Diabetes is considered a new pandemic of the modern world, and the number of sufferers is steadily increasing. Sustained hyperglycemia promotes the production of free radicals and leads to persistent, low-grade inflammation. Oxidative stress causes mitochondrial destruction, which along with activation of the hexosamine pathway, nuclear factor-κB (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), c-jun NH2 terminal kinase/stress-activated protein kinase (JNK/SAPK) or toll-like receptors (TLRs), leads to pancreatic β-cell dysfunction. However, there is also the protective mechanism that counteracts oxidative stress and inflammation in diabetes, mitophagy, which is a mitochondrial autophagy. An important part of the strategy to control diabetes is to lead a healthy lifestyle based on, among other things, regular physical activity, giving up smoking, eating a balanced diet containing ingredients with antioxidant potential, including vegetables and fruits, and using hypoglycemic pharmacotherapy. Tobacco smoke is a recognized modifiable risk factor for many diseases including diabetes, and it has been shown that the risk of the disease increases in proportion to the intensity of smoking. Physical activity as another component of therapy can effectively reduce glucose fluctuations, and high intensity interval exercise appears to have the most beneficial effect. A proper diet not only increases cellular sensitivity to insulin, but is also able to reduce inflammation and oxidative stress. Pharmacotherapy for diabetes can also affect oxidative stress and inflammation. Some oral drugs, such as metformin, pioglitazone, vildagliptin, liraglutide, and exenatide, cause a reduction in markers of oxidative stress and/or inflammation, while the new drug Imeglimin reverses pancreatic β-cell dysfunction. In studies of sitagliptin, vildagliptin and exenatide, beneficial effects on oxidative stress and inflammation were achieved by, among other things, reducing glycemic excursions. For insulin therapy, no corresponding correlation was observed. Insulin did not reduce oxidative stress parameters. There was no correlation between glucose variability and oxidative stress in patients on insulin therapy. The data used in this study were obtained by searching PubMed online databases, taking into account recent studies. Diabetes is a metabolic disease characterized by inadequate glycemic control . It can The treatment of patients with T1DM is based on insulin therapy, while the treatment of T2DM includes both oral drug therapy  and insulin administration . In patiThe goal of diabetes management is to maintain HbA1c at <7.0% for adults  and chilOxidative stress and inflammation play a major role in the pathogenesis of diabetes. The low antioxidant capacity of pancreatic β-cells results in pancreatic cell failure in both T1DM and T2DM ,11. T1DMIn the case of T2DM, prevention based primarily on lifestyle changes is essential . A key eNutrition can also be highly effective in terms of metabolic control among patients with diabetes; thus, many researchers have attempted to determine which dietary components have the most beneficial effects . ClinicaThe disproportion involving the predominance of prooxidant ROS over antioxidant substances (both enzymatic and non-enzymatic) is called oxidative stress ,25,26,27ROS are highly reactive derivatives of molecular oxygen. They owe their properties to an unpaired electron on the valence shell ; however2·−, which is a precursor to other ROS. The second location where ROS are produced in the body are in the phagocytic cells responsible for the respiratory burst. Infection by bacteria/fungi/parasites results in the activation of phagocytic cells. With the involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a respiratory burst occurs. As a result, O2·− is produced, followed by other ROS. Ultimately, bacteria/fungi/parasites are eradicated. To a lesser extent, peroxisomes and the endoplasmic reticulum are also responsible for endogenous ROS production [Approximately 90% of endogenous ROS are produced in the mitochondria through electron leakage from the respiratory chain, ultimately leading to the formation of Ooduction .A thorough understanding of the mechanisms of ROS action is crucial for the comprehension of the pathogenesis of diseases underlying oxidative stress. In addition, this understanding allows for the precise identification of therapeutic targets .2·−) in β-cells through the mitochondrial respiratory chain, as well as NADPH oxidase [ATP channels [2·−, H2O2, NO) and pro-inflammatory cytokines, including interleukin 1 (IL-1), which is a potent activator of the JNK pathway [The basis of the pathogenesis of diabetes, as well as the formation of its complications, is oxidative stress  and chro oxidase . Hypergl oxidase . Chronic oxidase . Using 8 oxidase . The pat oxidase , which w oxidase ,12, whic oxidase ,12,13 bychannels ,12 and ichannels ,13. Pancchannels ,12,13, achannels . Anotherchannels ,35. In achannels . Free rachannels ,12. Thischannels ,12, c-juchannels ,12. In T pathway . Derivat pathway . This sh pathway .An excess of RONS with associated reduced cellular antioxidant capacity also lies on the basis of diabetic complications, both micro- and macro-vascular. The mitochondrial overproduction of ROS leads to the activation of the advanced glycation end products (AGEs) molecular pathway, among others, resulting in the increased production of pro-inflammatory cytokines and growth factors ,37. FurtFocusing on the mechanisms to counteract oxidative stress and inflammation in diabetes, it is important to mention mitophagy, which is mitochondrial autophagy ,39. MitoRegular physical activity is an important part of the diabetes management strategy, providing many benefits, such as weight loss and improvement in Body Mass Index (BMI), a reduction in inflammatory parameters and oxidative stress biomarkers, increased tissue sensitivity to insulin, as well as the improved quality of life and well-being of patients. Regular exercises have been shown to increase the release of anti-inflammatory cytokines and they lead to a reduction in pro-inflammatory cytokines, e.g., TNF-α and interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 18 (IL-18), CRP, which play a role in the pathogenesis of diabetes .Chen et al.  conducteIt is known that chronic physical activity reduces ROS production, increases antioxidant potential, and enhances cellular sensitivity to insulin; however, it has not been determined which level of exercise intensity has the best antioxidant and anti-inflammatory potential. Mallard et al.  focused The effects of some of the listed types of physical activity on oxidative stress and inflammation are shown in Tobacco smoke contains a number of harmful compounds that can have deleterious effects on almost all organs and contribute to the development of many diseases, including T2DM ,48,49. CIn a meta-analysis conducted by Akter et al. , the aimImpaired glucose metabolism, insulin resistance and vascular complications have been shown to result from increased oxidative stress and excess ROS in patients with T2DM, and it has been speculated that antioxidant therapy may be beneficial in these patients. One antioxidant that could have applications in improving glycemic control and reducing cardiometabolic risk is water-soluble vitamin C . It has Mason et al.  conductePatients with T2DM are at risk of accelerated atherosclerosis due to elevated rates of inflammation and increased oxidative stress. It appears that vitamin E, particularly its most bioavailable form, tocopherol, may provide a dietary component or supplement with antioxidant and inflammation-reducing properties . VitaminWu et al.  conducteAll markers of oxidative stress and inflammation that were used in the vitamin C and E studies in this article are listed in The muscat grape is a rich source of polyphenols that possess a number of properties, including antioxidant potential. Banini et al.  set out Hokayem et al.  also conIt has been suggested that free radicals may play a role in triggering the autoimmune response involved in the destruction of pancreatic islet B cells in T1DM. Nemes-Nagy et al.  conducteMcDonald et al.  conducteIn some cases of T2DM, lifestyle modification may not be sufficient and pharmacological treatment must be implemented. The pharmacological treatment of T2DM is based on both oral medications and insulin therapy, while the treatment of T1DM involves the administration of insulin in the form of multiple daily injections or via an insulin pump . The groWang et al.  evaluateMetformin is a reference drug used as the first-line treatment in T2DM because it sensitizes to insulin, improves glycemic control and also reduces postprandial glucose levels, making it widely used ,69. A raA study by Rizzo et al.  showed tThe effects of exemplary drugs on markers of oxidative stress and inflammation are shown in In diabetes, oxidative stress leads to reduced insulin production, impaired insulin secretion, β-cell dysfunction and its apoptosis, reduced expression of the GLUT-4 receptor and impairment of the insulin signal transduction pathway. The above mentioned processes, as well as persistent, low-grade inflammation, lead to insulin resistance and T2DM. Excess ROS influences both the formation of diabetes mellitus and its complications, both micro- and macro-vascular, as well as diabetic neuropathy. However, there is a protective mechanism against oxidative stress and inflammation in diabetes, which is mitophagy. It results in the removal of dysfunctional mitochondria, which prevents the accumulation of ROS. A combination of physical activity and a proper diet is an important part of the management strategy for patients with diabetes, as it contributes to increasing cellular sensitivity to insulin. Among exercises, moderate-intensity training based on aerobic and stretching exercises is recommended, however, high-intensity interval training seems to have the most beneficial effect on average daily glucose levels and time in hyperglycemia. Most papers have shown that physical activity has a positive correlation between glycemic levels and oxidative stress. In terms of diet, increasing attention is being paid to natural sources of antioxidants; hence, a diet supplemented with polyphenols, vitamins C and E and fruits can effectively protect against the consequences of oxidative stress and thus reduce the risk of developing diabetes and other cardiovascular complications. Exploring the mechanisms by which oxidative stress and inflammation affect T2DM will result in better therapeutic targeting and antioxidant treatment, as is the case with imeglimin. Further studies would be useful to determine more precisely the correlation between glucose fluctuations and the severity of oxidative stress during pharmacotherapy. It seems that drugs from different groups of oral antidiabetic drugs can counteract oxidative stress through different mechanisms, so it may be beneficial to use combination therapy, as has been shown for metformin and pioglitazone. Insulin only caused a decrease in TXB2, while no decrease in other parameters, such as LTE4 and PGF2, was observed. Further studies are suggested. Factors limiting the reliability of the results are that the studies were conducted on a small number of participants, the duration of many of the studies was too short, and some of the studies were inaccurate, with no control trials.


