99% of all the transplantation centers nationwide, and >1,000 allogeneic HCTs performed for adults with AML are registered per year. We have been using the registry data to implement a number of studies focusing on adults with AML, and the large number of patients registered consecutively from nearly all transplantation centers nationwide represent real-world practice in Japan. This article reviews and discusses the results obtained from our registry-based studies pertaining to various conditioning regimens.
Case Report: Small intestinal metastatic breast cancer: A case report and literature review
Authors: Li Yishan , Zhang Lianru , Yu Huiping , Xin Xiaoyan , He Jian , Yao Yongzhong , Liu Baorui , Li Rutian , Xie Li
Published: November 2022

Breast cancer is considered a malignant tumor with the highest incidence among women and is prone to develop distant metastasis. Small intestinal metastasis of breast cancer, however, is relatively rare. This case report describes a 49-year-old Chinese female patient who presented with small intestinal obstruction and was diagnosed with lobular breast cancer with small intestinal and contralateral breast metastasis. Clinical manifestations, clinicopathological features and potential mechanisms of metastasis, along with diagnosis and treatment, are discussed with a review of the relevant literature. Although small intestinal metastasis is rare in breast cancer, we should keep high alert on the possibility of gastrointestinal metastasis when treating lobular breast cancer patients.
Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism
Authors: Shen Xianhuan , Chen Xinyi , Lu Jieluan , Chen Qing , Li Wenzhou , Zhu Jiahao , He Yaodong , Guo Huijuan , Xu Chenshu , Fan Xiaomei
Published: November 2022

Objective: The aim of this study was to establish a population pharmacokinetic (PPK) model of valproic acid (VPA) in pediatric patients with epilepsy in southern China, and provide guidance for individualized medication of VPA therapy.

Methods: A total of 376 VPA steady-state trough concentrations were collected from 103 epileptic pediatric patients. The PPK parameter values for VPA were calculated by using the nonlinear mixed-effects modeling (NONMEM) method, and a one-compartment model with first-order absorption and elimination processes was applied. Covariates included demographic information, concomitant medications and selected gene polymorphisms. Goodness-of-fit (GOF), bootstrap analysis, and visual predictive check (VPC) were used for model evaluation. In addition, we used Monte Carlo simulations to propose dose recommendations for different subgroup patients.

Results: A significant effect of the patient age and ABCB1 genotypes was observed on the VPA oral clearance (CL/F) in the final PPK model. Compared with patients with the ABCB1 rs3789243 AA genotype, CL/F in patients with GG and AG genotypes was increased by 8% and reduced by 4.7%, respectively. The GOF plots indicated the satisfactory predictive performance of the final model, and the evaluation by bootstrap and VPC showed that a stable model had been developed. A table of individualized dosing regimens involving age and ABCB1 genotype was constructed based on the final PPK model.

Conclusion: This study quantitatively investigated the effects of patient age and ABCB1 rs3789243 variants on the pharmacokinetic variability of VPA. The PPK models could be beneficial to individual dose optimization in epileptic children on VPA therapy.
Transcriptome analysis revealed the role of mTOR and MAPK signaling pathways in the white strain of Hypsizygus marmoreus extracts-induced cell death of human hepatoma Hep3B cells
Authors: Lee Kun-Tsung , Chen Li-Yun , Li Wei-Sung , Lee Hong-Zin
Published: November 2022

