Telomeres are the terminal regions of chromosomes that ensure their stability while cell division. Telomere shortening initiates cellular senescence, which can lead to degeneration and atrophy of tissues, so the process is associated with a reduction in life expectancy and predisposition to a number of diseases. An accelerated rate of telomere attrition can serve as a predictor of life expectancy and health status of an individual. Telomere length is a complex phenotypic trait that is determined by many factors, including the genetic ones. Numerous studies  indicate the polygenic nature of telomere length control. The objective of the present study was to characterize the genetic basis of the telomere length regulation using the GWAS data obtained during the studies of various human and other animal populations. To do so, a compilation of the genes associated with telomere length in GWAS experiments was collected, which included information on 270 human genes, as well as 23, 22, and 9 genes identified in the cattle, sparrow, and nematode, respectively. Among them were two orthologous genes encoding a shelterin protein (POT1 in humans and pot-2 in C. elegans). Functional analysis has shown that telomere length can be influenced by genetic variants in the genes encoding: (1) structural components of telomerase; (2) the protein components of telomeric regions (shelterin and CST complexes); (3) the proteins involved in telomerase biogenesis and regulating its activity; (4) the proteins that regulate the functional activity of the shelterin components; (5) the proteins involved in telomere replication and/or capping; (6) the proteins involved in the alternative telomere lengthening; (7) the proteins that respond to DNA damage and are responsible for DNA repair; (8) RNA-exosome components. The human genes identified by several research groups in populations of different ethnic origins are the genes encoding telomerase components such as TERC and TERT as well as STN1 encoding the CST complex component. Apparently, the polymorphic loci affecting the functions of these genes may be the most reliable susceptibility markers for telomere-related diseases. The systematized data about the genes and their functions can serve as a basis for the development of prognostic criteria for telomere length-associated diseases in humans. Information about the genes and processes that control telomere length can be used for marker-assisted and genomic selection in the farm animals, aimed at increasing the duration of their productive lifetime Telomeres are the terminal regions of chromosomes that ensuretheir stability and represented by evolutionary conservedtandemly repeated DNA sequences  of several kb in length . For example, theirlengths in humans at birth are 10–15 kb .3ʹ terminal end of a telomere is a single-stranded guanine-richDNA region (150–200 nucleotides), whose end interacts withthe double-stranded region to form the so-called T-loop at thetelomere end. T-loop formation and stabilization are ensuredby a shelterin complex . This structure prevents recognitionof a chromosome terminal region by repair proteins.DNA polymerase is unable to fully replicate the 3ʹ-end ofa linear DNA during cell division, which leads to a loss of50–200 nucleotides of the telomeric sequence at each celldivision . Telomere shortening can also befacilitated by other factors and processes 1,such as oxidative stress, inflammation, UV irradiation, effectsof toxic agents, DNA replication errors, etc. . These factors are likely to producedifferent effects depending on cell types and the organism’sdevelopment stage and species .http://vavilov.elpub.ru/jour/manager/files/Suppl_Ignatieva_Engl_27_3.pdf.Supplementary Materials are available in the online version of the paper:Telomere shortening initiates cellular senescence. Activationof DNA damage response signaling pathways results ina cell cycle arrest, which may in turn lead to apoptosis andeventually – to progressive tissue degeneration . The datacollected at the cellular level in vitro and in model organismslay the foundation for using the telomere length as a predictorof life expectancy and health status of an individual. Indeed,studies in humans , mice , sheep , cattle , wild birds , and other animals haveshown that shorter telomere length may be associatedwithreduced life expectancy. The studies in humans discovered anassociation between the telomere length and cardiovasculardiseases, cancer, diabetes, inflammation, and other pathologicalstates .Telomere shortening is prevented by telomerase, a specializedribonucleoprotein complex acting as a reverse transcriptase.In humans, telomerase is active in almost all thecancer cells studied , in blastocyst, in mostsomatic tissues at 16–20 weeks of development (except forbrain cells), and ovary and sperm cells at all ontogeneticstages (except for mature spermatozoids and oocytes) .Telomerase activity is controlled by the proteins regulatingexpression of telomerase components, their movementto various cell compartments, processing, and assembly aswell as by the proteins maintaining stability of the telomerasecomplex or, on the contrary, activating its degradation .The main stages of telomerase biogenesis are presented inFigure 2. The examples of proteins affecting the telomeraseactivity are presented in Suppl. Material 2. In addition, thetelomerase activity is also affected by the shelterin  and CST complex .Telomere length is a complex phenotypic trait determinedby multiple factors including genetic ones. The meta-analysisof heritability data for this trait performed in eighteen vertebratespecies showed the averaged heritability index of 45 %.The studies showed the value of 52 % in humans, 42 % – inHolstein cattle breed, 35 % – in hamadryas baboons, and5 % – in sheep .The problem of genetic basis of telomere length regulationis of interest for many researchers. The information on telomerase