RPP30) is a highly conserved housekeeping gene that exists in many species and tissues throughout the three life kingdoms . RPP30 is closely related to a few types of tumors in human diseases but has a very stable transcription level in most cases. Based on this feature, increasing number of studies have used RPP30 as an internal reference gene. Here, the structure and basic functions of RPP30 are summarized and the likely relationship between RPP30 and various diseases in plants and human is outlined. Finally, the current application of RPP30 as an internal reference gene and its advantages over traditional internal reference genes are reviewed. RPP30 characteristics suggest that it has a good prospect of being selected as an internal reference; more work is needed to develop this research avenue.Ribonuclease P protein subunit p30 ( RPP30) gene is included in the National Center for Biotechnology Information (NCBI ID#10556) database. RPP30 has been shown to be highly conserved in gene pool data, and many studies have shown that there are 16 homologous genes of RPP30 contained in many species from the three life kingdoms  (RPP30 is one of shared protein subunits of ribonuclease P (RNase P) and ribonuclease MRP (RMRP), which are widely expressed in various tissues and participate in many life processes of microscopic and macroscopic organisms. It should be noted that as a protein subunit, detection of RPP30 in different tissues is not uniform and stable, possibly because of the complex modification process after translation (The ribonuclease P protein subunit P30 ( NCBI ID#0556 dataaryotes) . As a hoRPP30 and the factors that may influence its expression are introduced for reference in further studies and in quality control. Abnormal gene expression or mutation studies have made some progress with regard to botanical diseases (RPP30 overexpression (RPP30 is associated with glioblastoma (GBM) pathogenesis and low bone mineral density (LBMD)  RPP30 expression level is affected by other factors are very limited, such as aging  protocols. Thus, the use of RPP30 as an internal reference gene for many applications, including detection of pathogens, calculation of the number of tumor cells, diagnosis of tumors, and some childhood diseases are discussed. In particular, the application of this gene in nucleic acid detection of SARS-CoV-2 demonstrates its great value as an internal reference  are discussed. Ideal reference genes should be stably expressed in different tissues and different life cycles. With increased research and more applications, the expression of β-actin and GAPDH has been observed to be related to physiological/pathological states, experimental conditions, and tissue type  at 90,871,974–90,908,556 and is 36,582 nucleotides in length, with 14 exons (https://www.ncbi.nlm.nih.gov/gene/). There are 16 homologous genes in primates, canine, bovine, Rodentia, Amphibia, Drosophila, Arthropoda, and Saccharomycetes. These data are obtained from NCBI (ID#10556). The highly conserved sequence and other characteristics of RPP30 are illustrated in a gene evolutionary tree in The highly conserved Human nuclear RNase P consists of 1 RNA subunit H1 and 10 conserved proteins, and the complex has a slender conformation similar to the overall shape of yeast RNase P shown by cryo-negative staining electron microscopy . The humRPP30, the domain and conserved site of the RPP30 protein may be identified, which will illustrate how conserved this protein is.The RPP30 protein subunit is homologous to the RNase P protein subunit of archaea and other eukaryotes, as shown in RPP30 mainly functions in catalysis, nuclear localization, assembly, and/or regulation of holoenzyme activity (https://www.genecards.org/) and Gene Ontology  databases were searched for the RPP30 gene to identify its basic functions. The gene’s molecular functions include binding proteins, catalyzing reactions, and so on , which is necessary for pre-tRNA cleavage  in S. cerevisiae causes disruptions in both RNase P and RMRP by inhibiting correct cleavage of the internal transcribed spacer I of rRNA surrounding the A3 site  that are classified into three major classes  . RMRP hacle mRNA –21. RNaskingdoms . RNase Pkingdoms . RNAs cokingdoms , 24–30. kingdoms , 31. Thekingdoms . RPP30, omplexes . RPP30, omplexes . RNase Pomplexes . Stolc a A3 site .in vitro, its activity in vivo requires protein cofactors  is suggested to have activity ofactors . In 2006and RMRP . UV–cros RNase P , 38. Iso RNase P , 39, 40. RNase P  and stab RNase P , 42–44.  PhopRNA . RPP30-Pterparts , 46–48. terparts . In Dictive fold , 50. In ive fold , 37, 51.La cells . Additioirus RNA .Arabidopsis, the RPP30 domain is present from 98–248 amino acids in gametophyte defective 1 (GAF1), which is important in female gametophyte development and male competence and has a universal contribution to plant development , which functions in suppressing innate immunity in rice and may upregulate expression of defense genes k01901 into RPP30 leads to complete sterility in females , RPP30 expression increases, which activates the transcription of defense genes  and is composed of hPOP1, RPP25, RPP30, and RPP40 , 59. ResNPM1) gene, located at human chromosome 5Q35, contains 12 exons and encodes a multifunctional shuttling protein that shuttles between the nucleolus and cytoplasm. NPM1 mutations happen in approximately one-third of acute myeloid leukemias (AMLs)  and the decreased RPP30 expression in elderly people could be a risk factor for GBM  cells promotes the proliferation of HA cells, while overexpression inhibits the activation of tumor-related pathways and the proliferation of HA cells, further confirming the close relationship between RPP30 and the occurrence and development of GBM  and tumors (RPP30 expression was significantly different in tumor tissues (higher) and non-tumor tissues in diffuse large B-cell lymphoma, pancreatic adenocarcinoma (PAAD) and thymoma (THYM) . RPP30 gene expression is high under epidermal development, cell differentiation, and keratinocyte differentiation processes, which play important roles in the differentiation of gastric epithelial cells. Recently, Kan et al. used TGCA RNA-seq to explore the role of RPP30 expression in gastric cancer. They found that RPP30 protein expression was positively correlated with the number of T helper 2 cells, active dendritic cells, and T helper 1 cells, and negatively correlated with the number of T helper 17 cells. They also found that RPP30 RNA expression in gastric cancer (GC) tissue is higher than that in normal tissue and higher RPP30 RNA expression is related to worse overall survival (OS) at the T1, T2, and N0 stages of the tumor. The mechanism may be that RPP30 RNA expression is upregulation via the G alpha S signaling pathway, neuronal system, and olfactory transduction, in addition to increasing cAMP levels, which are tightly correlated with GC histopathology. RPP30 could regulate tRNA modification, transcriptional replication, DNA repair, replication fork stagnation, and protein expression, which are correlated with cancer cell proliferation (The nucleophosmin (s (AMLs) . Martell samples . In patif exon 9 . These d for GBM . This stpathways . In addit of GBM . Correlarelation . The Gend tumors Figure 2feration , 66.RPP30 is indirectly related to some diseases, including lung diseases and pulmonary hypertension, secondary to autoimmune diseases , and GeneCards public databases. In RPP30 RNA expression levels calculated by different databases, RPP30 RNA expression levels of different organizations calculated by the same database are basically the same, which is consistent with the results obtained by Bgee involving gene expression data in animals. However, the expression of human RPP30 protein is not as stable as RPP30 RNA. There are differences in the expression of RPP30 protein among different tissues or cells and the RPP30 protein has weak expression in some tissues or cells, such as lymph node, brain, spinal cord, ovary, bone, colon, and liver secretion . Coronavirus disease 2019 (COVID-19) broke out in Wuhan, China in December 2019 and then spread widely around the world, with strong infectivity  gene loses heterozygosity in tumor cells, the number of tumor cells may be evaluated by the quantitative RT-PCR ratio of NF1 to RPP30, which may be used to evaluate the efficacy and side effects of tumor drugs, and may also be used in personalized adjuvant chemotherapy. Due to the different behavior of cells in vivo and in vitro, this method has some limitations   detection, the level of HIV DNA in CSF cells is not correlated with RPP30 levels, indicating that the detectability of HIV DNA does not depend entirely on the number of cells available in each sample. Then, the correlation between the level of HIV DNA in the CSF and the level of HIV RNA in peripheral blood cells, as well as the relationship between the virus inhibition and non-inhibition subgroups, may be analyzed to explore the detectability of HIV DNA level in CSF.id (CSF) . RPP30, RPP30 is used as an internal reference gene in diagnostic experiments , inter-laboratory , and inter-operational  studies, which confirms the high accuracy and precision of the RPP30 dd-PCR assay. In addition, Profaizer and Slev , and because it is widely expressed in different tissues whose gene sequences are conserved and homologous, such as in humans, chimpanzees, rhesus monkeys, mice, fruit flies, Saccharomyces cerevisiae, and archaea  and the Scientific research project of Anhui Medical University . The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.www.editage.cn) for English language editing.We would like to thank Editage (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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


N,N-Dimethylformamide (DMF) is widely used in chemical industries because of its excellent solvent properties. Poisoning accidents caused by DMF have been frequently reported, particularly hepatotoxicity; however, the hepatic pathological changes have rarely been described. This study aimed to summarise the pathological characteristics of the hepatotoxicity associated with DMF in clinical cases and to verify in animal models. Liver pathologies of two patients with liver failure due to DMF were retrospectively analysed. Thirty-six rats were categorised into the DMF group , carbon tetrachloride (CCl4) group  and control group . The general condition and changes in hepatic pathology at 48 h and 8 weeks were observed. Liver tissues of patients exhibited multiple unevenly distributed inflammatory and fibrotic lesions. The DMF-induced liver injury animal model was successfully established. Inflammation and fibrosis were heterogeneously observed throughout the liver in the DMF group, contrast to entirely homogeneous lesions in the CCl4 group. Specific hepatic pathological findings (heterogeneous lesions) caused by DMF detected for the first time in humans and animal model, may be significant in the clinical diagnosis of DMF poisoning. Because DMF is a colourless, amine-flavoured, and volatile liquid, it can be absorbed into the body through the skin and respiratory tract in the workplace [orkplace . Toxic eorkplace ,3,4,5 toorkplace , mitochoorkplace , calciumorkplace , as wellorkplace ,10, prolorkplace . A crossorkplace  showed torkplace . Zhang eorkplace  found thorkplace ,16,17. A22.1Two patients were diagnosed with occupational acute liver failure due to DMF and underwent liver biopsy in 900th Hospital of Joint Logistics Support Force between 2015 and 2018. Details such as general information, occupational exposure history, clinical manifestations, laboratory results, imaging findings, and liver histological examination findings were collected and analysed.2.2The animal studies were conducted in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals according to the regulation in the People’s Republic of China. The protocol was approved by the Committee on the Ethics of Animal Experiments of 900th Hospital of Joint