This study analyzes the most relevant authors, sources, cooccurrence of keywords, thematic map, and trend topics of the most recent and most cited research papers on semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA). Also, the content of the 25 most cited papers is summarized. A total of 2995 results appeared in an online electronic search performed on 14 August 2023 in the Scopus database using the term semaglutide. The most recently published 500 articles and most cited 200 documents were selected for bibliometric analysis. Network analysis visualization was conducted with the help of the VOSviewer software (version 1.6.18)  and Biblioshiny (it is a shiny application providing a web interface for bibliometrix) .After excluding duplicates and editorials, the data analysis found that 495 most recent documents were published in 279 journals by 2461 authors, and 200 most cited papers were published in 103 sources by 1241 authors. There is an increasing trend in the number of research papers from 2014 to 2022, with a peak in 2022. The most relevant authors in the most recent semaglutide research papers are Chen and Zhang. The pertinent authors of the most cited research papers on semaglutide are Lingvay and Khunti. The most common keywords used in the most recent and most cited research papers are semaglutide, obesity, diabetes mellitus type 2, glucagon-like peptide-1, glucagon-like peptide-1 receptor agonist, antidiabetic agent, liraglutide, and cardiovascular disease (CVD). The most relevant source is “Diabetes, Obesity and Metabolism” for the research papers on semaglutide. Trend topic analysis suggests that most of the research between 2020 and 2022 on semaglutide was done on non-insulin-dependent diabetes mellitus. The most cited papers provide essential insights into using semaglutide in managing type 2 diabetes mellitus (T2DM), obesity, and related conditions, along with their potential benefits, side effects, and possible mechanisms of action. This analysis highlights that the pharmacological effects of semaglutide extend beyond its role as a glycemic regulator. Traditionally, the emphasis on managing type 2 diabetes mellitus (T2DM) was centered around regulating blood sugar levels. However, contemporary treatment recommendations underscore the significance of a multifaceted approach. This strategy enhances various aspects, including cardiovascular (CV) risk factors, hyperglycemia, overweight/obesity, hypertension, and dyslipidemia .With increasing concerns about the long-term complications of T2DM and the challenges posed by the limited success of existing treatment options, exploring drugs that have the potential to control not only hyperglycemia but also other comorbidities, such as obesity and cardiovascular disease (CVD), has become paramount. On 4 June 2021, the US Food and Drug Administration (FDA) approved the use of semaglutide 2.4 mg for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure or cholesterol or T2DM) in addition to a reduced calorie diet and increased physical activity . Beyond Furthermore, it is the first GLP-1 RA to be given orally for treating T2DM. Oral administration does not appear to diminish its efficacy in reducing glucose or weight lowering . This coThis article aims to provide a comprehensive analysis of the research on semaglutide. It seeks to contribute to the ongoing discourse on the role of semaglutide in reshaping the therapeutic landscape for T2DM and potentially beyond. This study separately analyzed the most contributing authors, most relevant journals, cooccurrences of keywords, thematic map, and trend topics for the most recent and most cited papers on semaglutide. The study also includes a literature review of the 25 most cited documents on semaglutide.Materials and methodsSearch Strategy and Study Selection ProcessAn online electronic search was performed on 14 August 2023 in the Scopus database to identify the research done on semaglutide. The search term used was semaglutide. No filter was applied for the type of articles, species, language, gender, journal, age, or publication date in the database. The most recent 500 papers were selected for the bibliometric analysis. The most cited research papers were identified by arranging the research papers according to the number of citations in the Scopus database, and the most cited 200 research papers were selected for bibliometric analysis.The study selection process flow chart was generated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The datData AnalysisNetwork analysis and visualization were performed using the VOSviewer software (version 1.6.18)  . VOSviewReviewThe content of the top 20 most cited papers was analyzed and summarized. Our review included the following stages: identifying the research question and relevant studies, study selection, charting the data, collating, summarizing, and reporting the results .ResultsThe Search Results for the Most Recent Research PapersA total of 2995 results appeared from an online search in the Scopus database without applying any filter. Of these, 38.7% were reviews, 7.3% were notes, 3.9% were letters, 3.6% were editorials, 1.2% were errata, 1% were short surveys, 0.9% were book chapters, 0.4% were conference papers, and 43% were other articles. Five hundred most recent research papers were selected, of which 495 articles were left after removing duplicates and editorials. The total number of sources of research papers on semaglutide was 279, and the total number of authors was 2461. The type of documents selected for the analysis were articles, reviews, and short surveys, whereas book chapters, editorials, errata, letters, and notes were excluded from the analysis. After excluding the articles according to the above criteria, the total number of documents left was 425, published in 250 journals by 2295 authors. Out of 425 papers, 160 are reviews, eight are short surveys, and 257 are other articles . The other important sources are Frontiers in Endocrinology and Obesity, with 11 11.5%) research papers each , and “Diabetes, Obesity and Metabolism” alone contributed 21.3% of them Figure . The graThe core sources are analyzed according to Bradford’s law in Biblioshiny for the most cited research papers Figure . The shaKeywords and Trend: Topic AnalysisThe word cloud for the most cited research papers on semaglutide shows the most frequently used keywords in research papers. The following 23 keywords, not specific to the research subject, were removed so that subject-specific keywords can be seen more clearly in an image: human, humans, adult, female, male, review, RCT, controlled study, aged, nonhuman, systematic review, meta-analysis, cohort analysis, clinical articles, mouse, animal, animals, randomized controlled study, randomized controlled trials, middle-aged, priority journal, article, and semaglutide. The following two synonymous terms were also merged to obtain the actual frequency of use in research papers: glucagon-like peptide 1 receptor and glucagon-like peptide-1 receptor Figure . The mosThe trend topic analysis graph shows the frequency of keywords used in research papers on semaglutide. The most frequently used terms were semaglutide, non-insulin-dependent diabetes mellitus, and liraglutide between 2020 and 2022. The least used but most recent terms were glipizide, Food and Drug Administration, and consensus. Diabetes mellitus, antidiabetic agents, and glycemic control were used more commonly in 2020 Figure . This suResults of the Review of the Most Cited PapersOf the 25 most cited research papers, six are reviews, and others are guidelines and clinical trials. Ten articles are guidelines provided by the American Diabetes Association (ADA), one is guidelines provided by the European Association for the Study of Diabetes (EASD), one is guidelines provided by the American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease, and two are consensus reports. A total of 16 articles are related to the effect of semaglutide on diabetes, five related to obesity, two related to non-alcoholic fatty liver, and two related to both diabetes and obesity.The most cited paper has been cited 2302 times. It is based on the 2019 guidelines by the European Society of Cardiology on diabetes, pre-diabetes, and cardiovascular diseases in collaboration with the EASD . The sec“Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes,“ published in 2020  and 2021In a phase 3 trial, 1879 patients were randomly assigned in a 1:1:1:1 ratio to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg for 40 weeks. The study concluded that tirzepatide is non-inferior and superior to semaglutide in reducing weight and mean glycated hemoglobin level; however, more subjects experienced adverse events . AnotherOne review performed by Bornstein et al. cited 560 research papers that provided recommendations for the practical management of patients with diabetes and COVID-19 disease or at risk for metabolic disease based on the published literature and guidelines by the WHO, American Diabetes Association, and US Centers for Disease Control and Prevention for the management of COVID-19 . AnotherA review done by Nauck et al. suggests that GLP-1 RA lowers body weight by influencing the central nervous system and shares common mechanisms of action, which include enhancing insulin in response to hyperglycemia, suppressing glucagon secretion in hyperglycemia or euglycemia, slowing gastric emptying to prevent large post-meal spikes in blood sugar, and reducing calorie intake. Recently, an oral formulation of semaglutide (once daily) has been approved. Oral formulation possesses equivalent clinical effectiveness when compared to the once-weekly subcutaneous preparation. Furthermore, it has similar effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes. It is recommended as the preferred first injectable glucose-lowering therapy for T2DM, even before insulin treatment. Glucagon-like peptide-1 receptor (GLP-1 R) also reduces cardiovascular events, such as myocardial infarction, stroke, and associated mortality . It has According to the summary on T2DM management by the American Association of Clinical Endocrinology and the American College of Endocrinology, GLP-1 RA based on exendin 4 has been proven safe in cardiovascular disease. Still, they have not been shown to confer cardiovascular benefits. The risk of hypoglycemia with GLP-1 RA is low, and they reduce fluctuations in both fasting and postprandial glucose levels by stimulating glucose-dependent insulin secretion and suppressing glucagon secretion. GLP-1 RA should not be used in patients with a personal or family history of medullary thyroid carcinoma or those with multiple endocrine neoplasia syndrome type 2. No dose adjustment is required for semaglutide in chronic kidney disease, although renal function should be monitored in patients reporting severe adverse gastrointestinal reactions . AccordiAn animal study by Gabery et al. demonstrated that GLP-1 RA semaglutide reduces body weight through direct effects in the hypothalamus and the hindbrain. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus and interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles of rats. Semaglutide interacts with 10 brain areas: hindbrain areas directly with GLP-1 R interaction and secondary areas without direct GLP-1 RA interaction, such as the lateral parabrachial nucleus. The automated analysis of semaglutide revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. The transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed the upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. This study suggests that semaglutide lowers body weight by direct interaction with diverse GLP-1 R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure . The comDiscussionThere is an increasing trend in the number of research papers from 2014 to 2022, with a peak in 2022 (Figure Until now, no bibliometric analysis has been done on semaglutide; however, two have been identified on GLP-1 RA ,39. One The most cited documents, including clinical trials, reviews, and guidelines by the ADA, EASD, and American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease, suggest that semaglutide is effective in reducing obesity, major adverse cardiovascular events, non-alcoholic steatohepatitis, and the risk of new or worsening nephropathy in T2DM patients. No dose adjustment is required for semaglutide in chronic kidney disease, although renal function monitoring is recommended in patients reporting severe adverse gastrointestinal reactions. These findings align with a review done by Goldenberg and Steen in 2019 on semaglutide . The maiThe reviews and clinical trials in the manuscript highlight the drug’s benefits; however, Novo Nordisk, the only company with FDA-approved semaglutide, has funded many of the clinical trials. Therefore, more data from unbiased sources is required to support the findings of these studies.This study analyzed the most recent and the most cited research papers to find the latest and most relevant information. The study’s main limitation is that only one database was considered for the analysis, as it is impossible to merge the data from two different databases for analysis. Another limitation is that we reviewed the content and provided the summary for the most cited documents but not the most recent ones. Nevertheless, this study provides a comprehensive analysis of semaglutide research, and the highly cited papers offer essential insights into the use of semaglutide, a GLP-1 RA, in the management of diabetes, obesity, and related conditions, along with their potential benefits and adverse effects.Semaglutide, a new drug approved by the FDA on 4 June 2021, has demonstrated effectiveness in managing weight and reducing hyperglycemia ,30. TherSemaglutide, the only GLP-1 RA with oral formulation, has emerged as a frontrunner in this endeavor due to its remarkable efficacy in glycemic control and its potential to influence multiple facets of diabetes management. There is an increasing trend in the number of research papers from 2014 to 2022, peaking in 2022. The analysis highlighted that the most relevant authors in the most recent semaglutide research papers are Chen and Zhang and in the most cited research papers on semaglutide are Lingvay and Khunti. The most relevant source is “Diabetes, Obesity and Metabolism” for research papers on semaglutide. The most common keywords used in the research papers are semaglutide, obesity, T2DM, GLP-1, GLP-1 RA, antidiabetic agent, liraglutide, and cardiovascular disease. No collaboration between any country is found in any research paper. Trend topic analysis suggests that most of the research between 2020 and 2022 on semaglutide was done on non-insulin-dependent diabetes mellitus and included data on another drug, liraglutide. The most cited articles suggest that there is compelling data on the benefits of semaglutide in various clinical conditions, including obesity, cardiovascular events, diabetes management, and reverses steatohepatitis in persons with or without diabetes. Semaglutide can be used in chronic kidney disease without dose adjustment, although renal function monitoring in patients reporting severe adverse gastrointestinal reactions is recommended. However, GLP-1 RA should be used cautiously in the case of pancreatic disease and is contraindicated in patients with a history of medullary thyroid cancer. The common side effects reported are nausea, constipation, diarrhea, and vomiting. Neoplasia has also been reported in a few studies. Physicians are strongly advised to prescribe this medication with utmost caution, as long-term study results on its chronic use are not yet available, potentially revealing unknown adverse effects.Clinical trials with larger sample sizes and long duration are still needed for more generalizable data and to rule out any side effects that are very rare or occur after the long-term use of the drug.