The aim of this study was to investigate the anticancer mechanisms of white genius mushroom (WGM). WGM is a popular edible mushroom in Taiwan and has been demonstrated to mediate potent antiproliferation effects against human Hep3B liver cancer cells in our previous study. According to next generation sequencing technology and KEGG pathway enrichment analysis, mTOR and MAPK signaling pathways were markedly changed during treatment with WGM extracts in Hep3B cells. Therefore, this study examined the effects of WGM extracts on the expression of mTOR and MAPK signaling pathway-related proteins, such as PI3K, Akt, mTOR, Ras, Raf, MEK, ERK, p38 and JNK in Hep3B cells. According to the results of immunoblotting, we demonstrated that the protein expression of the members of PI3K/Akt/mTOR and MAPK signaling pathways were involved in WGM extracts-induced cell death. Furthermore, the inhibitors of PI3K/Akt/mTOR and MAPK signaling pathways such as rapamycin, MK2206, LY3214996 and SB202190, blocked the induction of cell death and vacuoles formation induced by WGM extracts. This study also demonstrated that WGM extracts is able to inhibit Hep3B cell migration and colony formation in a dose-dependent manner. In addition to being a very popular food, WGM should be a pharmacologically safe natural agent for cancer treatment. Therefore, WGM might be designed to develop into a dietary chemopreventive agent for the cancer treatment.
Assessment of the effectiveness and efficiency of the West Africa medicines regulatory harmonization initiative by the member countries
Authors: Owusu-Asante Mercy , Darko Delese Mimi , Walker Stuart , Salek Sam
Published: November 2022

Background: The West Africa Health Organization launched the West Africa Medicines Regulatory Harmonization Project (WA-MRH) in 2017 with the overarching objective to improve the availability of high-quality, safe and effective medicines and vaccines by the 15 countries in the Economic Community of West African States region. Although this project has made significant progress towards the realisation of its goals, challenges still remain. The aims of this study were to evaluate the effectiveness and efficiency of the WA-MRH, examine what challenges are being encountered and identify strategies that would strengthen the process for realising the initiative’s goals.

Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from assessors representing the seven active NMRAs in the joint assessment procedure that identified the benefits, challenges and recommendations for improving the performance of the WA-MRH project.

Results: The benefits of the joint assessment procedure include time savings to manufacturers resulting from submitting one dossier and the same response package to multiple countries resulting in access to the multiple African markets within the same timeframe. Additionally, some of the NMRAs have been able to strengthen their technical capacity as a result of this initiative. Key challenges to the project include the lack of a robust information technology system that would enable dossier tracking and constraints in human resources needed to support dossier submissions and the assessment process.

Conclusion: This study identified the strengths of the WA-MRH initiative as well as strategies for improvement and achievement of its objectives. The centralised submission of a dossier and its tracking is key to the regulatory assessment process. This research has demonstrated that amongst other considerations, a robust information technology system, coupled with the necessary human resource capacity would greatly enhance the effectiveness and efficiency of the WA-MRH initiative.
Associations of HLA-A and HLA-B with vancomycin-induced drug reaction with eosinophilia and systemic symptoms in the Han-Chinese population
Authors: Wang Chuang-Wei , Lin Wei-Chen , Chen Wei-Ti , Chen Chun-Bing , Lu Chun-Wei , Hou Hsin-Han , Hui Rosaline Chung-Yee , Wu Jennifer , Chang Chih-Jung , Chang Ya-Ching , Chung Wen-Hung ,   Taiwan Severe Cutaneous Adverse Reaction Consortium
Published: November 2022

Vancomycin is a commonly used antibiotic; however, it can cause life-threatening severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). A previous study has reported a strong association between HLA-A*32:01 and vancomycin-induced DRESS in European ethnicity. Herein, we aim to investigate the genetic predisposition of vancomycin-induced DRESS in the Han-Chinese population. In this study, we enrolled a total of 26 patients with vancomycin-induced DRESS, 1,616 general population controls, and 51 subjects tolerant to vancomycin. In vitro granulysin-based lymphocyte activation tests (LAT) were conducted among 6 vancomycin-induced DRESS patients who were concomitantly receiving other medicines. HLA-A and HLA-B genotypes were determined by sequencing-based typing. Our results found that vancomycin-induced DRESS was associated with HLA-A*32:01 [odds ratio (OR) = 7.8, 95% confidence interval (CI) = 1.7–35.8; p-value = 0.035], HLA-B*07:05 (OR = 32.3, 95% CI = 2.8–367.7; p-value = 0.047), HLA-B*40:06 (OR = 4.7, 95% CI = 1.3–16.1; p-value = 0.036) and HLA-B*67:01 (OR = 44.8, 95% CI = 7.2–280.4; p-value = 0.002) when comparing the vancomycin-induced DRESS patients with the general population controls. LAT results showed that granulysin significantly increased in the vancomycin-induced DRESS patients upon vancomycin stimulation (4.7 ± 3.7 fold increased), but not upon other co-medicines. This study identified that, in addition to HLA-A*32:01, HLA-B*07:05, HLA-B*40:06, and HLA-B*67:01 were also genetic markers for vancomycin-induced DRESS in the Han-Chinese population. Associations of ethnic variances in HLA with vancomycin-DRESS were observed.
Light exposure during development affects physiology of adults in Drosophila melanogaster
Authors: Damulewicz Milena , Tyszka Aleksandra , Pyza Elzbieta
Published: November 2022