Logistics Support Force. All animals were sacrificed by peritoneal injection of sodium pentobarbital.Thirty-six sterile Sprague-Dawley rats aged 6–7 weeks and weighing 200 ± 20 g were purchased from the Zhejiang Provincial Laboratory Animal Centre (Licence Number: SCXK (Zhejiang) 20140001). The animals were kept in the Animal Experimental Centre of the 900th Hospital of Joint Logistics Support Force. After adaptive feeding for 1 week, they were randomly categorised into 3 groups.2.2.1Twelve rats were injected with DMF  intraperitoneally at a dose of 10 mL/kg as a 40% saline solution  once a week. At 48 h and 8 weeks, 6 animals in each treatment were euthanised and liver tissue samples were collected.2.2.24  at a dose of 1 mL/kg as a 50% olive oil solution twice a week. At 48 h and 8 weeks, 6 animals in each treatment were euthanised and liver tissue samples were collected.Twelve rats were intraperitoneally injected with CCl2.2.3Twelve rats were intraperitoneally injected with normal saline at a dose of 10 mL/kg once a week. Euthanasia was conducted after 48 h and 8 weeks.3The liver tissues including patient and rat samples were fixed in 10% formaldehyde solution overnight and embedded in paraffin before 3 µm thick sections were cut from the tissue blocks. The staining methods and reagents that haematoxylin and eosin (HE) staining, reticular fibre staining, and Masson staining need were conducted according to the standard protocols established by pathology department of 900th Hospital of Joint Logistics Support Force. The staining results were examined independently by two pathologists.Ethics approval: Informed consent for the collection of clinical information was obtained in accordance with the Declaration of Helsinki and this study was approved by the ethics committee of 900th Hospital of Joint Logistics Support Force (2020-044). The written informed consent was obtained from these two patients. Patients and the public were not involved in the design and conduct of our research.44.1Case 1: A 36-year-old man was admitted to the hospital with chief complaints of abdominal distention, fatigue, and jaundice that persisted for 2 weeks. The patient had a history of exposure to DMF owing to his job at a leather factory 2.5 months before admission (the first 2 months of drying operation and the next 0.5 month of stirring operation). The patient experienced somnolence and was found to be positive for asterixis. The whole-body skin and sclera had turned severely yellow, with petechiae and ecchymosis noted in both lower limbs. The abdominal shifting dullness was positive. The biochemical analysis revealed: alanine aminotransferase (ALT) 589 U/L, aspartate aminotransferase (AST) 559 U/L, total bilirubin (TBIL) 411 µmol/L, direct bilirubin (DBIL) 273.6 µmol/L, prothrombin activity (PTA) 23%, and fibrinogen 0.83 g/L. Results of serological tests for hepatitis virus, cytomegalovirus, and EB virus were negative. Autoimmune antibodies, ceruloplasmin, and anti-hepatic antigens were not detected. No complications of other organ damage were found. Thus, there were indications of acute severe dimethylformamide poisoning, acute liver failure, and hepatic encephalopathy (phase A2). After admission, the patient received anti-hepatic encephalopathy, infusion of albumin and plasma, prothrombin complex, plasma exchange, and other therapies, and after 2 weeks, he gained consciousness. After 123 days of treatment, liver and coagulation functions returned to normal at discharge . On the 78th day of admission, according to the enhancement CT, multiple intrahepatic nodules were significantly enlarged, evenly enhanced in the arterial phase , and isoCase 2: A 50-year-old man was admitted to the hospital with chief complaints of abdominal distention, abdominal pain, and poor appetite with yellowing of the skin and sclera that persisted for 1 week. The patient was employed at the local leather factory 5 months before the onset (the first 4 months of drying operation and the next 1 month of coating process). He had a history of exposure to DMF and no alcohol abuse. The shifting dullness was positive. Serological tests for hepatitis virus, cytomegalovirus, and EB virus, autoimmune antibodies and ceruloplasmin were all negative. Biochemical investigations revealed: ALT 321.2 U/L, AST 304.5 U/L, TBIL 231.8 µmol/L, DBIL 127.3 µmol/L, PTA 27%, and fibrinogen 1.06 g/L. The patient was diagnosed with acute severe dimethylformamide poisoning and acute liver failure. Liver protection drugs, infusion of plasma and albumin, and plasma exchange were administered after admission. The symptoms improved, and jaundice faded away, with the PTA gradually recovering. The patient was discharged from the hospital 33 days after admission, returning for re-examination 40 days after discharge. Liver function and coagulation function were normal (the tendency chart can be seen in Supplement Clinicopathological changes in the livers of both patients were mainly characterised by multiple unevenly distributed lesions of inflammation and fibrosis. Some liver tissues exhibited features of moderate chronic hepatitis , accompa4.24 treatment was used to induce the classic model of liver fibrosis.To further observe and verify this specific pathological feature, we successfully created an animal model of DMF-induced liver injury. Meanwhile, as a positive control, CCl4 group, the rats in the DMF group were more depressed, hypoactive, and insensitive to external stimuli. None of the above symptoms were found in the negative control group. Probably because of drug toxicity, one rat each in the DMF group died after 36 h and 7 weeks, respectively, and two rats died in the CCl4 group in the seventh week. No rats died in the negative control group.Compared with the CCl4 group. At 48 h, 6 rats were euthanised and liver tissues were stained using HE. DMF group exhibited occasional focal-point-like necrosis and slight swelling of central lobular hepatocytes, with partial inflammatory cells infiltrating the portal area and surrounding central veins (4 group, diffuse hepatocyte degeneration was observed, including balloon-like degeneration and steatosis, spot-like necrosis, and partial apoptosis of hepatocytes around the central vein in area 3, accompanied by some inflammatory cell infiltration. Furthermore, there were a small number of inflammatory cells infiltrating the portal area (In the acute phase, liver inflammation in the DMF group was less severe than that in the CClal veins . In the tal area .4 groups (4 group were light. Furthermore, a portion of the liver tissue protruded from the surface in the DMF group, whereas no such changes were observed in the CCL4 group.By the eighth week, rats were sacrificed to assess chronic liver injury after modelling. The liver surface showed a round and blunt edge, and the liver lobe proportion was unbalanced in both DMF and CCl4 groups . The liv4 group, liver tissues showed entirely homogeneous and significant inflammation and diffuse homogeneous distribution of micronodular cirrhosis (The liver tissues of the DMF group exhibited varying and heterogeneous extent of degeneration or necrosis and heterogeneous distribution of fibrosis . The HE irrhosis . The hepirrhosis . The difirrhosis . The str5DMF is a known hepatotoxic chemical capable of volatilisation at room temperature, and it can be absorbed through the skin and respiratory tract even when wearing gloves and masks . The occAlthough poisoning accidents involving occupational exposure to DMF have frequently been reported, pathological changes in the liver have rarely been described. A previous study reported severe liver injury in a patient exposed to DMF for 2 months. Liver biopsy revealed prominent post-necrotic fibrosis after massive hepatic necrosis, primarily in zone 3, and hepatocyte degeneration in the surrounding tissues, consistent with our study findings . TrevisaIn this study, uneven distribution of multiple inflammation and fibrosis sites was noted in DMF-induced liver injury. Under the microscope, polymorphic inflammation, such as hepatocyte degeneration, necrosis, apoptosis, or regeneration, as well as heterogeneous distribution of fibrosis, were noted simultaneously. This phenomenon was considered a specific liver pathology due to DMF poisoning. As is described above ,25, patiIn the present study, this specific liver pathology of DMF poisoning is an aid to diagnosis. Liver puncture is not a prerequisite for the diagnosis of DMF poisoning, which is clinically based on a short-term exposure history of a significant amount of DMF, clinical manifestation, laboratory examination of liver damage, and investigation of the work environment after excluding other possible causes of liver damage. For patients with unexplained liver injury, liver biopsy should be conducted as soon as possible if there is no contraindication. Hence, considering special pathological changes in hepatotoxicity in patients, a model of liver injury induced by DMF in rats was established to validate or evaluate liver histopathology.4 is currently the most used standard drug for creating liver fibrosis animal models as it can be administered through various routes and has the advantages of simplicity and low cost [4 was used as the positive control.The DMF concentration required for modelling through inhalation is high, and this cannot truly simulate occupational exposure to DMF. Additionally, subcutaneous administration of DMF is more irritating as it causes skin erosion and ulceration . Therefolow cost . Therefo4 are both chemical substances, the pathological characteristics of liver damage caused by these are different. In the present study, we found hepatocyte injury and inflammatory response were mild, while hepatocytes were extensively denatured, necrotic, and the inflammatory was prominent in the CCl4 group. Fibrosis distribution was not uniform and the fibrous cords were thin in the DMF group. In contrast, CCl4-induced hepatic fibrosis was diffuse, with the formation of pseudolobules throughout the field of vision, and the fibre strands were thick.Although DMF and CClin vivo and cause lipid peroxidation. After intraperitoneal injection of DMF, the drug enters the liver parenchyma through the portal vein. The uneven distribution of the drug and its metabolites in the structural unit of the hepatic acinar may lead to uneven liver injury. Because DMF is less toxic than CCl4, liver cells are mainly degenerative without prominent necrosis and inflammatory infiltration in the lobules and portal area is not obvious. Heterogeneous fibrosis was accompanied by uneven inflammation. Collagen fibres formed are thin and mainly distributed in the portal area. During the late stage, there was no fibrosis interval reconstruction of hepatic lobules after massive necrosis of liver cells. However, diffuse distribution of hepatic lobules of fibrous tissue can be observed around the large veins, owing to reduced blood supply, severe ischaemia and hypoxia in this area, which results in post-necrotic cirrhosis.The reason for the specific pathological changes may be attributed to the toxic effect of DMF ,35,36. MIn conclusion, we first found that uneven distribution and polymorphism of liver inflammation and fibrosis were detected in both humans and animals exposed to DMF. When encountering liver damage of unknown aetiology, the specific pathological finding could be a useful clue for the clinical diagnosis of DMF poisoning. Moreover, to our knowledge, an animal model of DMF-induced liver fibrosis has been established for the first time. However, the mechanism remains unclear. Hence, further studies in clinical and animal experiments are required. Additionally, varying extent and distribution of liver fibrosis including no fibrosis, mild–severe fibrosis and cirrhosis in this model could occur simultaneously in the same individual, which can provide self-contrast advantages in liver fibrosis research on the pathogenetic and progression mechanism to avoid individual differences of animals.