BDNF, COMT, and SLC6A4 genes. We found a significant negative correlation between COMT_1 amplicon methylation and acute symptom scores, with BDI-II (R(22) = 0.190, p = 0.033), IDS-C (R(22) = 0.199, p = 0.029), and HAM-A (R(22) = 0.231, p = 0.018) all showing a similar degree of correlation. Our results suggest that DNA methylation follows flexible dynamics, with methylation levels closely associated with acute clinical presentation rather than with the duration of anxiety and depression. These results provide important insights into the dynamic nature of DNA methylation in anxiety and affective disorders and contribute to our understanding of the complex interplay between stress, epigenetics, and individual phenotype.Depression and anxiety are common mental disorders that often occur together. Stress is an important risk factor for both disorders, affecting pathophysiological processes through epigenetic changes that mediate gene–environment interactions. In this study, we explored two proposed models about the dynamic nature of DNA methylation in anxiety and depression: a stable change, in which DNA methylation accumulates over time as a function of the duration of clinical symptoms of anxiety and depression, or a flexible change, in which DNA methylation correlates with the acute severity of clinical symptoms. Symptom severity was assessed using clinical questionnaires for anxiety and depression , and the current episode and the total lifetime symptom duration was obtained from patients’ medical records. Peripheral blood DNA methylation levels were determined for the  Mental health is critical for overall well-being as it affects all areas of life, including work, relationships, social functioning, and physical health. Mental disorders often co-occur with other illnesses, making them an important comorbid factor that can worsen health outcomes . Today, Depression and anxiety are thought to have multiple causes. Both occur clustered in the same families, although no gene has yet been shown to cause either disorder . The latThere is increasing evidence that a common mechanism underlies these depressive and anxiety disorders, which calls into question the need for a strict distinction between these clinical categories ,11. BothOnce stress has been recognized by the individual, activation of the hypothalamic–pituitary–adrenocortical axis leads to the release of glucocorticoids, resulting in various changes, including epigenetic modifications of genes and chromatin remodeling ,15. EpigA prerequisite for epigenetic modifications is the presence of the so-called epigenome editing tools, which allow for DNA methylation induction as well as deletion. This is performed using enzymes, such as DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) methylcytosine dioxygenases. De novo methylation is catalyzed by DNA methyltransferase  and mainSLC6A4 gene, which encodes the serotonin transporter, and the COMT gene, which encodes the enzyme catechol-O-methyltransferase, responsible for the degradation of catecholamines [In an effort to understand the biological basis of mental disorders mediated by stress, researchers are focusing on DNA methylation studies of candidate genes, particularly those involved in monoamine transmission and neuroplasticity. The monoamine hypothesis states that dysregulations of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, underlie the development of anxiety and depression ,26. Stroolamines . Similarolamines ,28. Seveolamines ,29,30,31olamines ,33,34 haIn addition, the timing and duration of stress exposure have been shown to play a critical role in the development of stress-related disorders. Several studies have linked stress exposure during specific sensitive periods to psychopathological symptoms later in life , with spBDNF, COMT, and SLC6A4 genes were selected as they have been previously implicated in signaling pathways that are potentially disrupted in depression and can therefore be considered candidate genes for depression. In addition, these three genes have the potential to interact with each other [BDNF, COMT, and SLC6A4) in peripheral blood, correlate with the duration and acute severity of anxiety and depression symptoms measured with clinical scales . This would inform us whether DNA methylation dynamics are different in chronic depression than in acute anxiety and depression. Based on the results of previous studies, we assumed that DNA methylation would conform to one of our proposed models. Under the flexible model, we expected that DNA methylation of our candidate genes would vary depending on the acute severity of anxiety and depression symptoms measured using clinical scales. This would imply that stress-induced changes during periods of increased symptom severity could lead to observable changes in the methylation levels. In contrast, in the case of the stable model, we assumed that DNA methylation would change as a function of the duration of stress exposure and that cumulative effects would lead to increasing changes in methylation patterns over time. As mentioned earlier, depression and anxiety symptoms often co-occur. Anxiety has previously been observed to impair responses to treatment for depression, leading to poorer outcomes, delayed or incomplete remission, and increased risk of relapse [In this study, we investigated DNA methylation dynamics in a clinical context. The ch other ,43,44,45 relapse ,47,48. GThe study included 25 Caucasian patients (16 women), aged 28 to 67 years (mean age 51 years), admitted to the University Psychiatric Clinic Ljubljana due to a clinically manifested depressive disorder or anxiety disorder. Diagnoses were confirmed using ICD-10 criteria by trained psychiatrists. Inclusion criteria were a diagnosis of depressive disorder (F32 and F33), anxiety, or stress disorder , age over 18 years, and written consent to participate in the study. Exclusion criteria were bipolar disorder, psychotic disorder, substance use disorder, or significant systemic or neurological disease that might affect brain function. All subjects were taking medication at the time of this study. One participant was excluded from regression analysis due to missing methylation data on the COMT_1 amplicon.The study was approved by the Medical Ethics Committee and all participants signed an informed consent form .Clinical questionnaires included the Beck Depression Inventory (BDI-II ) to asseBDNF, COMT, and SLC6A4 genes, which were selected for their associations with stress, anxiety, and depressive disorders, focusing on monoamine systems and neuroplasticity. The densest DNA methylation is usually found in the so-called CpG islands (CGIs), which are located in the promoter region and/or in the first intron. To locate these regions and map the target sequences in each gene of interest, we used the UCSC Genome Browser, Human Genome Build 19 (hg19) [DNA methylation analysis was performed for the 9 (hg19) . The tarThese genes and their coordinates in the human genome are given in Venous blood samples were coded to ensure data confidentiality and stored at −70 °C until DNA isolation. DNA isolation from the blood samples was performed using the DNA Mini Kit , according to the manufacturer’s instructions. Gene methylation analysis was facilitated through DNA-to-bisulfite conversion, in which DNA is treated with sodium bisulfite. This causes the deamination of cytosine (C), converting cytosine into uracil (U). The presence of methylation makes the conversion into U impossible, leaving a C behind. A total of 1000 ng of DNA was converted into bisulfite using the EpiTect Fast Bisulfite Kit  and eluted in 50 μL of elution buffer, yielding purified DNA at a final concentration of 20 ng/μL.After bisulfite conversion, polymerase chain reaction (PCR)-based methods were used to study DNA methylation ,57. Primhttps://eu.idtdna.com/pages/tools/oligoanalyzer (accessed on 24 November 2021) [Using BiSearch (v2.63)  and IDT er 2021) , primer A modified 16S protocol from Illumina  was usedThe second round of PCR was performed to label each subject with a uniquely identified sequence, following the 16S Metagenomic Sequencing Library Preparation protocol . This alThe sequences of the forward and reverse primers for each amplicon, the sequence of the NGS adapters, the annealing temperature for each primer, and the length of each amplicon without adapters can be found in Amplicons from the second round of PCR amplification were subjected to size selection , followed by concentration determination. The concentration of each subject library was measured using an ultrasensitive fluorescent nucleic acid dye that allowed for the quantification of double-stranded DNA . The final library was prepared through equimolar pooling of the individual subject libraries to a final library with a molar concentration of 40 nM. The final library was diluted and denatured, according to the recommendations detailed in the Illumina MiniSeq System Denature and Dilute Libraries Guide. The final library was sequenced on the Illumina MiniSeq sequencer using the MiniSeq Mid Output Kit (300 cycles)  with 150 bp paired-end reads.The FastQC tool (v0.14.1)  was usedThe methylKit package (v3.17)  and the mBDNF_1, mBDNF_2, mBDNF_3, mBDNF_4, mBDNF_5, mBDNF_6, mBDNF_7, mBDNF_8, mBDNF_9; mCOMT_1, mCOMT_2, mCOMT_3; mSLC6A4_1, and mSLC6A4_2) and age as possible independent variables. Similarly, to test the second hypothesis, we regarded the current episode duration and the total disease duration as candidate dependent variables, and the mean percentage of CGI methylation of each amplicon  and age as possible independent variables. We included patient age as a possible independent variable, as epigenetic changes have been shown to increase with age [COMT_1. All statistical analyses were performed with R (vx64 4.1.2) [In analyzing the nature of DNA methylation dynamics, we considered two hypotheses: that DNA methylation is a flexible phenomenon and reflects current depression symptoms, measured with the clinical scales, or that it is a cumulative change reflected with the duration of the current episode or the total duration of the disease. Therefore, to test the first hypothesis, we regarded the clinical scores  as possible dependent variables, and the mean percentage of CGI methylation of each amplicon   in RStud4 4.1.2) .mBDNF_1, mBDNF_2, mBDNF_3, mBDNF_4, mBDNF_5, mBDNF_6, mBDNF_7, mBDNF_8, mBDNF_9, mCOMT_1, mCOMT_2, mCOMT_3, mSLC6A4_1, and mSLC6A4_2), hereafter referred to as “epigenetic variables”. In order to determine which epigenetic variables displayed a linear correlation with the clinical questionnaires and age, a correlation matrix was calculated. Of all the epigenetic variables, only mCOMT_1 showed a linear relationship with all the clinical questionnaires . The correlation matrices for all the epigenetic variables, clinical variables, and duration of the disorder are shown in mCOMT_1. The results showed a significant regression equation for BDI-II  = 5.17, R2 = 0.190, p = 0.033), IDS-C  = 5.47, R2 = 0.199, p = 0.029), and HAM-A  = 6.59, R2 = 0.231, p = 0.018)  A–C. Thesp > 0.05) or the total lifetime duration of the disorder (p > 0.05)  .mCOMT_1 amplicon. First, we computed the correlation matrix between the dependent variables , which revealed a significant degree of correlation between BDI-II, IDS-C, and HAM-A (p < 0.001), as shown in mCOMT_1 in a linear regression model. A significant regression equation was found, F = 7.80, p = 0.011, with an R2 of 0.262, indicating that 26% of the variance in PC1 could be predicted using mCOMT_1  to the methylation pattern of the  mCOMT_1 D.mCOMT_1 is a better predictor of the composite variable PC1 than of the individual clinical variables . As the components of the clinical picture  are similarly reflected in the composite variable PC1, it is likely that the methylation levels are similarly related to all of them.In summary, our results suggest that the methylation level of mCOMT_1 showed a significant correlation with the clinical variables, we examined whether there is a significant difference between