Light is one of most important factors synchronizing organisms to day/night cycles in the environment. In Drosophila it is received through compound eyes, Hofbauer-Buchner eyelet, ocelli, using phospholipase C-dependent phototransduction and by deep brain photoreceptors, like Cryptochrome. Even a single light pulse during early life induces larval-time memory, which synchronizes the circadian clock and maintains daily rhythms in adult flies. In this study we investigated several processes in adult flies after maintaining their embryos, larvae and pupae in constant darkness (DD) until eclosion. We found that the lack of external light during development affects sleep time, by reduction of night sleep, and in effect shift to the daytime. However, disruption of internal CRY- dependent photoreception annuls this effect. We also observed changes in the expression of genes encoding neurotransmitters and their receptors between flies kept in different light regime. In addition, the lack of light during development results in decreasing size of mushroom bodies, involved in sleep regulation. Taking together, our results show that presence of light during early life plays a key role in brain development and affects adult behavior.
Signaling pathways in cutaneous wound healing
Authors: Krizanova Olga , Penesova Adela , Sokol Jozef , Hokynkova Alica , Samadian Amir , Babula Petr
Published: November 2022

Wound healing is a very complex process, where variety of different pathways is activated, depending on the phase of healing. Improper or interrupted healing might result in development of chronic wounds. Therefore, novel approaches based on detailed knowledge of signalling pathways that are activated during acute or chronic cutaneous wound healing enables quicker and more effective healing. This review outlined new possibilities of cutaneous wound healing by modulation of some signalling molecules, e.g., gasotransmitters, or calcium. Special focus is given to gasotransmitters, since these bioactive signalling molecules that can freely diffuse into the cell and exert antioxidative effects. Calcium is an important booster of immune system and it can significantly contribute to healing process. Special interest is given to chronic wounds caused by diabetes mellitus and overcoming problems with the inflammation.
Performance factors that negatively influence shooting efficiency in women’s basketball
Authors: Vencúrik Tomáš , Milanović Zoran , Lazić Anja , Li Feng , Matulaitis Kęstutis , Rupčić Tomislav
Published: November 2022

The purpose of the present study was to examine the influence of selected factors (possession duration, game quarter, defensive pressure, shooting distance from the basket, and heart rate level) on shooting efficiency on Under-19 (U19) and senior level of women’s basketball competition (second division). The analysis procedures included five U19 and six senior-level games, containing 224 and 252 shooting attempts, respectively. Binary logistic regression identified the opponent’s defensive pressure and shooting distance from the basket as significant predictors of shooting efficiency in both categories. When defensive pressure was high, the chance for the missed shot was 3.5 (95% CI; 1.43–8.52) and 3.19 (95% CI; 1.4–7.26) times more likely than it was under the minimum defensive pressure for U19 and senior category, respectively. Shooting efficiency significantly decreased when the horizontal distance from the basket increased. In U19, a chance for a missed shot was 4.63 (95% CI; 2–10.712) and 5.15 (95% CI; 1.91–13.86) times higher for medium and long-distance (respectively), compared to short-range shooting. In the senior category, the chance for the missed shot was 3.9 (95% CI; 1.83–8.31) and 3.27 (95% CI; 1.43–7.52) times higher for medium and long-distance (respectively) when compared to a short distance. The possession duration, game quarter, and heart rate level were identified as insignificant predictors. Therefore, the aforementioned findings suggest that basketball players and coaches may benefit from designing training sessions where the defender puts pressure on the shooting player as in a real game situation and balanced the frequency of shooting from different distances from the basket.