Based on this risk model, patients were divided into high and low risk groups. By exploring differentially expressed genes, enrichment functions and tumor immune microenvironment in patients in high and low risk groups, the results showed that patients in the low risk group were significantly enriched in immune signaling pathways. Besides, immune cells content, immune function activity was significantly better than the high-risk group. Eventually, we also investigated the sensitivity of patients with different risk groups to ICB immunotherapy and chemotherapy drugs. In conclusion, the risk model could effectively predict the survival and prognosis of patients, and explore the tumor microenvironment status of ovarian cancer patients to a certain extent, and provide promising and novel molecular markers for clinical diagnosis, individualized treatment and immunotherapy of patients.Ovarian cancer is the most lethal heterogeneous disease among gynecological tumors with a poor prognosis. Necroptosis, the most studied way of death in recent years, is different from apoptosis and pyroptosis. It is a kind of regulated programmed cell death and has been shown to be closely related to a variety of tumors. However, the expression and prognosis of necroptosis-related genes in ovarian cancer are still unclear. Our study therefore firstly identified the expression profiles of necroptosis-related genes in normal and ovarian cancer tissues. Next, based on differentially expressed necroptosis-related genes, we clustered ovarian cancer patients into two subtypes and performed survival analysis. Subsequently, we constructed a risk model consisting of 5 genes by LASSO regression analysis based on the differentially expressed genes in the two subtypes, and confirmed the strong prognostic ability of the model and its potential as an independent risk factor  Ovarian cancer (OC) is the deadliest malignancy of gynecological tumors, causing approximately 150,000 female deaths each year . TherefoNecroptosis, a regulated programmed cell death, is mechanistically similar to apoptosis and morphologically similar to necrosis, whose key regulators of necroptosis include receptor interacting protein kinase 1, and mixed lineage kinase domains such as pseudokinase, together forming a necrosome complex , 5, thushttps://xenabrowser.net/datapages/) and TCGA , and then normalize the expression profile data to remove batch effects for further analysis. The RNA-seq data and clinical information in external validation cohort were downloaded from the GEO  were displayed in We obtained the RNA-seq data, mutation data and related clinical information of normal ovarian tissue and ovarian cancer tissue from GTEX . STRING and correlation analysis were used to explore the interaction network of these differentially expressed genes (DEGs) (cutoff = 0.2). Furthermore, we performed function analyses to investigate the enriched functions and pathways of the DEGs.By searching the previous literature, we obtained 75 necroptosis genes in NMF clustering was performed to identify stable sample clusters based on 50 iterations according to the Brunet method using genes associated with energy metabolism. In addition, the cluster number, represented by k, was set as 2–10, whilst the best cluster number was calculated based on the cluster cophenetic correlation and the observed consensus map. The mean silhouette width of the consensus membership matrix was determined using the “NMF” function in the R package.P value of 0.05, and we eventually obtained 7 genes closely associated with prognosis. To further construct the risk model, the “glmnet” package was used to perform LASSO regression analysis using 10-fold cross-validation and a P-value of 0.05, and 1,000 cycles’ running. For each cycle, 1000 random stimuli were set to prevent overfitting. Ultimately, a 5-gene model was successfully constructed, and the risk score formula is as follows: Risk Score= ∑ Xi × Yi . Based on this formula, patients in the TCGA database were divided into high-risk and low-risk groups according to the median score, and each patient’s risk score and survival status were presented in the form of a heatmap, while Rtsne and stats were used for dimensionality reduction analysis to distinguish the patients between high and low risk groups. Kaplan-Meier analysis was utilized to identify the differences in overall survival (OS) between high and low risk groups. Finally, in order to evaluate the predictive power of the risk model, the “survival”, “survminer” and “timeROC” packages calculated the area under curve (AUC) values for 1, 3, and 5 years. Besides, the GEO cohort was used to validate the risk model. Patients in the validation set were also divided into high and low risk groups by applying the median risk scores, and PCA, ROC, and Kaplan-Meier (KM) analyses were also applied to the GEO dataset.Based on the obtained clinical information of ovarian cancer, univariate Cox analysis was used to identify prognosis-related genes as the Cox Before the analysis, we screened and grouped for clinical characteristics. Owing to the differences in age between patients, we used age = 65 as the distinguishing criterion according to the screening criteria of previous researches. Besides, we divided Grade 1-2 into one group, and Grade 3-4 into another group to better compare survival analysis results. To investigate whether risk score could be an independent risk factor for ovarian cancer patients, univariate and multivariate COX analyses were used to investigate clinical traits such as age, grade and risk score, and the results were presented in the form of forest plots.We integrated clinical characteristics with risk scores and applied the rms R package to construct the nomogram predicting 1, 3, 5-year survival probabilities of patients, and a calibration curve to verify predictive power.P value of survival analysis, and the C-index value of the model.Based on the model constructed in this study, we compared the risk models that have been constructed in previous studies, and identified the predictive ability of the model by calculating the ROC value of different models, the Patients in the TCGA cohort were divided into high and low risk groups according to the median risk score, and the limma package was used to identify differentially expressed genes (|log2FC| ≥ 1 and FDR < 0.05). Based on these differential genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed.The somatic mutation information of patients was downloaded from TCGA, and the frequency of somatic mutation of each patient and the mutation frequency of different genes were calculated by the maftools package. Meanwhile, based on the risk model, the mutation spectrum of patients in the high and low risk groups was estimated to compare whether there existed significant difference between the groups. In addition, the calculated TMB scores were compared to explore the difference and the relationship in the high and low risk groups.Copy-number variant (CNV) refers to copy number variation, which greatly enriches the diversity of genetic variation in the genome. GISTIC software was used to identify genes exhibiting significant amplification or deletion.via gsva package. Except for that, the correlation between the signature and immune cell markers was investigated. Cell markers were chosen according to CellMarker databaseIn order to estimate the immune infiltration of ovarian cancer patients, the CIBERSORT program was used, and the R package “Cibersort” was used to obtain the normalized enrichment score of 22 immune cells in the high and low risk groups, and the KM survival analysis of high and low immune infiltrating cells and functional patient survival prognosis. Other than that, ssGSEA was conducted to calculate the scores of infiltrating immune cells and to evaluate the activity of immune-related pathways To explore the correlation between risk models and chemotherapy in ovarian cancer patients, the pRRophetic package was used to calculate the sensitivity of patients in high and low risk groups to multiple chemotherapeutic agents.The expression of immune checkpoint molecules was compared between high and low risk groups, and we explored whether there was a significant difference between high and low risk patients on ICB treatment.via Pearson correlation analysis, visualized by the corrplot package.The content of immune cells and immune genes in each sample was integrated, and the association between immune genes, immune cells, and TMB and risk scores was investigated Adjacent non-tumor and ovarian cancer tissues were obtained from the Gynecology and Obstetrics in Renmin Hospital of Wuhan University. All the patients provided informed consent and were approved by the Ethics Committee of Renmin Hospital of Wuhan University to collect 9 cases of OC tissues and corresponding paracancerous tissues. The clinical parameters were displayed in NDRG2, ALDH2, DIABLO, TARDBP, KLF9, HMGB1, CFLAR, FAS, SQSTM1, SIRT2, RNF31, SIRT3, BCL2, CYLD and TSC1 were downregulated in tumor tissues, while HSPA4, CASP8, PANX1, RIPK1, FADD, LEF1, SPATA2, EZH2, TNFSF10, DDX58, MYCN, TNF, PGAM5, CXCL1, PLK1, TNFRSF21, IDH2 and CDKN2A were upregulated . P = 0.022, 0.047) . Among them, UBD, ISG20, BATF2, CXCL11, HLA-DOB and CXCL13 were prognostic protective genes, while ATP1A3 was a risk gene  + (0.278* ATP1A3 exp.) + (-0.037* ISG20 exp.) + (−0.275* CXCL11 exp.) + (−0.517* HLA-DOB exp.). Based on the risk score, we divided 379 patients into high and low risk groups (P < 0.001). ROC analysis was used to verify the predictive performance of the model, and the results showed that the AUC was 0.620 at 1 year, 0.638 at 3 years, and 0.707 at 5 years, suggesting that the model had good sensitivity and specificity  and risk score  were independent risk factors as shown in UBD, ISG20, CXCL11, and HLA-DOB were significantly decreased, while the expression of ATP1A3 was increased in high-risk patients. Unfortunately, we found that age and grade did not appear to be significantly different between high and low risk. Nevertheless, we further performed a survival analysis on clinical characteristics, and we found that in patients younger than and older than 65 years and pathological grade 3-4, the survival prognosis of patients with low-risk scores was significantly better than that of high-risk groups. This also