mCOMT_1 and gender. We used all the data for this analysis, as no outliers were present (p = 0.0896). Therefore, an independent-samples t-test was performed, which revealed no significant difference in the methylation levels of mCOMT_1 by gender (t(23) = 1.79, p = 0.086). These findings indicate that gender does not have a statistically significant impact on the methylation levels of mCOMT_1 in our dataset.Biological sex is among the more important factors linked to stress vulnerability, making women more likely to suffer from depression and anxiety . We aime present . Given tBDNF, COMT, and SLC6A4, involved in the pathophysiology of stress-related disorders, i.e., pathways involved in neurotransmitter systems and neuroplasticity. This study has uncovered the following findings: (i) DNA methylation correlates with acute symptom severity, as assessed using the clinical questionnaire scores , and not with the duration of the current episode or the lifetime duration of the disorder, (ii) DNA methylation contributes equally to different aspects of the clinical picture , and (iii) gender has no significant effect on the methylation levels.Previous studies have shown that exposure to stressful situations can affect the epigenetic patterns of the epigenome ,32. BuilEpigenetic marks are widely recognized as useful biomarkers in somatic disease ,74,75,76COMT_1 amplicon (p < 0.05). We observed a negative correlation between COMT_1 methylation and symptom severity, such that hypomethylation was associated with higher scores on each clinical questionnaire , indicating a more severe clinical picture  polymorphism, which has been associated with psychiatric disorders, particularly depressive disorders [Val/Val polymorphism causes a change in the COMT enzyme to a more active form, causing the increased degradation of catecholamines, and is associated with the occurrence of anxiety and depression symptoms. In addition, COMT_1 methylation may be more sensitive to acute stress, similar to what Wiegand and colleagues have observed [As mentioned earlier, symptoms . Clinicaisorders . Similarobserved , or lessCOMT_1 methylation showed similar levels of correlation with all the clinical variables that were tested, explaining approximately 19% of the variance for BDI-II, 20% for IDS-C, and 23% for HAM-A, respectively. Given this, we wanted to test whether grouping symptoms into principal components improved or worsened the predictive value of COMT_1 methylation. The first principal component, PC1, improved the predictive value of COMT_1 methylation, as it explained up to 26% of the variance. Thus, these results suggest that the anxiety and depression symptom domains are less likely to show independent relations with COMT gene methylation. Thus, our second hypothesis, that clinical variables have an independent and differential relation with DNA methylation, was not confirmed. These results add to the literature supporting the existence of common mechanisms in depression and anxiety.As methylation levels could potentially reflect specific clinical symptoms that can vary between the acute and chronic forms of anxiety and depression, we wanted to use specific clinical questionnaires to examine whether there was a relationship between individual clinical variables and methylation. IDS-C and BDI-II address depressive symptoms, whereas HAM-A assesses anxiety. COMT values were different for the two genders assessed, as this has been shown to be an important factor in vulnerability to mental disorders, with women being more prone to depression and anxiety disorders [COMT_1 methylation when we compared the female and male subjects in this sample (In addition, we investigated whether isorders ,105. Estisorders . Our dats sample .BDNF and SLC6A4, show interactions between DNA methylation and the use of psychotropic medications [Several aspects must be considered when interpreting our results. First, our sample was small, resulting in a low statistical power. Therefore, it is possible that additional associations between the clinical variables and epigenetic markers might be found in future studies with larger samples. In addition, the sample used was quite heterogeneous and unevenly represented in terms of age and gender, which we tried to take into account in our analysis. Second, due to the nature of our research problem, which was to compare acute and chronic anxiety and depressive disorders, we included patients who may have substantially differed in terms of their psychotropic treatment. Given the small and heterogeneous sample size, it was not possible to test the effects of the type of therapy on the methylation levels. Several genes, including ications , such asications ,109. TheEpigenetic mechanisms represent a sophisticated apparatus that allows for stable and dynamic changes to coexist in a gene-specific manner. The precise mechanisms controlling these gene-specific changes remain elusive. By understanding the common mechanisms underlying depression and anxiety, we can develop more individualized and effective interventions that address the complex nature of comorbid symptoms. Further research is needed to explore the broader epigenetic landscape and its relationship to phenotypic changes in response to stress over time.


Akkermansia muciniphilia, which has been shown to improve response to anti-PD-1 therapy. We also show that quercetin and, to a greater extent, Cyclophosphamide increased the systemic frequency of T cells and NK cells. In addition, Cyclophosphamide alone and in combination with quercetin reduced the frequency of Treg, which is consistent with an antitumor immune response. On the other hand, Cyclophosphamide did not significantly alter the host microbiome, suggesting complementarity between microbiome- and immune-mediated mechanisms in potentiating the antitumor action of Cyclophosphamide by quercetin. Overall, these results support the potential for microbiota-centered dietary intervention to overcome resistance to chemoimmunotherapy in TNBC.Immunotherapy targeting program cell death protein 1 (PD-1) in addition to chemotherapy has improved the survival of triple-negative breast cancer (TNBC) patients. However, the development of resistance and toxicity remain significant problems. Using the translationally relevant 4T1 mouse model of TNBC, we report here that dietary administration of the phytochemical quercetin enhanced the antitumor action of Cyclophosphamide, a cytotoxic drug with significant immunogenic effects that is part of the combination chemotherapy used in TNBC. We observed that quercetin favorably modified the host fecal microbiome by enriching species such as  Traditionally, cancer has been considered a cell-autonomous disease, and its treatment has focused on agents that target the neoplastic cells themselves. This theory has been replaced by the concept that tumor development and progression depend upon the interaction between cancer cells and multiple cell types surrounding the tumor, constituting the tumor microenvironment (TME) and systemic metabolic, inflammatory, and immune mechanisms ,2. The iAbundant evidence in the literature indicates that the gut microbiome plays a critical role in the antitumor effects of chemotherapy and immunotherapy in preclinical models and humans ,22,23,24Using the translationally relevant 4T1 in vivo mouse model of TNBC ,28, we rp < 0.05) starting at day 10 of treatment. On the other hand, the antitumor effect of 50 mg/kg/BW was more modest and not statistically significant. Hence, the 50 mg/kg/BW dose was selected for our subsequent experiments testing the combination treatment. No treatment-related toxicity was observed. Body weights and food intake were not different among groups, indicating no adverse effects of Cyclophosphamide. The effect of Cyclophosphamide at different doses on tumor volume using the 4T1 mouse model. The goal of this initial bioassay was to determine an effective but suboptimal dose of Cyclophosphamide to be used later in combination with quercetin to maximize our ability to detect possible additive/synergistic effects on the inhibition of tumor growth. As can be seen in p < 0.05)  the 2.5% was the most effective concentration in potentiating the antitumor action of Cyclophosphamide. The individual and combined effects of this dose of quercetin and Cyclophosphamide are shown in  < 0.05) . No statp < 0.001), showing distinct microbial communities within each treatment group. Quercetin induces a more dramatic separation of samples from the control than Cyclophosphamide in PCoA, additionally enhancing Cyclophosphamide-driven differences in their bacterial composition  was not affected, β-diversity  was significantly impacted , Adlercreutzia, Desulfovibrionaceae, Lachnospiraceae, and especially Akkermansia muciniphila compared to the control. In combination with Cyclophosphamide, it induces presence of Erysipelotrichaceae, Mogibacteriaceae, Roseburia, RF39 (Mollicutes), Rikenellaceae, Adlercreutzia, Akkermansia muciniphila, Lachnospiraceae, and Bifidobacterium pseudolongum. Differential abundance analysis revealed that quercetin significantly induces abundant representatives of Akkermansia muciniphilia, which has been shown to improve response to anti-PD1 therapy [Overall, quercetin favorably modifies the microbiome with enrichments of species such as  therapy ,30, thusIndividual and combined effects of quercetin and Cyclophosphamide on host immunity. Flow cytometric analysis of tumor bearing mice splenocytes revealed that both quercetin and Cyclophosphamide increased the frequency of total CD3+ cells and NK cells, although this increase was more dramatic with Cyclophosphamide . A similTNBC, the breast cancer phenotype associated with the worst prognosis ,14,15, dUsing the translationally relevant 4T1 syngeneic mouse model of TNBC ,28, thesAkkermansia muciniphila  in 100 µL of phosphate-buffered saline (PBS) were injected into one axillary mammary fat pad per mouse of 5–6-week-old female immunocompetent BALB/c mice . Mice were kept in a pathogen-free animal facility and housed at standard conditions  and allowed to acclimatize for one week before injecting 4T1 cells. A Vernier caliper was used to measure tumor growth twice a week, and tumor volumes were calculated using the formula V(mm3) = L  × W (minor axis)/2. The mice had access to water and food (AIN93M) ad. Lib.; body weights and food consumption were measured twice a week during the progress of the bioassay. Our animal studies were conducted according to the National Institutes of Health, USA, prior to their initiation. The Penn State College of Medicine Institutional Animal Care and Use Committee  reviewed and approved all experiments (USDA Registration Number: 23-R-0021).Experimental System. In these experiments, we used the 4T1 mouse model, a syngeneic in vivo model of TNBC, which has been successfully used in our laboratories  and otheCyclophosphamide dose response study. Before testing the potentiating effect of quercetin on Cyclophosphamide, we needed to determine an optimal dose of Cyclophosphamide that exerts antitumor action without causing toxicity. Four groups of mice (n = 5/group) injected with 4T1 cells one week before they were randomly assigned to receive i.p. control vehicle, 25, 50, or 75 mg/Kg BW of Cyclophosphamide. After the tumor cells injection, a second drug dose was administered on day 21. Tumor volume and body weight were monitored as described above. Although Cyclophosphamide has not been used in the 4T1 mouse model, these doses were comparable to those reported in the literature in other mouse models .Individual and combined effects of quercetin and Cyclophosphamide. We selected a dose of Cyclophosphamide of 50 mg/kg BW. While effective, this dose was suboptimal (see Results), thus allowing us to test the potential additive/synergistic effects of adding dietary quercetin. We used quercetin at 1, 2.5, and 5% in the diet since the literature data documented that mice tolerated these dietary levels . Hence, Microbiome analysis. Microbiome analysis of fecal specimens was performed, as recently published by us . BrieflyImmune studies. The determination of the frequency of lymphocyte populations in the spleens of mice from the different treatment groups was performed by flow cytometry, as published by us . Spleensp-values were not adjusted for multiple comparisons. Statistical Analysis of tumor growth. The linear mixed-effect model for repeated measures was used to analyze the tumor growth data  using tImmune Cell Analysis. Statistical differences in the means of immune cell frequencies were evaluated by ordinary one-way ANOVA with multiple comparisons using Prism (v. 10.0.1). Our results support the complementarity between microbiome and immune-mediated mechanisms in potentiating the antitumor action of Cyclophosphamide by quercetin in a well-defined animal model of TNBC.