confirmed that the risk model we constructed was an independent risk factor , TTN (23%) and MUC16 (11%) (TP53 (84%), TTN (24%) and USH2A (9%)  (P=0.083) . The most common mutation classification was missense mutation, and the most common mutation type was SNP, followed by DEL, and finally INS. Besides the most SNV class is C>T mutation (via UCSC (https://xena.ucsc.edu/), which demonstrated that nearly all genes had CNV referred to the loss or gain of copies of a genomic DNA region in OC. The most frequent gain of function of gene was MYC, while the loss was SIRT3  were an important molecular mechanism in many human diseases . Therefore, we explored the CNV landscape of the necroptosis-related genes in OC +T cells, T cells CD4 memory resting, T cells CD4 memory activated, M1 Macrophages, Mast cells activated and Neutrophils were enriched in different risk groups. The levels of memory CD8+T cells, M1 Macrophages and Neutrophils were higher in the low-risk group than in the high-risk group. The levels of Naive B cells, T cells CD4 memory resting, T cells CD4 memory activated and Mast cells activated were higher in the high-risk group than in the low-risk group , T cells CD4 memory activated (P<0.001), T cells follicular helper (P<0.001), T cells gamma delta (P=0.002) had significantly higher prognosis than low-level, low-level M2 macrophages (P=0.028), Mast cells activated (P=0.038), Monocytes (P=0.002), Neutrophils (P=0.006), Plasma cells (P=0.011), T cells CD4 memory resting (P=0.028), Tregs (P=0.028) had significantly better prognosis than highly enriched patients (P=0.004), APC co inhibition (P<0.001), B cells (P=0.005), CCR (P=0.006) and other immune cells . Interestingly, the findings showed that patients in high risk group responded more sensitively to the low risk group via the CTLA-4 and PD-1 immunotherapy  , also known as IFN-inducible T cell alpha chemokine, primarily mediates the recruitment of T cells, natural killer (NK) cells, monocytes and macrophages at the site of infection via cognate G protein-coupled receptors CXCR3, such as CXCL9 and CXCL10  express in humans, encoded by the ATP1A 1-4 genes. The α3 isoform encoded by  neurons . At presHLA-DOB, it belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DOA) and a beta chain (DOB), both anchored in the membrane. At present, there are few studies on the involvement of HLA-DOB in tumor mechanisms. The expression of HLA-DOB in multiple myeloma was significantly higher than that in normal plasma cells, suggesting that it was a potential target for immunotherapy  can be found in the article.This study was approved by the ethics committee of the Renmin Hospital of Wuhan University (WDRY2020-K218).YC and WH designed the study. ZW, GC and FD collected the clinical information, gene expression data, and data analysis. ZW and GC wrote the manuscript and SL provided revisions. All authors contributed to the article and approved the submitted version.This study was supported by the China Medical Association Clinical Medical Research Special Fund Project (grant number 17020310700); National Natural Science Foundation of China ; Key Research and Development Program of Hubei Province (2020BCB023); the Fundamental Research Funds for the Central Universities (grant number 2042020kf1013); Educational and Teaching Reform Research Project (grant number 413200095); Graduate credit course projects (grant number 413000206).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chemerin as an inflammatory biomarker has gained attention in its biomarker capability. Several studies measured its levels in chronic kidney disease (CKD), as one of the common non-communicable causes of mortality and morbidity. Hence, this systematic review and meta-analysis aimed to investigate this association.PubMed, Scopus, Embase, and the Web of Science databases were systematically searched for studies investigating chemerin levels in any CKD stage ) and comparing it with healthy controls. Random effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI).A total of eight studies were included, comprised of 875 individuals, with a mean age of 56.92 ± 11.78 years. All studies had high quality based on the New Castle-Ottawa Scale (NOS). Meta-analysis revealed significantly higher levels of chemerin in CKD patients compared to healthy controls . Additionally, HD patients had statistically higher levels of chemerin than controls . In meta-regression, publication year accounted for 23.50% and 24.17% of heterogeneity for these analyses, respectively.Chemerin can be potentially used as a biomarker in CKD patients, which can suggest the inflammatory pathways for the disease. Further research is warranted for the assessment of its clinical applications and enlightening its role in the pathophysiology of CKD. More than 10% of the adult population had markers for renal disease, according to large-scale, nationally representative screening programs carried out in the 2000s .Chemerin was initially identified as a chemokine found in the inflammatory fluids of cancer and rheumatoid arthritis patients . It is aSome studies reported that kidney function is inversely related to circulating chemerin in CKD patients. Blaszak et al. expressed that the mean serum chemerin level in stages 3 and 4 of CKD was 70% higher than the control group and according to a study conducted by Rutkowski et al., the serum chemerin concentration decreased to values observed in control subjects after successful kidney transplantation , 8. In aTo combine recent data of investigations on chemerin in recent years, addressing the link of this unique marker with CKD, a thorough evaluation, and meta-analysis of original research publications were undertaken in this study.22.1In November 2022, a comprehensive search of worldwide web databases, including PubMed, SCOPUS, Web of Science, and Embase, was conducted. The keywords utilized were “chemerin” AND “chronic renal disease”, in addition to other pertinent keywords, which were explained in detail in 2.2The inclusion criteria were: 1) studies assessing chemerin levels in patients with CKD and controls and 2) studies evaluating chemerin levels in patients with CKD undergoing dialysis ) and controls. We excluded: 1) studies without a control group; 2) studies without exact concentration of chemerin levels, after emailing the corresponding author; 3) non-English articles; and 4) letters, commentaries, case reports, conference abstracts, and reviews.2.3Two reviewers (AHB and PB) individually reviewed titles and abstracts for relevant articles based on inclusion and exclusion criteria, after eliminating duplicates from the initial search. Then, the entire texts of included papers were evaluated, and in cases of disagreement, a discussion with the third reviewer (AK) finalized the conclusion. Lastly, the references to the included papers were investigated.2.4Using a data extraction sheet, two independent reviewers (AHB and PS) extracted the following information from each study: 1) First author’s name, publication year, and country of conduct; 2) the demographic characteristics of the cases ; 3) plasma and/or serum chemerin concentration in each group; 4) chemerin gene polymorphism alleles for each study. In situations where precise data regarding the concentration of chemerin were unavailable, we contacted the corresponding author of the investigations.2.5The “Newcastle-Ottawa Quality Assessment Scale” (NOS) for observational studies was used for the quality assessment of included studies . Two aut2.6Random-effect meta-analysis was used to determine the standardized mean difference (SMD) and 95% confidence interval (CI) of chemerin concentrations in CKD and control groups. The p-values <0.05 were used as the cutoff for statistical significance.Where median and interquartile range or median and range were presented in the studies, they were transformed to mean and standard deviations (SDs) following the methods recommended by Luo et al. and Wan et al. , 11. In To calculate the heterogeneity, we utilized Higgins’ I-square test based on Cochrane’s Q. The heterogeneity thresholds for low, moderate, and high heterogeneity were 25%, 26-75%, and 75%, respectively. Due to the high heterogeneity among studies, random-effect meta-analysis (restricted maximum likelihood (REML)) was employed. We performed a sensitivity analysis by omitting each study and examining the effect on the total effect size. To identify potential outliers, Galbraith plots were also used and analyzed. To identify the source of heterogeneity, meta-regression of the sample size, mean age, female percentage, and publication year was also performed. In addition to Egger’s and Begg’s statistical tests, publication bias was evaluated using a visual examination of funnel plots , 14.33.1Our search included 381 records from PubMed (n = 74), SCOPUS (n = 117), Web of Science (n = 84), and Embase (n = 106). After removing 178 duplicates, 156 records were excluded based on title and abstract screening. Assessment of full-texts resulted in excluding 39 articles due to not reporting chemerin levels, not assessing chemerin levels in CKD, review articles, and conference abstracts. Details of the identification of studies are illustrated in Eight studies with 875 participants were included in our study that measured serum levels of chemerin in CKD patients and controls –19 Tab, 8, Egyp3.2I2: 98.29%).Pooling of the eight studies comparing CKD in any stage and healthy controls revealed significantly higher chemerin levels in CKD patients .Assessment of chemerin levels in HD patients in comparison with controls was done in eight of the studies. Random-effect meta-analysis showed statistically higher chemerin blood concentrations in HD cases : as a result of kidney damage, itself either caused by reduced renal clearance or increased production, and (2) as a cause of kidney damage, through a variety of proinflammatory, endothelial, and oxidative mechanisms. These two axes, in turn, implicate chemerin both as a marker for CKD diagnosis, as well as a possible target for the treatment of a variety of kidney diseases.The strengths of this study include precise compliance with PRISMA protocols, including a comprehensive search of relevant databases and the independent screening of search results by two reviewers. The measured outcomes are mostly identical and directly comparable. The major limitation of this analysis was the relevant differences among included studies’ populations and the small sample size of them, resulting in a limitation in the generalizability of the findings. Secondly, few subgroup analyses were performed, which introduces a possible source of bias. Third, we calculated mean and SDs from median and IQRs with the methods suggested by Luo et al. and Wan et al. , 11, whi5Evidence from recent studies suggests that the cytokine chemerin is consistently elevated in patients diagnosed with CKD and in patients undergoing HD compared to healthy controls. This evidence can be used to justify the inclusion of chemerin as one of several possible biomarkers for future models used to classify patients into CKD vs. normal as well as to predict the future course of their disease. Evidence from additional studies is needed to solidify and confirm this observed association as well as to specify pitfalls, including specific comorbidities or covariates, that cause the observed association to fail to replicate.The original contributions presented in the study are included in the article/AHB: Writing - original draft/Conceptualization/Formal analysis/Visualization, PS, PB, and NA: Writing - original draft/Review and Editing, Data curation, AK: Supervision/Conceptualization/Writing - Review and Editing, SP: Writing - Review and Editing. All authors contributed to the article and approved the submitted version


Globally, Alzheimer’s Disease (AD) accounts for the majority of dementia, making it a public health concern. AD treatment is limited due to the limited understanding of its pathogenesis. Recently, more and more evidence shows that ferroptosis lead to cell death in the brain, especially in the regions of the brain related to dementia.Three microarray datasets  related to AD were downloaded from Gene Expression Omnibus (GEO) datasets. Ferroptosis-related genes were extracted from FerrDb database. Data sets were separated into two groups. GSE5281 and GSE9770 were used to identify ferroptosis-related genes, and GSE28146 was used to verify results. During these processes, protein–protein interaction (PPI), the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, the differentiated values of ferroptosis-related genes were determined by receiver operator characteristic (ROC) monofactor analysis to judge their potential quality as biomarkers.https://cn.string-db.org/) and Cytoscape with CytoHubba, the top 10 genes  were identified as target genes. GO analysis revealed that response to carboxylic acid catabolic process, organic acid catabolic process, alpha-amino acid biosynthetic process and cellular amino acid biosynthetic process were the most highly enriched terms. KEGG analysis showed that these overlapped genes were enriched in p53 signaling pathways, longevity regulating pathway, mTOR signaling pathway, type 2 diabetes mellitus and ferroptosis. Box plots and violine plots were created and verified to confirm the significance of identified target genes. Moreover, ROC monofactor analysis was performed to determine the diagnostic value of identified genes. Two genes  were subsequently obtained. For the tow genes, STRING was used to obtain the five related genes and determined enriched GO terms and KEGG pathways for those genes.Twenty-four ferroptosis-related genes were obtained. Using STRING (Our results suggest that ASNS and SENS2 may serve as potential diagnostic biomarkers for AD and provide additional evidence regarding the essential role of ferroptosis in AD. The number of people suffering from Alzheimer’s disease (AD) are increasing globally, and AD influences many aspects from daily lifestyle to family expenditures . AD is tScientists have deemed that the hippocampal brain region is responsible for the function of memory, learning and spatial information in animal and human research . ExploraIn Ferroptosis is a unique pattern of cell death that has gained attention in the field of AD research. However, the current studies of AD and ferroptosis lack exploration at the genetic level, although they may help to diagnosis AD and identify therapeutic targets for AD. Therefore, the purpose of the current study was to identify potential biomarkers related to ferroptosis and AD and to provide additional perspective for the research and treatment of AD.Three AD-related microarrays datasets GSE9770 , GSE5281p-value <0.05. The GSE 28146 dataset underwent the same processing flow with the exception of being merged with any other datasets. DEGs were adjusted by the Benjamini–Hochberg method to process the p-values.The datasets were processed used R Studio as follows: firstly, after obtaining the raw data of the three datasets, gene expression was normalized and log2-transformed using the LIMMA package  for norm1 is the world’s first database related to ferroptosis that includes genes and substances (2 was used to obtain the PPI (protein–protein interactions) with a 0.4 (medium confidence) minimum required interaction score. Cytoscape V3.9.1 software (FerrDbbstances . Ferroptsoftware  was thenThe 10 selected genes were used to perform GO (Gene Ontology) analysis to determine BP , CC (cellular component), and MF (molecular function) term enrichment and perform KEGG (Kyoto Encyclopedia of Genes and Genomes pathway) enrichment. Final significant genes also underwent GO and KEGG enrichment analyses.The significance of the 10 selected genes were checked again by comparing GSE28146 and the union dataset of GSE9770 and GSE5281 and visualized, respectively. Then, ROC monofactor analysis was performed in these two datasets to find the clinical and diagnostic value of ferroptosis-related biomarkers in AD patients. In the GSE28146 dataset, significant genes were identified not only by expression changes in AD but were also associated with the stage of dementia, which provided phenotype information.p-value at <0.05. As a result, there were 1,731 down-regulated genes and 1,317 up-regulated genes. GSE28146 was similarly processed, and the results are shown in p-value <0.05. The total 235 ferroptosis-related genes obtained from the FerrDb database (see text footnote 1) included driver, suppressor, and inducer genes. In Three datasets, GSE9770, GSE5281, and GSE28146, were downloaded from the GEO database and processed using the LIMMA package  in R stuSESN2, ASNS, MTOR, SCL3A2, DDIT3, UBC, GLS2, PRDX1, GOT1, and ATG16L1 were identified as hub genes and are shown with their categories in The names and the categories of the 24 ferroptosis-related biomarker candidate genes are shown in Gene Ontology term enrichment was determined for the 10 biomarker candidates and included analysis for enriched BP, MF, and CC . KEGG enp < 0.01. Surprisingly, all genes showed that the expression is down-regulated in hippocampal region in AD patients vs. health person, except the SESN2 which show the opposite trend  in AD patients vs. people without AD. ASNS and SESN2 expression levels in the GSE28146 dataset were similar to that seen in the union set. Phenotypic subgroups were created according to the stage of dementia. There were no gene differences within the subgroups (ASNS and SESN2 was greater than 0.7 in the m1 curve, and ATG16L1, GOT1, and SESN2 exceeded 0.7 in the m2 curve. Thus, ASNS and SESN2 were chosen as biomarker candidates with potential diagnostic value in AD.After selecting the 10 genes, the GSE28146 dataset was used to verify results. In ubgroups . ROC monASNS and SESN2, and the networks were visualized (GOT2, CAD, ASS1, ATF4, and CEBPB are co-expressed with ASNS. GO and KEGG analysis results of these six genes are presented in SESN2, based on the six related genes, is also shown (The STRING database was used to identify the co-expressed protein network of sualized . Five inso shown .Aging consists of many processes, including loss of protein homeostasis, DNA damage, lysosomal dysfunction, epigenetic changes, and immune dysregulation, and it does not mutually and linearly relate to disease . As normSCL40A1, a ferroptosis-related gene, is associated with cognitive impairment in type I diabetes (ASNS may be a predictive biomarker in those tumors or cancers; however, assays also indicate an association between ASNS and neurodegeneration diseases. SENS2 shows a similar trend to ASNS findings. In the study of carcinoma, SENS2 was identified as a tumor suppressor gene (SESN2 may be a prognostic biomarker for hepatocellular cancer (SESN2/3 knockout mice may allow characterization of its role in aging and metabolic-related disorders. Furthermore, SESN2 may inhibit the production of ROS and produce antioxidant effects, making it a potential target for the treatment of AD and neurodegenerative diseases, as AD neuronal death is likely caused by oxidative damage (More and more scholars are studying the field of ferroptosis and neurodegenerative diseases. An animal study suggested that diabetes . Moreovediabetes . In the diabetes . ASNS masor gene . More spr cancer . A mousee damage . Surprise damage . In summe damage . HoweverIn conclusion, after processing and validating, ASNS and SESN2 were identified, which pays little attention on the correlation with AD. In our study, ASNS and SESN2 was regarded as the candidate biomarker of diagnosis of AD and even the therapeutic target in the further study. However, we fail to find the gene providing the clinic value of distinguishing the stage of dementia. Because more ferroptosis-related genes have been finding and more hippocampal region samples are needed.There are several limitations to the current study. First, the datasets chosen and used for analysis—specifically the merged dataset GSE9770–did not provide specific dementia state information. Therefore, there may be limitations regarding AD patient selection and access to DEGs. In addition, because there are few microarrays in the hippocampus of AD patients and the hippocampus of people without AD, only the three datasets used in the present study were available for continuous verification. Finally, the overlapped genes verified in this study need to be supported by future studies and verified by laboratory evidence.The datasets presented in this study can be found in online repositories. The names of the repositories and accession numbers can be found in the article/supplementary material.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.