China's growing workforce of young employees has propelled its economy towards becoming a global power. However, with evolving workplace difficulties and uncertainties, the rate of employee turnover is also rising, which affects every department in companies, in addition to impacting costs and finances. This study explored the influences of five core job characteristics, work relationships, and work conditions on young Chinese employees' retention intentions, mediated by employee well-being. Using a quantitative cross-sectional approach, 804 responses were obtained from young Chinese workers. We also employed partial least squares structural equation modeling to analyze and forecast the extent of the impact of this study's independent variables. The empirical findings revealed that job autonomy, skill variety, task significance, feedback, work relationships, and work conditions indirectly influenced the retention intentions of young workers in China, with employee well-being acting as a mediator. However, the impact of task identity on employee well-being and retention intentions was insignificant. Our study contributes to the literature on employee retention intentions by demonstrating the importance of young employees' perceptions of work design-related aspects and extending the application of the job characteristics model. Hence, firms face unprecedented challenges in the engagement and retention of young employees . TherefoChina is the most populous country in the world, with the largest share of young workers. The China State Council categorizes young employees as those aged between 14 and 35 years . Based oYoung workers have several unique characteristics. Previous studies have pointed out that young workers have an identity independent from that of their organizations and are less loyal towards their organizations than older workers ,14. TheyTherefore, to fill this research gap, this study investigates the impact of factors such as work design, work relationships (WRs), and work conditions (WCs) on young Chinese employees' RIs, with employee well-being (EW) serving as a mediator in this relationship. This study seeks to understand how young Chinese workers' perceptions of work design influence their RIs. In doing so, this study combines the job characteristics model (JCM) and the job demand-resources (JD-R) model to determine the associations among job characteristics, WRs, WCs, EW, and RI. The JCM and JD-R models offer well-established, comprehensive, and practically relevant frameworks for understanding young Chinese employees’ RI. These two theories have been tested and validated in various cultural contexts, including China. Their applicability to the Chinese context suggests that they may provide useful insights for organizations seeking to retain young employees ,21. PrevBased on this discussion, a conceptual framework was developed and empirically tested among young Chinese workers. This study explores the mechanism by which the core job characteristics, WR and WC, influence the RI of young workers in China, given that these factors are particularly relevant for young Chinese workers, who have unique expectations and work values compared to other demographics . In this22.12.1.1The JCM is a widely accepted model for job redesign. To better understand RI, this study used the JCM as a suitable and appropriate theoretical model to examine the factors influencing employee RI in the context of work design. The JCM argues that enriching or complex jobs are associated with increased job satisfaction, motivation, and work performance . More sp2.1.2As an extension of the JCM, the JD-R model has gained popularity among researchers, guiding the understanding of specific workplace characteristics that can lead to positive and negative organizational outcomes . The JD-2.22.2.1Work design has a significant influence on organizational success and individual well-being . HackmanH1JA positively influences EWH2SV positively influences EWH3TI positively influences EWH4TS positively influences EWH5FB positively influences EWMotivational job characteristics are key resources that stimulate work engagement . Wan et 2.2.2H6WRs positively influence EWWith the growing global concern for employee well-being in organizations, more attention should be paid to the influence of WRs . Sias et2.2.3H7WCs positively influence EWWCs reflect the environment in which a job is performed . WCs inc2.2.4H8EW positively influences RIAccording to recent managerial practices, EW refers to psychological, physical, and social well-being . In this2.2.5In this study, we argue that EW mediates the relationships among five core job characteristics, WR, WC, and RI. In other words, work-related factors influence RI by fostering EW. Satisfaction with the physical environment enhances EW. Previous research has demonstrated that employees who are satisfied with their physical working environment tend to have higher levels of job satisfaction, work performance, and psychological well-being . Furtherm1-7: EW mediates the relationship between JA, SV, TI, TS, FB, WRs, and WCs on RIHAll associations hypothesized are presented in 33.1http://www.wjx.cn/), a widely used and practical online questionnaire management tool in China. Online data collection was conducted between August 16, 2022, and September 10, 2022. To ensure that all the participants were Chinese adults who were employed and aligned with the background of this study, judgmental questions were used for exclusion. Prior to the formal questionnaire, all participants signed an informed consent form in which they were informed of the purpose of data collection, the final destination of the data, and their right to withdraw from participation at any time. In addition, to prevent possible problems with small sample sizes, this study collected data from a relatively larger sample than the calculated minimum sample size [This study used a quantitative approach to test the associations between variables. Rahi  noted thple size . After s3.2Overall, the scale for this study was developed based on previous literature, and the questionnaire was designed using simple, unbiased wordings so that the respondents could easily understand the questions. The English version of the items used is presented in supporting material S1, Survey Instrument. Five questions were used to measure JA as adopted from Morgeson and Humphrey . The SV 3.3First, to investigate CMV issues, we used Harman's single-factor test in which one fixed factor was extracted from all principal constructs that explained less than 50% of the variance . Single 3.4p-values. The results showed that the p-values of Mardia's multivariate skewness and kurtosis were both <0.05, indicating non-normality of the data. Subsequently, this study used PLS-SEM with SmartPLS 4.0, to test the measurement and structural models. First, bootstrapping was conducted for the measurement model to assess the reliability and validity of the research model, as well as the goodness of fit and variance inflation factor between variables. Blindfolding was then conducted to test the structural model that examined the relationship between the exogenous and endogenous latent variables [Checking the multivariate normality of the data is crucial for selecting appropriate data analysis methods . In thisariables .44.1S2:Discriminant Validity showed that all loadings were more than 0.5, which is higher than the respective cross-loading values. These results suggest that the construct is suitable for blindfolding and evaluating the structural model in the next step.Hair et al.  recommen4.2R2) and effect sizes (f2). The R2 value represents the variance in the dependent variable as explained by the independent variables. In other words, it is the proportion of variability in the data explained by the measurement model. The values of R2 ranged from 0 to 1, with a higher value indicating that the model had greater explanatory power. As shown in R2 value was 0.257 for EW, indicating that 25.7% of the EW variation could be explained by JA, SV, TI, TS, TS, FB, WR, and WC. This moderate R2 value was considered acceptable because this study was not designed to identify which factors generally affect EW and RI; rather, it attempted to identify how JA, SV, TI, TS, TS, FB, WR, and WC affect EW and RI in the context of work design. In terms of RI, the R2 value was 0.231, indicating that EW explained 23.1% of the variation in turnover intention.Verifying the reliability and validity of the outer model allowed us to evaluate the inner-path model estimates. We calculated the coefficients of determination  using JA, SV, TI, TS, FB, WRs, WCs, and EW as variables and RI as the target construct. The objective was to identify the input variables that are important despite their low performance and thus have a strong overall effect on the construct. Consequently, by focusing on poorly performing, but crucial variables, an IPMA can provide detailed information on the most effective managerial actions. As shown in 51), the findings revealed that job autonomy positively influenced employee well-being. This result is in line with previous research conducted by Clausen et al. [2 is supported, which supports the findings of prior studies on employees’ work engagement [3, we found no positive relationship between task identity and employee well-being. This finding conflicts with a recent study by Jiang et al. [This study investigated the impact of five core job characteristics on the well-being of young Chinese employees. Consistent with our hypothesis , which supports the findings of prior studies [7). Edwards et al. [The results also reported a significant positive impact of WR on EW . Prior studies have typically focused on the negative association between employee well-being and turnover intention [Furthermore, this study sheds light on the relationship between EW and RI among young Chinese workers. Specifically, this study revealed that employees’ emotional well-being positively influences their RIs . These findings are consistent with those of Schaufeli and Taris [M6), which supports the findings of several previous studies [M7), consistent with McGuire and McLaren [M3). This may be attributed to the cultural values of Chinese workers, who prioritize collectivism and cooperation in their work [The results of the mediation analysis confirmed that four of the five core job characteristics  had an indirect effect on RI mediated by EW , such as work engagement and job satisfaction. Future research could attempt to integrate more constructs related to work design into the study model to reveal a deeper and more generalized understanding.Chen Xuelin: Conceived and designed the experiments; Performed the experiments; Wrote the paper. Abdullah Al Mamun: Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper. Mohammad Enamul Hoque: Conceived and designed the experiments; Performed the experiments; Wrote the paper. Wan Mohd Hirwani Wan Hussain: Conceived and designed the experiments; Performed the experiments; Wrote the paper. Qing Yang: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper. All authors approved the final version of the manuscript and give their consent for submission and publication.The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.


Dear Editor,The burden of TB is particularly heavy in correctional facilities, driven by overcrowding, a high proportion of people with TB risk factors, and poor sanitation, ventilation and access to medical care.® MTB/RIF Ultra . Sputum samples were also collected from participants who had normal CXR but had a productive cough lasting longer than 14 days, and participants who had normal CXR with a history of HIV, and had either fever, weight loss, or night sweats. Participants eligible for Ultra testing were also evaluated by a physician for possible clinical diagnosis of TB. Women who were diagnosed with TB were referred to the local health authority for treatment initiation. We calculated the number needed to screen (NNS) to detect one case of TB, defined as the number of radiographs divided by the number of cases of TB diagnosed, and the number needed to test (NNT) to detect one case of microbiologically confirmed TB, defined as the number of Ultra tests divided by the number of positive Ultra results. Written informed consent was obtained from all participants and the study was approved by the institutional review board of the Universidad Peruana Cayetano Heredia, Lima, Peru.We implemented a TB screening program in six women’s prisons in the regions of Lima, La Libertad, Arequipa, and Tacna, from August, 2020 to June, 2021. Free voluntary screening was offered to all women, but they were excluded if they were receiving treatment for active TB. We first asked participants about 1) the presence of symptoms: productive cough lasting longer than 14 days, cough of any other type, weight loss in the preceding 30 days, fever lasting longer than 7 days, and night sweats, 2) personal history of TB in the past, 3) exposure to a person with TB in the preceding 2 years, and 4) history of diabetes mellitus or HIV infection. A digital CXR was obtained for every participant, regardless of symptoms. The findings were analyzed using the artificial intelligence software qXR , and classified as normal or abnormal according to the manufacturer’s default settings for TB. Women with abnormal CXR were asked to provide a sputum sample for analysis using Xpertn = 50), normal CXR with productive cough for more than 14 days (n = 32), or HIV and fever, weight loss or night sweats (n = 7) ; 22 women (1.1%) reported living with HIV and 152 (7.5%) reported having diabetes mellitus. A history of prior TB was reported by 127 (6.2%) women, and 386 (19.1%) reported having been exposed to someone with TB in the preceding 2 years. Symptoms were reported by 995 (48.9%) women, productive cough for longer than 14 days by 34 (1.2%), and cough of any type by 154 (15.1%). In addition, 99 (4.9%) had experienced fever for longer than 7 days, 483 (23.9%) had lost weight in the preceding 30 days, and 216 (10.7%) had night sweats. All 2,035 women underwent CXR, of whom 93 (4.6%) met criteria for Ultra testing based on either an abnormal CXR ( (n = 7) . All 93 During an active case-finding program, we diagnosed TB in 0.6% of the women screened in prisons in Peru. To the best of our knowledge, this is the first report of active case-finding focused on TB in incarcerated women. Although the yield of TB is lower than that reported for men in prisons in Peru,There are limitations to using our screening program data to draw conclusions about TB prevalence among women in prison in general. First, the intervention took place during the COVID-19 pandemic and to reduce crowding and protect those at highest risk, the government allowed for early release of individuals with comorbidities, who would have also been at higher risk of TB.We found a significant burden of TB among females in prison in Peru. Routine and systematic strategies of active case-finding using CXR, followed by molecular testing at entry and periodically during incarceration may increase timely TB detection. This could help reduce transmission, morbidity, and mortality in this high-risk vulnerable population.


During the last 20 years, molecular alterations have gained increasing significance in the diagnosis and biological assessment of tumors. Gliomas represent the largest group of tumors of the central nervous system, and the main aim of this review is to present the current knowledge on molecular pathways and their alterations in gliomas. A wide range of new insights has been gained, including evidence for the involvement of the WNT pathway or the hippo pathway in the pathobiology of gliomas, indicating a broad involvement of different pathways formerly not considered to play a central role in gliomas. Even new aspects of angiogenic, apoptotic, and metabolic pathways are presented, as well as the rapidly growing field of epigenetic processes, including non-coding RNAs. The two major conclusions drawn from the present review are the distinct interconnectivity of the whole spectrum of molecular pathways and the prominent role of non-coding RNAs, especially circular RNAs, in the regulation of specific targets. All these new insights are discussed, even considering the topic of the resistance to therapy of gliomas, along with aspects that are still incompletely understood, like the role of hydroxymethylation, or even ferroptosis, in the pathobiology of gliomas. Gliomas are the most frequent brain tumors, representing approximately 80% of all tumors of the central nervous system ,2. In re++ by disrupting its mobilization in vitro or in experimental models provided evidence for reduced tumor cell invasion and for the extended survival of animals with different tumor types, including glioblastomas [mice [mice [The overexpression of the tyrosine kinase receptors (RTKs) and their ligands is among the most frequent alterations in glioma tumorigenesis, leading to alternate autocrine or paracrine stimulatory loops and to the aberrant activation of RTKs and their downstream molecular pathways. The RTKs consist of a transmembrane domain, an extracellular ligand-binding domain, an intracellular tyrosine kinase domain, and tyrosine residues leading to downstream activation after their phosphorylation. Due to a variety of molecular changes, such as oncogenic mutations, the silencing of tumor-suppressor genes, gene amplification, or epigenetic changes, overactivated RTKs may contribute to the oncogenic phenotype. The effects of this dysregulation include the overexpression of growth factors or RTKs themselves, or even their involvement in autosomal genetic or epigenetic changes, such as mutations, chromosomal rearrangements, or promotor methylation ,3,7. Ovelastomas ,11. The lastomas ,13,14. Tlastomas ,16. Focaas [mice ,18. An ias [mice . Integrias [mice . Other ias [mice . Based oce [mice . Of notece [mice . Althougce [mice ,24,25,26NF1 encodes neurofibromin, which is a physiological suppressor of RAS, and NF1 mutations are responsible for the absence of this natural suppression. BRAF gene mutations such as BRAFV600E lead to overactivation of the MAPK pathway, which has led to successful attempts to target this mutation with dabrafenib or trametinib in children and adult patients [INK4a/CDK4/RB1 pathway often shows alterations in gliomas. Inactivation of pRB1 through its phosphorylation mediated by CDK4/6 is one way to promote tumor progression. This activation of the cell cycle transition from G1 to the S phase is supported by an increased release of the transcription factor E2F. p16INK4a and even cyclin-dependent kinase 2 types A and B (CDKN2A/B) are regulators of CDK4/6-mediated pRB1 phosphorylation so that the loss of normal function of pRB1 can be triggered by alteration of either of these proteins. The interconnectivity of all these pathways is confirmed by the fact that key molecules such as CDKN2A/B are involved in the p16INK4a/CDK4/RB1 pathway and the TP53/MDM2/MDM4 pathway [Drosophila, and it remains to be determined whether this also applies to other species [Overactivation of receptors by their corresponding ligands or also by alternative or pathological stimuli such as mutations leads to the increased stimulation of various signaling pathways that contribute to the pathogenesis and progression of gliomas. All of these signaling pathways have a complex network of connections, confirming their role in numerous cellular processes. A good example is the PI3K/AKT/PTEN pathway, which is involved in several processes such as proliferation, glucose metabolism, or cell survival. The first step within the activated pathway is the recruitment of phosphatidylinositol 3-kinase (PI3K), which phosphorylates phosphatidyl inositol bisphosphate to triphosphate PIP2 to PIP3). Normally, PTEN (phosphatase and tensin homologue) blocks PiP3 signaling and AKT (protein kinase B) activation, inhibiting proliferation. Frequent PTEN mutations in glioblastomas lead to a blockade of this inhibition and a complete activation of this signaling pathway with its main effector molecule, the serine/threonine kinase mTOR . mTOR itself leads to a promotion of cell growth and cytoskeletal organization through the activation of the multiprotein complexes, mTORC1 and mTORC2 ,28,29. T to PIP3.patients . The tumpatients ,32,33. T pathway ,34. The  pathway . Its cen pathway ,37. Diff pathway . VPS25 i pathway . One inh pathway . The inh species . The NOT species . In glio species . This si species ,42,43. T species ,45,46,47 species . The hip species ,50. Invo species . The deg species ,50. The  species ,52. As t species ,50.gene for telomerase reverse transcriptase (TERT) that lead to TERT overactivation, thereby preventing tumor cells from apoptosis. TERT mutations are found in many glioblastomas, whereas mutations of the X-linked gene of α-thalassemia (ATRX), leading to inactivation of the ATRX protein and induction of ALT, are found in many IDH-mutated astrocytomas. Of note, TERT mutations and ATRX mutations are mutually exclusive in gliomas, and the exact mechanism of how ATRX mutations, in particular, induce ALT in gliomas is still under investigation [UV irradiation resistance-associated tumor-suppressor gene (UVRAG) [The angiogenic pathways in tumors are highly interconnected, as the activation of factors also leads to the activation of other downstream signaling pathways that promote tumorigenesis. The most important pro-angiogenic factor is vascular endothelial growth factor receptor (VEGFR), but other factors also contribute to tumor angiogenesis, such as fibroblast growth factor receptor (FGFR), angiopoietins 1 and 2 (Ang1 and Ang2), erythropoietin (EP), transforming growth factor beta (TGF-β), and matrix metalloproteinases (MMPs) . The inctigation ,73,74,75tigation  and eventigation . Another (UVRAG) . A major (UVRAG) . mice, confirming the importance of glucose and glutamine pathways in the growth of malignant gliomas and providing a potential therapeutic strategy [EGFR gene with deletion of exons 2-7, present in the majority of glioblastomas with EGFR amplification. An important effect of EGFRvIII is the activation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1), which induces the formation of the protein DeltaMax by splicing the Myc-interacting protein Max. DeltaMax is a potent promoter of glycolysis and tumor growth in vivo, and a study of 131 glioblastoma patients showed a significant correlation between increased expression of hnRNP-A1 and glycolytic genes with shorter overall survival [An important alteration in metabolism, especially in highly proliferating gliomas, is that tumor cells meet their energy requirements by glycolysis instead of oxidative phosphorylation. This phenomenon is known as the Warburg effect and results in a high rate of glycolysis in proliferating tumor cells, including an overproduction of lactate. In the absence of significant efflux, increased cellular lactate inhibits glioma invasion. Therefore, accelerated lactate efflux is necessary to promote tumor cell invasiveness . This lastrategy . In IDH-strategy . Under pstrategy ,85. Disrstrategy . Anotherstrategy ,88. One strategy . Tumor dsurvival . In addisurvival ,92. Moresurvival . The impsurvival . Homo sapiens are certainly still largely unknown. So far, the focus has been on investigating the DNA methylation profile in diseases and even gliomas. In gliomas, DNA methylome analysis can be performed using bisulfide PCR or even novel strategies, such as nanopore sequencing, but most clinical applications are still based on chip arrays with a readout of more than 800,000 methylation sites. A statistical comparison of the results with thousands of reference samples from the “Classifier of Molecular Neuropathology” [forkhead box