Identifying what prompts or hinders women’s help-seeking behaviour is essential to ensure timely diagnosis and management of gynaecological cancers.To understand the factors that influence the help- seeking behaviour of women diagnosed with gynaecological cancer.Systematic review and narrative synthesis of studies from high-income settings worldwide.Five databases were searched for studies, of any design, that presented factors related to the help-seeking behaviour of women diagnosed with a gynaecological cancer. Data from the articles were extracted and presented using narrative synthesis, which was both inductive and deductive. The COM-B  model of behaviour change was used as a framework.In total, 21 studies were included in the review. Inductive synthesis presented three main themes of factors related to the help-seeking behaviour of women diagnosed with gynaecological cancer: patient factors, such as knowledge of symptoms; emotional factors, including previous healthcare experience, embarrassment, and trust; and practical factors, including time and resources. Deductive synthesis demonstrated that capability , opportunity , and motivation  are all required to initiate help-seeking behaviour.Although it is a journey of defined steps, the help- seeking behaviour of women with symptoms diagnosed with gynaecological cancer is influenced by personal and societal factors. Interventions to improve help seeking will need to address the specific identified factors, as well as capability, opportunity, and motivation. It is known that embarrassment, fear of cancer, and poor symptom knowledge may affect how quickly patients would present should they develop symptoms of a gynaecological cancer,10 Such issues surround the intimate nature of gynaecological cancer symptoms, and the investigation and examination necessary to diagnose gynaecological cancers; however, it is not yet known to what degree these cultural issues influence patient help-seeking behaviour and potential diagnostic delay.The importance of cultural issues in detecting cancer early has been highlighted by the James Lind Alliance .11 to identify what prompts, or hinders, patients’ help-seeking behaviour when they have symptoms of gynaecological cancers has the potential to identify targets for intervention that aim to achieve more-timely help seeking. This model suggests that behaviour consists of three components:capability — the knowledge and skills needed to engage in help-seeking behaviour;opportunity — the external factors that influence help seeking; andmotivation — the internal processes that influence help seeking.Using the COM-B  behaviour change model 11 to ideIdentifying the factors associated with patients’ help-seeking behaviour is important and may lead to the development of effective interventions that have the potential to shorten diagnostic delay. This narrative review aimed to understand what factors affect the help-seeking behaviour of women diagnosed with gynaecological cancer.12 were followed. Initially performed in June 2020, the search was repeated in March 2022.A systematic review was conducted and the protocol was registered on PROSPERO (registration number: CRD42020197677). The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteriaThe search strategy (see Supplementary Box S1) included two terms — healthcare seeking and gynaecological cancer — their synonyms, and Medical Subject Headings terms. Searches were conducted in five databases — Cochrane Library, MEDLINE, CINAHL, Embase, and Web of Science — from inception to the time of the study being undertaken. In addition, the reference lists of identified articles were searched manually. The search strategy was developed with input from a medical librarian.involved patients aged ≥18 years, who had been diagnosed with, or who had symptoms of, a gynaecological cancer;involved GPs, trainee GPs, nurse practitioners, gynaecology specialists, and emergency care practitioners; andexamined the facilitators and barriers to help-seeking behaviour for patients who had been diagnosed with a gynaecological cancer or had symptoms potentially indicative of a gynaecological cancer.All original research articles from 1996 until March 2022 were included, be they controlled or uncontrolled quantitative studies, or qualitative studies. Studies were included if they:limited to patients aged <18 years;not written in English, or were editorials, unpublished work, or academic theses; and/or13conducted in medium- and low-income countries, as defined by the World Bank.Excluded studies included those that were:The outputs from the searches were imported into the EndNote reference managing tool, and duplicates were removed. All titles, abstracts, and full- text articles were assessed independently at all stages by two researchers using DistillerSR computer software. All titles were screened against the inclusion and exclusion criteria; abstracts of remaining studies were assessed for eligibility. Any disagreements were resolved by discussion between the researchers. Full texts were obtained for all abstracts that met the inclusion and exclusion criteria.et al.14 Data were analysed using thematic analysis15 and framework analysis.16 Thematic analysis enabled the emergence of themes and subthemes, while framework analysis was based on the concepts of the COM-B behaviour change model.11 Detailed methodology of the data-extraction process is given in Supplementary Box S2.Data from the selected full-text articles were extracted independently by two reviewers. Synthesis was narrative and followed the recommended sequence described by Popay Independent dual quality assessment of each included article was performed using the relevant validated Critical Appraisal Skills Programme (CASP) tool; poor study quality did not affect the inclusion of individual articles.7,17–36 The reasons for exclusions are shown in A PRISMA diagram outlines the study search and inclusion process . The sea7,20,25,27–29,35,36 five in the US,22,31–34 two in New Zealand,19,24 two in Canada,26,30 and one in each of Germany,18 Australia,21 and Denmark;17 one multi-centre study was conducted in both Switzerland and Germany.23 Nine studies used qualitative methodology,18–21,23,25,26,30,36 seven were cohort studies,22,24,28,29,32–34 two used mixed methods,17,27 two were systematic reviews,7,35 and one was a cross-sectional study.31 A summary of study results can be seen in Supplementary Table S1; quality assessment is shown in Supplementary Tables S2–S4.Eight studies were conducted in the UK,Individual factors are identified and contextualised to reflect the COM-B behaviour change tool to give an overall assessment of help seeking .Initial reading of the data identified three themes, and second-level analysis identified several subthemes; these are outlined in 17–20 When sensations persist, are painful, worsen, interfere with daily life, or have increased permanency, visibility, or palpability, they are more likely to be determined as symptoms.7,18,19 The years of normal blood loss through menstruation, or even postpartum, lead to some women normalising abnormal vaginal bleeding.19,21,24Bodily sensations need to be considered a symptom for patients to seek help; sensations that could be understood in the context of a patient’s life were not determined as symptoms.7,17,19,21,23,24,26–30,34,36 Some women had not heard of the cancer with which they were diagnosed,19,23,30 while many reported poor symptom knowledge and health literacy.19,24,28–30 Symptom misattribution was common, especially in those who had vague symptoms or who were diagnosed with ovarian cancer.7,17,21,26,27,36Thirteen articles highlighted the influence of symptom knowledge.17,24,28,29,31 Multimorbidity increased delay,32 as did being divorced or widowed.32 Younger women (aged <25 years) exhibited a delay in help seeking in a study of women diagnosed with cervical cancer,29 whereas having a higher socioeconomic status was associated with less delay.17 Lawton et al 24 and Ashing-Giwa and Rosales31 described the influence of ethnicity on help-seeking behaviour: delay was seen in women of Latin American origin in the US and Maori women in New Zealand.24,31Five studies reported an association between demographic factors and help- seeking behaviour.31,32,34 Taught negative attitudes towards gynaecological symptoms was found to contribute to the avoidance of help-seeking behaviour, and such attitudes could cultivate embarrassment, with perceived associations between sexuality and gynaecological symptoms.19,23 Concern about the pain or discomfort associated with the examination could also deter help seeking.33 The stigmatisation by clinicians of women who were overweight or the attribution of health complaints to obesity could lead to avoidance of health care.19,30Fear of finding cancer was found to be an important contributor to delay.18,20 The legitimisation of symptoms by clinicians was also found to be important: not explaining about possible causes of symptoms, or not offering alternative diagnoses and advice if symptoms persisted could contribute to patient delay.35 A lack of trust in clinicians could also impair help-seeking behaviour,32 as could previous benign diagnoses34,35 and the finding that some women feared embarrassment from being considered a hypochondriac or time waster.20,34,35The influence of family and friends was, however, important, and their encouragement could promote help- seeking behaviour.19,20,33 The pressure of time required in a consultation to discuss symptoms of what some felt was a private matter also delayed help- seeking behaviour.19 In a study of African-American women, having a self-reported barrier to seeking care was associated with prolonged symptom duration prior to presentation, although there was no description of these barriers.32 Patients’ prioritisation of others’ health — for example, that of family members — also delayed help-seeking behaviour.18,26Caring responsibilities, inconvenient clinic times, and being busy or short of time could all lead to the avoidance of help-seeking behaviour.33In countries with insurance-based health care, cost could be a deterrent.Capability refers to whether patients have the knowledge, skills, and abilities required to engage in help seeking. It has two components:psychological; andphysical.19,21–24,29,30 Many symptoms of gynaecological cancers — especially ovarian cancer — can be vague, and misattribution of these symptoms as non-serious contributed to delays.7,17,25–27 Additionally, although vaginal bleeding can indicate an underlying malignancy, it is also a normal physiological process; greater delay was observed in women with vaginal bleeding compared with those with urinary bleeding, which is considered non- physiological.28Patients need to know what the symptoms of a disease are; without this, they lack the capability to initiate help seeking.physical — for example, time; andsocial — for example, cultural norms.Although capability initiates help-seeking behaviour, women must have the opportunity to access healthcare services in which they have trust. In the context of this model, opportunity refers to the external factors that make help seeking possible; and again, has two components:19 as could lack of trust in physicians.32 Social responsibilities such as prioritising family members also led to delays.18,20,26,33 Opportunity was also determined by social influencers: taboo and embarrassment about the association between gynaecological symptoms and sexuality could lead to delay.19,23 Additionally, not wanting to be seen as a time waster or hypochondriac also contributed to delay.7,20,35 Discussion with family and friends could reinforce the belief that symptoms are worthy of health care seeking.18,20 Difficulty navigating a healthcare system — for example, because of cost or getting to a clinic or surgery — deterred help-seeking behaviour.33Lack of time and being busy could delay help seeking,reflective — for example, based on previous experience; andautomatic — for example, resulting from fear and inhibition.Motivation refers to the internal processes that influence a patient’s decision to seek help. Its two components are:31,33,34 Moreover, previous healthcare experience of stigmatisation and discrimination could reduce motivation, leading to delay.19,30,32 Examination or symptoms that had previously been reassuring or suggestive of benign disease could decrease motivation,20,21,34,35 as could concerns about painful examination.33 Renzi et al also reported that a lack of explanation for symptoms or lack of advice about what to do if symptoms persisted could also contribute to delay.35Fear of finding cancer was an important demotivator to help seeking.Help-seeking behaviour is complicated. This narrative review has identified patient, emotional, and practical factors that influence help seeking. Although symptoms and symptom knowledge were highlighted as being key, it is clear that knowledge alone is not sufficient to positively affect help-seeking behaviour. Patients’ previous experiences must motivate them to seek help and the opportunity to do so must be available; health care must be trustworthy, and social responsibilities — such as employment and caring roles — must not impede access.This review has been systematically conducted and is the first, of which the authors are aware, to examine the help- seeking behaviour of women diagnosed with a gynaecological cancer using the COM-B framework. The data presented provides a comprehensive summary of the available evidence, as well as highlighting the gaps in knowledge. The combination of thematic and framework analysis has added a robustness to the results.The studies were mostly observational and their quality varied. They were heterogeneous, cancer types and research methods varied, and outcomes were self- reported and descriptive. There was also heterogeneity in study participants and healthcare systems investigated. As a result, the lack of commonality does not permit definitive conclusions.37 Symptom knowledge is a key element of help-seeking behaviour and others have reported that lack of knowledge can lead to delay,5,8,38 whereas increased knowledge can positively influence help seeking.39–41 Women’s interpretations of gynaecological cancer symptoms as normal or trivial, or attributing them to pre- existing illness, can lead to delay in help seeking.20,40 Although symptom knowledge has been associated with higher income and higher educational attainment, it has been reported as being lower in older women.42Patients are aware that early diagnosis is important.20,43 as has the influence of friends and family.44 The positive effect of social support was confirmed by Whitaker et al.40The effect of competing demands has also been described previously,45 It is unclear whether these changes will persist or change as the course of the pandemic changes.The COVID-19 pandemic appeared to alter help-seeking behaviour, with evidence that concerns about overburdening an overstretched healthcare system affected patients’ decision to seek help.28,40,46 Lack of trust in the healthcare system has also been observed to cause delay.40 Fear can both prompt and delay help seeking.8,40,47Worrying about wasting GP time is a known concern for patients and can cause help-seeking delay.48 Although symptom knowledge is important, women’s decisions to seek help are also influenced by societal norms and previous experiences of help seeking. This review highlights areas of patient behaviour that have potential for intervention, for example, improving symptom knowledge.Many health-promotion interventions focus on improving knowledge but do not result in improved cancer diagnosis.46,49 the Royal College of General Practitioners and Royal College of Obstetricians and Gynaecologists have suggested that primary care consultations be increased to 15 minutes,50,51 but the mismatch between resources and demand makes this a challenging target. When asked what they believed were the biggest barriers to presentation for women with gynaecological cancer symptoms, GPs cited lack of awareness and vagueness of symptoms — that is, capability — suggesting that reluctance to present was best managed by patient education.52 Only 14% of GPs questioned felt improving access to health care would reduce presentation delay.52Societal demands — for example, care responsibilities — are difficult to influence. Time pressures during consultations and fragmentation of primary care have been reported as contributing to decreased patient centredness, which is associated with reduced symptom reporting;et al, GPs also cited embarrassment as a barrier to presentation.52 Reluctance to discuss health concerns is associated negatively with help seeking.53 Although it has been shown that many women are embarrassed to discuss gynaecological health with clinicians, much of the evidence is anecdotal or from third- sector surveys.54 More research is needed to explore the influence of embarrassment, and societal and cultural influences, surrounding gynaecological cancer and its symptoms on patient behaviour and help seeking.In the same study by Evans Although a journey of defined steps, help-seeking behaviour of women with symptoms who are diagnosed with gynaecological cancer, is influenced by personal and societal factors. Interventions to improve help seeking will need to address the identified factors, as well as capability, opportunity, and motivation.