A2 gene (FOXA2), which plays a role in prostate cancer and whose promoter methylation leads to activation of the FOXA2 gene expression [The term epigenetics refers to molecular processes involved in the regulation or alteration of gene expression that are not associated with a change in gene sequence. The three most important epigenetic processes are methylation, histone alterations, and regulation by so-called “non-coding RNA molecules”. The molecular basis for the methylation of DNA or other biomolecules are methyltransferases classified according to the ‘Enzyme Nomenclature Database’ of subclass 2.1.1 . DNA metthology”  contributhology” . Althougthology” ,99. The thology” ,100. Sevpression ,102. Tempression . For othpression . The rolpression . Overexppression ,106,107.pression ,110,111.pression . This hipression , but it pression ,115. Anopression ,116. Nonpression ,118. Thepression ,119,120.pression . Since tpression ,50,121. pression ,123,124,pression ,126  is widely accepted ,146,147.The distinct interconnectivity of molecular cellular signaling pathways in terms of their involvement in tumorigenesis and glioma growth due to dysregulation and alterations is an important recent finding in glioma research. The second most important discovery in recent years is the recognition of the significant impact of the group of non-coding RNAs (ncRNAs) on molecular pathobiology in tumors, as it appears that ncRNAs, especially circular RNAs (circRNAs), have an overriding influence on the regulation of molecular signaling pathways in gliomas. Most circRNAs are formed by circularization of exon sequences, and only a few circRNAs are formed from introns . Most ciRegarding tumor angiogenesis in gliomas, the search for targeted fixed points is currently an important goal, and in particular, experimental progress has been made by simultaneously targeting VEGF and Ang2 in a mouse model with prolonged animal survival . There aA particular advance in recent years has been the introduction of molecular criteria for the diagnosis and/or classification of specific tumor entities since the fourth edition of the WHO classification of central nervous system tumors in 2016 . Since t


Garlic contains sulfur volatiles that cause a bad odor after consumption. The objective of this study was to understand how yogurt and its components cause deodorization. Raw and fried garlic samples were mixed with various treatments and measurements of volatiles were conducted using a selected-ion flow-tube mass spectrometer. Frying garlic significantly reduced almost all sulfur volatile compounds. Raw garlic was deodorized more than fried garlic by all of the treatments. Fat, protein and water significantly reduced the concentration of sulfur-based volatiles in garlic. At the same concentration, either fat or protein produced higher deodorization, depending on the hydrophobicity of the volatile. Whey protein, casein and their complex all caused deodorization. Increasing the pH to 7 or heating changed the structure of the proteins and decreased the deodorization of the volatiles, showing the importance of proteins for deodorization. As the quantity of fat increased, the deodorization of the volatiles also increased. Foods with higher fat or protein content can be formulated to offer a potential solution to reduce the unpleasant odor associated with garlic consumption. Allium sativum L.) as a spice in the food industry is common [The use of garlic  ,7, pear,Several different mechanisms have been proposed for deodorization. The raw vegetables, fruits and herbs were proposed to cause deodorization due to their enzymatic and phenolic activity ,8,9,11. Yogurt is a fermented milk product that is popular among consumers for its health-promoting, nutritional and sensorial properties. Yogurt has 0.15–5% fat, 3–10% protein and 70–87% water depending on the type of yogurt [The volatiles responsible for most of the pungent odor in both raw and fried garlic are allyl methyl disulfide, diallyl disulfide, allyl mercaptan and allyl methyl sulfide ,16. AllyHowever, a few volatiles increase when garlic is fried. 2-vinyl-4H-1,3-dithiin increased in fried garlic . Other sBecause of variability in raw material and the frying process, each treatment was compared to a control made from the same batch of garlic to accurately determine the extent of deodorization by the treatment. The addition of yogurt significantly reduced the concentration of almost all of the volatiles in both raw and fried garlic . Yogurt The yogurt interacts with the sulfur volatiles in garlic, decreasing the concentration of garlic volatiles. We theorize that the reduction was due to the fat, proteins and water present in the yogurt. When garlic is treated with milk, there is a reduction in the concentration of sulfur-containing volatiles ,13. The Next, 9% butter fat or milk protein were added to raw garlic and fried garlic . The conWhether fat or protein was more effective at deodorization depended on the volatile . For diaWater (pH 7) and water adjusted to pH 4.4 were added to garlic to isolate the effect of water and pH . When waYogurt (pH 4.4) deodorized the garlic, resulting in a high level of reduction (99%) in allyl mercaptan, allyl methyl disulfide, allyl methyl sulfide and diallyl disulfide . HoweverAs the pH is increased to 7, the casein micelle–whey protein complex breaks down. At pH 7, casein carries a net negative charge, which results in an electrostatic repulsion between the casein molecules, preventing the formation of the micelle structure. Whey protein is in a stable soluble state, which restricts its binding ability ,37. Due The yogurt (pH 4.4) was also heated to 80 °C to denature the proteins. Heating the yogurt resulted in less deodorization of garlic volatiles as compared to unheated yogurt (pH 4.4). When yogurt is heated, the increase in kinetic energy disrupts the bonds in the proteins, resulting in the unfolding and denaturation of both casein and whey protein ,38. ThisTwo forms of whey protein, casein or milk protein, were mixed with either raw or fried garlic. All of the proteins caused significant deodorization of almost all volatiles . ProteinThe type of protein that was most effective at deodorization was different for raw versus fried garlic . In raw The form of the protein generally made no significant difference, but when there was a difference, the concentrate was more effective than the isolate. At first, it would logically seem that the isolate, with a higher protein content, would create greater deodorization. However, during the production of concentrates, the proteins undergo less processing than for isolates. Additional processes for the purification and separation of isolates are used. Due to this additional processing, some of the protein structure is changed or denatured, and thus the structures of the proteins are more intact in concentrates than in isolates . The morThe quantity of butter also affects the deodorization of malodor- producing garlic volatiles. Garlic was mixed with a solution of water containing 3, 10, 20, 40 or 80% butter. Both water and fat reduce volatile levels. The addition of butter to the water significantly increased the deodorization of both raw and fried garlic sulfur volatiles . In bothGarlic cloves  were peeled by hand. Using a knife, peeled garlic cloves were cut into slices of approximately 1 mm thickness. Sliced garlic was held for 30 min at room temperature before frying or addition of treatments. Fried garlic was stir-fried in hot canola oil , (125 °C). A temperature drop was seen immediately after the addition of chopped garlic into the hot oil. The frying continued until the temperature reached 125 °C again, at approximately 12 min. The oil was removed from the fried garlic using tissues and the garlic was cooled at room temperature for 15 min.Different treatments were used for the determination of the deodorization of the garlic. Because of variability in raw material and the frying process, one batch of garlic was prepared and used for one set of treatments with its control. Thus, there was a different control for each set of treatments . For water, 100 mL water at pH 4.4 or pH 7 and 100 g whole milk plain yogurt  at pH 4 or pH 7 were used. To adjust the pH, hydrochloric acid was used for acidic pH and sodium hydroxide was used for basic pH. Heating involved briefly immersing the raw or fried garlic mixed with whole fat yogurt  packed in a Ziplock bag in boiling water, followed by rapid cooling. For protein, a mixture of 50 mL water and 50 g non-fat dry milk powder  was used. For different proteins, 9% whey protein isolate , whey protein concentrate , calcium caseinate , micellar casein , milk protein isolate  or milk protein concentrate  was used. The proteins were rehydrated by mixing using a magnetic stirrer for 4 h. For the quantity of fat, a 100 mL solution of water containing 3, 10, 20, 40 or 80% of unsalted butter  was heated, mixed, then cooled to room temperature before using. The raw or fried garlic (6 g) mixed with 100 mL of each treatment was placed in a 500 mL Pyrex bottle. The raw or fried garlic (6 g), was used as a control.The raw or fried garlic (6 g) was mixed with 100 mL of each treatment. The sample was placed in a 500 mL Pyrex bottle capped with a polytetrafluoroethylene (PTFE)- faced silicone septa cap and held for 30 min at room temperature. The headspace volatiles of the garlic sample were measured via an 18-gauge passivated needle connected to the inlet of the selected-ion flow-tube mass spectrometry (SIFT-MS) machine  using a selected ion mode (SIM) scan at 20 °C ± 2 and the SIFT-MS headspace method. The SIFT-MS was calibrated with the standard gases benzene, toluene, isobutane, ethylene, tetrafluorobenzene, hexafluorobenzene and octafluorobenzene. Syft VOICE-200 software  was used to analyze the volatiles. 2-vinyl-4H-1,3-dithiin is a mixture of 2-vinyl-4H-1,3-dithiin and 3-vinyl-4H-1,2-dithiin, and 2,3-dimethylpyrazine is a mixture of 2,3-dimethylpyrazine, 2,5-dimethylpyrazine and 2,6-dimethylpyrazine. Three replicates were conducted for each deodorizing agent. A blank was used before testing the samples. An empty 500 mL Pyrex bottle was used as the blank. The scanning time for each headspace reading was 95 s. Volatiles tested are given in ® Pro version 16.0.0 (512340) . Three replicates of data for each test were obtained. Data were analyzed using one-way analysis of variance (ANOVA) and comparison of all pairs was performed using Fisher’s least significance difference (LSD). Significance was defined as p ≤ 0.05.The data were coded, entered and analyzed using JMPFrying garlic significantly reduced the concentration of almost all sulfur volatile compounds. Yogurt also significantly reduced the headspace concentration of all major odor- producing garlic volatiles, including allyl methyl disulfide, diallyl disulfide, allyl mercaptan and allyl methyl sulfide, in both raw and fried garlic. The components responsible for the deodorization of the volatiles were fat, protein and water. At the same concentration, fat was a more effective treatment for the reduction in diallyl disulfide and allyl methyl disulfide, whereas protein seemed to be a more effective treatment for the reduction in allyl methyl sulfide and allyl mercaptan. The proteins whey protein isolate, whey protein concentrate, micellar casein, calcium casein, milk protein isolate and milk protein concentrate were all effective in deodorizing the garlic volatiles. The concentrate form of proteins was more effective than the isolate form in the deodorization of volatiles. pH has no effect on the deodorization of garlic volatiles but affects the proteins by changing the conformation of the protein, which changes the binding of volatiles. Heating yogurt decreases its ability to deodorize the volatiles as heating denatures proteins, which results in weakening of the bonds of the proteins, leading to less deodorization. The amount of fat also affects the concentration of volatiles, with higher quantities of fat making a more hydrophobic environment, leading to more effective deodorization. The results suggest that consuming yogurt or foods with proteins and fat may help reduce the bad odor produced by garlic. Follow- up studies will focus on the effectiveness of these treatments at deodorizing the breath after the consumption of garlic. Protein and fat can be used as a natural deodorizer to mask the strong smell of garlic in processed foods. New products can be formulated to minimize the pungent odor of garlic using fat and dairy proteins.


An immune-suppressive disease known as chicken infectious anemia (CIA) develops after infection with chicken infectious anemia virus (CIAV). This study involved a systematic analysis of the epidemiology and genomics of CIAV in the provinces of Henan, Anhui, Jiangsu, and Hubei in China. The positive rates of the samples from each province flock ranged from 50% to 80%. Meanwhile, coinfections of CIAV with Marek’s disease virus, avian leukosis virus, infectious bursal disease virus, and fowl adenovirus were also identified. This study revealed the diversity of CIAV genomes as well as key mutation sites and intricate recombinants. The study findings underscore the importance of CIAV surveillance and provide a basis for further investigation into the evolution and molecular characteristics of CIAV strains.To evaluate the recent evolution of CIAV in China, 43 flocks of chickens from the provinces of Henan, Jiangsu, Hubei, and Anhui were screened via polymerase chain reaction during 2020–2022. Of these, 27 flocks tested positive for CIAV nucleic acids, including 12 which were positive for other immunosuppression viruses. Additionally, 27 CIAV strains were isolated, and their whole genomes were sequenced. The AH2001 and JS2002 strains shared the highest identity at 99.56%, and the HB2102 and HB2101 strains shared the lowest identity at 95.34%. Based on the genome sequences of these strains and reference strains, a phylogenetic tree was constructed and divided into eight main branches. Most of the strains were grouped with the East Asian strains, whereas the HB2101 strain belonged to the Brazil and Argentina cluster. A recombination event was detected in multiple strains, in which AH2002 recombined from KJ728827/China/2014 (from Taiwan Province) and HN2203, and AH2202 recombined from KX811526/China/2017 (from Shandong Province) and HN2203. All the obtained strains had a highly pathogenic Gln amino acid site at position 394 of the VP1. Overall, our findings demonstrate the importance of CIAV monitoring and provide data that aid in understanding the evolution of CIAV. The viral disease known as chicken infectious anemia (CIA) is caused by the chicken infectious anemia virus (CIAV) and leads to significant economic loss to the poultry industry worldwide ,2. YoungCIAV was first isolated in Japan in 1979 and has since been found to spread both vertically and horizontally . HorizonCIAV belongs to the Anelloviridae family and the Gyrovirus genus . HematopIn numerous areas of China, CIAV has been detected in poultry farms, and its isolation from specific pathogen-free chickens may explain its widespread dissemination and vaccine contamination . ReticulTo evaluate the recent evolution of CIAV in China, molecular characteristics of 27 CIAV were systematically analyzed on the basis of their genome sequences, including phylogenic mutation and recombination analysis. Our findings demonstrate the importance of continuous CIAV monitoring and provide data that can help in understanding the recent evolution of CIAV.During 2020–2022, 430 clinical samples  were obtained from dead chickens which exhibited symptoms of depression, anorexia, emaciation, growth retardation, or pale skin. These birds were obtained from 43 chicken flocks (10 chickens per poultry flock) from the Chinese provinces of Henan, Anhui, Jiangsu, and Hubei. All the samples were stored at a temperature of −80 °C.Following the manufacturer’s instructions, viral DNAs and RNAs were separately extracted from the chicken samples using a commercial kit . Three primer pairs, as described previously, were used for the detection and genome amplification of CIAV . The firMeanwhile, ALV , IBDV , FAdV , REV , and Marek’s disease virus (MDV)  were also detected via PCR assay, as previously described ,20,21,222, 0.6 M of each primer, and 0.75 U of PlatinumTM Taq DNA Polymerase were prepared in 1× supplied PCR buffer . Amplification was performed using the following conditions: the predenaturation step at 95 °C for 5 min, 35 cycles of the denaturation step at 95 °C for 30 s, the annealing step at 60 °C  for 30 s, the extension step at 72 °C for 30 s , and a final extension step at 72 °C for 10 min. Both positive and negative controls were included, and the amplified products were subsequently separated via 1% agarose gel electrophoresis. The purified amplicons were cloned into a pMD18-T simple vector  and sequenced . To perform PCR, 100 ng of DNA template, 0.2 mM of each dNTP, 2 mM of MgClThe CIAV present in the positive samples was cultured in MDCC–MSB1 lymphoblastoid cell lines following the previously described protocol . Brieflyhttps://www.chiplot.online/ (accessed on 26 May 2023)). In addition, the amino acid (aa) mutation sites of VP1 were summarized to assess genetic markers known to be associated with virulence.Whole genome sequences of the 27 CIAV strains along with references were aligned and identified using the Lasergene 7.0 software . Next, an identity heatmap was created using an online program (http://www.evolgenius.info/evolview/ (accessed on 17 August 2023)) was used to visualize the generated phylogenetic tree [The maximum likelihood method available in the molecular evolutionary genetics analysis (MEGA X) program was used with 1000 bootstrap replications to perform evolution analysis . The onltic tree .To investigate the possibility of intergenic recombination, a total of 105 complete CIAV genomes from obtained and reference strains were analyzed. The Recombination Detection Program (RDP4), which includes the methods of GENECONV, BOOTSCAN, MaxChi, CHIMERA, SISCAN, and 3Seq, was used for the prediction of recombination events and the identification of potential parental sequences .https://wemol.wecomput.com/ui/#/ (accessed on 19 June 2023)).To visually reflect the VP1 structure change caused by the mutations in the CIAV isolates in this study, the tertiary structures of the VP1 of these isolates and the reference strain of SD24 were modeled using AlphaFold2.3.0 (n = 3), REV (n = 2), ALV (n = 4), and IBDV (n = 2); additionally, one flock of quadruple infection was also identified (CIAV with FAdV + ALV + MDV). In CIAV-negative flocks, one flock each from Henan, Anhui, and Jiangsu was tested to be positive for IBDV, REV, and MDV, respectively. The infection and coinfection status of CIAV, ALV, IBDV, FAdV, REV, and MDV in various flocks was displayed via the UpSet map in Samples from 43 poultry farms were tested, and the results showed that 27 flocks were positive for CIAV, including 8 out of 13 (61.54%) from Jiangsu, 8 out of 12 (66.67%) from Henan Province, 6 out of 9 (66.67%) from Hubei, and 5 out of 9 (55.56%) from Anhui. The positive rates of the samples from each flock ranged from 50% to 80%, with an average of 69.3%. CIAV isolates were successfully obtained from positive samples in each flock. Among the 27 CIAV-positive flocks, 11 flocks of dual infections were caused by CIAV and the following coinfecting viruses: MDV  on the basis of at least five independent detection methods . Figure Previous studies have shown that aa position 394 is a major genetic determinant of pathogenesis, and sites 75, 89, 125, 139, 141, and 144 are related to viral replication and transmission ,27,28. ICIAV has been identified in chicken populations worldwide since it was originally discovered in China in 1996, posing a considerable threat to the poultry industry ,30. We sThe evolutionary tree of the 27 strains analyzed in this study and 78 reference strains revealed eight main branches, with the majority of the strains being closely related to the Chinese strains. However, the HB2101 strain showed a closer relationship to strains from Brazil and Argentina. The mechanisms and factors that contribute to the natural transmission of similar CIAV strains across borders remain to be determined. According to a previous study, local dissemination and long-distance migration are the main factors influencing CIAV evolution in South America. . It is sDue to its genetic diversity, the VP1-enconding gene is commonly targeted for sequence analysis . SeveralRecombination is thought to be the main catalyst for viral evolution and the source of most viral mutations . We discIn conclusion, our study has revealed the complex infection status of CIAV in central and eastern China, the diversity of CIAV genomes, and key mutation sites and intricate recombinants. These findings provide a basis for further investigation into the evolution and molecular characterization of CIAV strains.