Management of tumor lysis syndrome (TLS) associated with cancer chemotherapy for malignant tumors is important because of its potentially fatal course. The use of rasburicase, a recombinant urate oxidase, is recommended for TLS; however, because rasburicase is an enzymatic drug, one should be cautious of anaphylaxis during administration. Using claims data in Japan, we investigated the rate of rasburicase re-administration and the occurrence of anaphylaxis during re-administration in patients with hematopoietic malignancies in a multicenter setting. Re-administration of rasburicase was defined as administration after an interval of 21 days from the first dose. Of 373 patients, 18 were re-administered rasburicase (re-administration rate: 4.8%). No patient developed anaphylaxis. The median number of days from the first to the last dose of rasburicase was 256.5 days (interquartile range: 138.8–455.8 days). The median daily dose was 7.5 mg (4.5–11.3 mg), and the median total dose was 33.8 mg (19.1–64.1 mg). This claims database analysis revealed that the re-administration rate of rasburicase was low in Japanese patients with hematopoietic malignancies, suggesting that rasburicase was being used appropriately, and that associated anaphylaxis was not observed. Tumor lysis syndrome (TLS) is a metabolic disorder caused by rapid destruction of tumor cells and is induced by cancer chemotherapy for malignant tumors. It can lead to a fatal outcome; hence, its management is important . TLS oftConversely, rasburicase is an enzymatic drug, and its administration produces antibodies; thus, it is necessary to monitor for and manage rasburicase-induced anaphylaxis appropriately. Japanese clinical trials have confirmed antibody production in 10% of patients treated with rasburicase . Allen eTherefore, in this study, we survey the rate of re-administration of rasburicase and the occurrence of anaphylaxis during re-administration in patients with hematopoietic malignancies at multiple centers in Japan using claims data.In this retrospective cohort study, we used the JMDC database . This isBetween January 2005 and September 2019, 21,489 patients with hematopoietic malignancies (ICD-10 codes C81–C96 and D46) had their data recorded in the database. Among these patients, those aged 15 years or older who underwent rasburicase re-administration were included in this study.According to the ethical guidelines for epidemiological research in Japan, if informed consent cannot be obtained due to the method or content of the epidemiological research, it must be approved by the ethics committee and permitted by the director of the research institution, and thus, its requirement can be waived. In addition, for observational research that only uses previously acquired data, it is not always necessary to obtain informed consent from the research participant; however, information regarding how the research was conducted must be disclosed. Therefore, with the approval of our Institutional Ethics Board, we provided the participants the option to opt out of the study on our laboratory homepage. Since this study is a database study, we did not obtain patient informed consent.Patient data were collected following the administration of the first dose of rasburicase. In accordance with the definition provided by Allen et al., re-administration of rasburicase was defined as the administration of rasburicase after an interval of 21 days from its initial administration . The monThe Charlson Comorbidity Index (CCI) score was based on the ICD-10 code reported by Quan et al. ,12. CCI Patient characteristics were baselined at the first administration of rasburicase. Data extracted included the age, sex, all hematopoietic malignancies, CCI scores and associated comorbidities, antineoplastic drugs, concomitant use of allopurinol and febuxostat (uric acid production inhibitors), doses, number of courses, and days of rasburicase administration, and number of days between the first and last rasburicase administration.The rasburicase re-administration rate and incidence of anaphylaxis in the re-administered patients were calculated. Values are presented as the number of cases (%) or median (interquartile range (IQR)).Rasburicase was prescribed to 409 patients, of whom 36 were excluded from the analysis. Rasburicase was then re-administered to 18 of the remaining 373 patients .The rasburicase re-administration rate was 4.8%. No patient was assigned an ICD-10 code for anaphylactic shock. One patient was prescribed adrenaline injections (given the ICD-10 code for septic shock) and also received antibiotics. Therefore, no patient developed anaphylaxis.The median age at baseline was 56 years (36–59 years). The study population comprised 12 men (66.7%). Hematopoietic malignancies were mainly acute lymphocytic leukemia in five cases (27.8%), acute myeloid leukemia in three cases (16.7%), and Mantle cell lymphoma and non-Hodgkin’s lymphoma in two cases (11.1%). The median CCI score was 5.5 (3.8–9.3), and 12 patients (66.7%) had a CCI score ≥5; thus, the number of high-risk patients was high. Comorbidities associated with the CCI score were mainly mild liver disease in 13 cases (66.7%); peptic ulcer disease in 9 cases (50%); congestive heart failure, diabetes without chronic complications, and chronic pulmonary disease in 8 cases (44.4%); and metastatic solid tumors in 5 cases (27.8%). The following antineoplastic drugs were administered: cytarabine ; cyclophosphamide, vincristine, and doxorubicin ; and rituximab . Allopurinol and febuxostat were co-administered in four (22.2%) and two (11.1%) patients, respectively.The median number of courses of rasburicase was 2 (2–4). Furthermore, the median total days of rasburicase administration was 5.5 days (3.8–9.8 days). The median number of days between administration of the first and last doses was 256.5 days (138.8–455.8 days). The median dose administered per day was 7.5 mg (4.5–11.3 mg/day), while the median total dose was 33.8 mg (19.1–64.1 mg). The patient characteristics are summarized in To the best of our knowledge, this is the first survey performed to verify the re-administration rate of rasburicase and the associated incidence of anaphylaxis using claims data. This survey was conducted at 23 facilities, a number that is approximately three times larger than the number of facilities involved in clinical trials in Japan [The JMDC database comprises real-world medical practice data, including information on medical fee statements. All medical fee claims at insurance medical institutions are collected by the insurer; thus, even if a patient receives treatment at multiple medical institutions, all medical treatment details can be obtained using the database . RasburiTLS is caused by the destruction of tumor cells; nucleic acids are metabolized to xanthine and subsequently uric acid, resulting in hyperuricemia. In addition, hyperphosphatemia and hyperkalemia occur concurrently. When blood pressure decreases and inflammation occurs due to cytokines, acute renal failure develops. Subsequently, the amounts of uric acid, potassium, and phosphorous exceed the urinary excretion capacity, and large amounts of these materials suddenly enter the blood and are released into the body. This can lead to various TLS pathologies, including renal failure, arrhythmia, seizures, and even death . RasburiAllen et al. reported that the incidence of anaphylaxis after re-administration of rasburicase was 6.2%; however, anaphylaxis did not occur in any patient in our study . In JapaIn this study, 4 out of 18 patients received rasburicase at multiple centers: 3 patients received rasburicase at two centers and 1 received it at three centers. It is unclear whether the treatment histories of these patients were shared between the centers. In order to prevent anaphylaxis due to rasburicase, it is necessary to understand the administration history. Therefore, it is important to interview the patients, prepare medical information documents, and direct medical personnel to provide support to ensure that the patients themselves can maintain their treatment history.In clinical practice, it is assumed that rasburicase re-administration may be required during repeated courses of cancer chemotherapy in patients at a high risk of TLS. In a Japanese clinical trial, an antibody measurement test revealed no antibody production from the start of rasburicase administration (0.20 mg/kg) to day 8 after administration. However, antibodies were confirmed in 12% and 8% of the patients on day 29 and at 6 months (±2 months) after administration, respectively . The risThis study has some limitations. First, the number of patients was small. However, it is necessary to accumulate such evidence one by-one. Second, rigorous verification by weight-equivalent dosage was not possible due to the lack of information on the patients’ body weight. Third, the JMDC database is mainly limited to data on employees of large companies and their families under the age of 75 years; hence, the development of anaphylaxis in the elderly, employees of small and medium enterprises, and self-employed people and their families have not been evaluated.Claims database analysis revealed that the re-administration rate of rasburicase was low in patients with hematopoietic malignancies in Japan; anaphylaxis was not observed following rasburicase re-administration.