Additionally, the aHRs (95% CIs) of all-cause death for those aged 66–75, 76–85, and >85 years (compared to those aged ≤65 years) were 1.29 (1.23–1.36), 2.00 (1.89–2.12), and 3.26 (2.97–3.59), respectively. The aHR (95% CI) of all-cause death for those with a Charlson comorbidity index (CCI) ≥ 1 compared to those with a CCI of 0 was 1.34 (1.28–1.40). The aHR (95% CI) of all-cause death for men compared to women was 1.56 (1.50–1.62). When comparing the sarcopenia and nonsarcopenia groups, the aHRs (95% CIs) for lung, liver, colorectal, breast, prostate, oral, pancreatic, stomach, ovarian, and other cancers were significantly higher. Conclusion: Our findings suggest that the onset of sarcopenia prior to cancer diagnosis may be linked to reduced survival outcomes in cancer patients.Purpose: The relationship between the onset of sarcopenia prior to cancer diagnosis and survival outcomes in various types of cancer is not well understood. To address this gap in knowledge, we conducted a propensity score-matched population-based cohort study to compare the overall survival of cancer patients with and without sarcopenia. Patients and Methods: In our study, we included patients with cancer and divided them into two groups based on the presence or absence of sarcopenia. To ensure comparability between the groups, we matched patients in both groups at a ratio of 1:1. Results: After the matching process, our final cohort included 20,416 patients with cancer  who were eligible for further analysis. There were no significant differences between the sarcopenia and nonsarcopenia groups in terms of confounding factors such as age (mean 61.05 years versus 62.17 years), gender , comorbidities, and cancer stages. In our multivariate Cox regression analysis, we found that the adjusted hazard ratio  of all-cause death for the sarcopenia group compared to the nonsarcopenia group was 1.49 (1.43–1.55;  Sarcopenia is a condition marked by the reduction of muscle mass, strength, and physical performance ,2. It isSarcopenia has a range of causes, including changes in endocrine function, proinflammatory cytokine activation, decreased alpha motor neurons in the spinal cord, reduced physical activity, and insufficient protein intake ,9,10,11.The impact of sarcopenia on long-term survival appears to be significant across a broad range of cancer types. Sarcopenia diagnosis before a cancer diagnosis is crucial to differentiate cancer-related sarcopenia from cancer-treatment-induced sarcopenia. In this study, we used a head-to-head propensity score matching (PSM) approach including patients with cancer with and without sarcopenia to determine the oncological outcome of overall survival (OS) in these patients.For this study, we obtained data on patients with and without sarcopenia from the Taiwan Cancer Registry database (TCRD). These patients received a cancer diagnosis between 1 January 2008 and 31 December 2017, with the index date being the date of a cancer diagnosis. The follow-up period for these patients extended from the index date to 31 December 2019. The study protocols were reviewed and approved by the Institutional Review Board of Tzu-Chi Medical Foundation. In addition to the cancer registry database, we also used data from the Collaboration Center of Health Information Application, which provided additional information on cancer type, stage, and treatment for each patient [To be included in this study, patients had to be over the age of 20 and have a diagnosis of cancer without metastasis. We defined cancer patients as those with primary cancer. Patients with a history of cancer before the primary cancer diagnosis date (index data) were excluded from the study. The TCRD was used to verify the accuracy of all enrolled patients with primary cancer. Additionally, patients with synchronous or metachronous cancers were excluded from the cohort. To ensure that we included adult patients at risk of cancer, we defined our study population as those aged 20 years or older in Taiwan. Additionally, cancer patients with metastasis can have different survival outcomes depending on the extent of metastasis. Therefore, to avoid bias, we excluded patients with cancer and metastasis. Sarcopenia diagnosis was made before the cancer diagnosis date, and patients who did not have sarcopenia before the cancer diagnosis date were included as controls.Sarcopenia is a muscle disease that results from adverse muscle changes that accumulate over a person’s lifetime. It is a common condition among older adults, but it can also occur earlier in life. The EWGSOP2 consensus paper defines sarcopenia as having low muscle strength as a key characteristic . The diaThe previous study employed the following protocol to define sarcopenia : before To analyze the time from the index date to all-cause death for patients with cancer with and without sarcopenia, we used a time-dependent Cox proportional hazards model that was adjusted for potential confounders. To account for potential confounders when comparing all-cause death between the sarcopenia and nonsarcopenia groups, we used propensity score matching. The variables used for matching included age, sex, Charlson comorbidity index (CCI) score, diabetes, hyperlipidemia, hypertension, end-stage renal disease (ESRD), liver cirrhosis, acute myocardial infarction (AMI), coronary artery disease (CAD), stroke, hepatitis B and C, congestive heart failure, dementia, chronic pulmonary disease, rheumatic disease, liver disease, diabetes with complications, hemiplegia and paraplegia, renal disease, acquired immune deficiency syndrome (AIDS), cancer type, cancer stage, income levels, and urbanization see . We exclComorbidities were identified based on ICD-9-CM or ICD-10-CM codes in the main diagnosis of inpatient records or if the patient had at least two outpatient visits within one year. Comorbidities that were present six months before the index date were recorded. Continuous variables are presented as the mean ± standard deviation or median (first quartile and third quartile), as appropriate. To match participants at a ratio of 1:1, we used the greedy method and matched participants with a propensity score within a caliper of 0.2  based onTo understand the relationship between mortality and sarcopenia in patients with various types of cancer, a sensitivity analysis was conducted using inverse probability of treatment weighting (IPTW) for all-cause death in propensity score-matched sarcopenia and nonsarcopenia groups. The analysis adjusted for covariates listed in p value of less than 0.05 was considered statistically significant. Overall survival (OS) was estimated using the Kaplan–Meier method and the differences in OS between the sarcopenia and nonsarcopenia groups with cancer were determined using the stratified log-rank test to compare survival curves, stratified according to the matched sets [The statistical analyses for this study were conducted using SAS version 9.4 . The matching procedure was implemented using the PROC PSMATCH procedure in SAS . A two-thed sets .There was a total of 103,925 cancer patients included in the registry during the selected time frame. Before PSM, out of all the cancer patients included in the registry, 14.9% were diagnosed with sarcopenia prior to their cancer diagnosis. This means that there were 15,527 sarcopenic cancer patients out of the total of 103,925 cancer patients, while the remaining 88,398 were nonsarcopenic cancer patients. Therefore, the percentage of sarcopenic patients out of all cancer patients is approximately 14.9%.p < 0.001; Propensity score matching resulted in a final study cohort of 20,416 patients, with 10,208 in both the sarcopenia and nonsarcopenia groups. The characteristics of these patients are listed in p < 0.001). Several explanatory variables were found to be significantly associated with an increased risk of all-cause mortality. These included older age, being male, and having a CCI score of 1 or higher. Specifically, the aHRs (95% CIs) of all-cause mortality for those aged 66 to 75, 76 to 85, and over 85 years (compared to those aged 65 or younger) were 1.29 (1.23 to 1.36), 2.00 (1.89 to 2.12), and 3.26 (2.97 to 3.59), respectively  in the sarcopenia group compared to the nonsarcopenia group.A stratified analysis based on IPTW was conducted to examine the distinct age groups and CCI scores, and the results are presented in a forest plot in The results of the stratified analysis of the distinct age groups and CCI scores based on IPTW are presented as a forest plot in p < 0.001). This difference in OS between the two groups was statistically significant.Cachexia is different from sarcopenia, which refers to the loss of skeletal muscle mass that is often two SDs below values that are adjusted for sex and age . Most ofSarcopenia has been shown to be a significant predictor of survival in various types of cancer . SarcopeSeveral previous meta-analyses have indicated that there is a link between sarcopenia and increased mortality in cancer patients ,39,40. HAll confounding factors associated with mortality were balanced between the sarcopenia and nonsarcopenia groups receiving cancer treatment . Cancer Our sensitivity analysis of a broad range of cancer types (including the top 10 most common cancers in Taiwan) found that sarcopenia significantly increased the risk of all-cause mortality in patients with lung, liver, colorectal, breast, prostate, oral, pancreatic, stomach, ovarian, and other types of cancer (as shown in After conducting a sensitivity analysis of the CCI, sex, and age (which were identified as significant independent factors for OS in cancer patients in One of the strengths of our study is that it is the first, largest, and longest-term follow-up comparative cohort study to examine the primary endpoint of OS in cancer patients with and without sarcopenia. To eliminate selection bias, PSM was used to ensure that the covariates between the two groups were homogenous for cancer patients (as seen in This study has a few limitations that should be noted. Firstly, as all the patients enrolled in the study were Asian, it is unclear whether these results apply to non-Asian populations. However, there is no evidence to suggest that there are significant differences in oncological outcomes between Asian and non-Asian cancer survivors. Secondly, the diagnoses of all comorbid conditions were based on ICD-9-CM or ICD-10-CM codes. While the Taiwan Cancer Registry Administration regularly reviews medical charts and interviews patients to verify the accuracy of diagnoses, a large-scale randomized trial comparing carefully selected patients with sarcopenia onset prior to cancer diagnosis and those without sarcopenia would be necessary to gain more specific information on the population characteristics and disease occurrence. However, it is important to note that these measures do not completely eliminate the possibility of error in diagnosis, and hospitals with outlier charges or practices may be audited and face penalties if malpractice or discrepancies are identified. Finally, it is worth noting that the Taiwan Cancer Registry database does not include data on dietary habits or body mass index, which may be risk factors for OS. Despite this limitation, the study has several strengths, including the use of a nationwide population-based registry with detailed baseline information and the ability to conduct long-term follow-up through the linkage of the registry with the national Cause of Death database. The observed effects in this study were both statistically significant and of a large magnitude, indicating that they are unlikely to be affected by these limitations.Our findings suggest that the onset of sarcopenia before cancer diagnosis may be associated with a reduction in OS and poorer OS in patients with lung, liver, colorectal, breast, prostate, oral, pancreatic, stomach, ovarian, and other types of cancer compared to those without sarcopenia. The impact of sarcopenia onset prior to cancer diagnosis on survival was stronger in patients with a longer life expectancy, such as those with breast, prostate, or colorectal cancer, a CCI of 0, female patients, or younger patients.