components and proteins involved in telomere lengthregulation  canbe found in The Telomerase Database (http://telomerase.asu.edu/) . Joyce and co-workers (2018)presented a set of 80 human genes with telomere-related functions.The GWAS data also indicate a polygenic nature of telomerelength heritability. For instance, the GWAS Catalog (https://www.ebi.ac.uk/gwas/) cites 99 human genes that either includeor neighbor the telomere length-associated allelic variants.One of the largest GWA studies presents the data on 138 humangenomic loci, whose allelic variants are associated withtelomere length .In addition to the telomere length association data gatheredusing GWA studies in various human population samples,the data obtained in other animal species also appear to be of interest. However, these studies are rather scarce and areavailable only for Holstein–Friesian cattle , house sparrow nestlings , andC. elegans .The objective of this review was to characterize the geneticbasis of telomere length regulation using the GWAS datacollected in various human populations and to compare themwith the results of similar experiments in other animal species.For this purpose, (1) the data on genes identified in GWAStelomere length experiments were systematized; (2) functionalannotation of genes was performed, and the set of biologicalprocesses affecting telomere length was identified.The data on telomere length-associated genes were obtainedfrom the papers available in the PubMed database (https://pubmed.ncbi.nlm.nih.gov/) using such keywords as ‘telomerelength’ and ‘GWAS’. Functional annotation of genes wasperformed using information obtained from the papers presentingGWAS data, PubMed, The Telomerase Database (http://telomerase.asu.edu/) queries, and the DAVID knowledgebase(https://david.ncifcrf.gov/) .Human genes identified through GWA studiesPubMed queries produced 18 scientific papers presenting theresults of identifying telomere length-associated polymorphicloci in human genome based on GWAS data. These paperswere analyzed, and the data on 270 telomere length-associatedgenes were collected . Most genes (262)were identified in European-ancestry population samples, thedata on 15 genes were obtained from the studies in SoutheastAsian population samples , five genes were identified as a result of trans-ethnicmeta-analysis of Singaporean Chinese and European ancestrydata , and one gene was found in AfricanAmericans .The data on functional significance in the context oftelomere length regulation were presented by the authors ofGWA studies for 52 genes out of 270 .The fact that the data on gene significance in the context oftelomere length regulation were unavailable for a number ofloci reflects the capabilities and limitations of GWAS methodology.Most loci identified by GWAS and associatedwith the trait of interest are located in intergenic regions. Asa rule, in these cases, the set of candidate genes includes thenearest genes, whose functional significance is often difficultto interpret. To identify the mechanisms and genes, throughwhich intergenic variants affect the studied traits, additionalexperiments are required. For example, it was shown thatT-to-C substitution of rs1421085 in the intron of FTO geneaffects the expression of IRX3 and IRX5, whose transcriptionstart sites are far away (~520 and ~1160 kb) from rs1421085.Main functional groupsof human telomere length-associated genesA functional classification was performed for a set of 52 humangenes for which there was information about their functionalsignificance in the context of telomere length regulation. As a result, several functional groups ofgenes have been identified Genes encoding telomerase components: TERC is thetelomerase RNA component acting as a matrix for DNA strandextension at the telomere end and TERT is a reverse transcriptaseenzyme subunit .Genes encoding shelterin proteins: components of thiscomplex  can bindto both double-stranded and single-stranded telomeric DNAregions , stabilize them, protect them from exonucleases, reduce telomerase access, and inhibit the proteinsactivated by damaged DNA and involved in double-strandedbreak repair . TheGWAS data on telomere length association were obtained forthe genes coding for five out of six shelterin proteins  .Genes encoding CST proteins: CTC1, STN1, TEN1. CSTcomplex acts as a telomerase negative regulator at the late Sto G2 phase of the cell cycle  .Genes encoding proteins involved in telomerase biogenesisand regulating its activity. One of these genes, ZCCHC10,encodes a protein regulating telomerase synthesis at transcriptionallevel: ZCCHC10 suppresses TERT transcription. Processing and assembly of a telomeraseRNA subunit involves DKC1, NAF1, and SHQ1 , ribonuclease PARN, exoribonuclease DIS3, thecomponent of a nuclear exosome targeting (NEXT) complex,ZCCHC8 , SMUG1 , and CELF4/BRUNOL4 . Noncanonicalpolymerase TENT4B/PAPD5 ,trimethylguanosine synthetase TGS1 , andEXOSC10 RNA exosome component cause a decrease in the level of active TERC. The assemblyof telomerase nucleoprotein complex involves ATPaseRUVBL1/pontin  and telomerase-associatedprotein TEP1 . Two proteins (WRAP53/WDR79/TCAB1 and NOLC1/NOPP140) provide telomeraseaccumulation in Cajal bodies, the small nuclear organelleswhere processing of small nuclear and nucleolar RNAs andassembly or ribonucleoprotein complexes occur . Telomerase activityis modulated by activator protein SMG6/EST1A, which alsobinds to a single-stranded DNA , and PMLprotein, whose isoform PML-IV suppresses telomerase activity.Genes encoding proteins regulating functional activityof shelterin proteins. CSNK2A2 and CSNK2B are the subunitsof casein kinase which phosphorylates TERF1, increasingits binding to telomeres .ATM serine/threonine kinase, on the contrary, decreasesTERF1 binding to the telomeric DNA . PeptidaseUSP7 and ubiquitin ligase SIAH1 activate proteasomaldegradation of POT1 and TERF2, respectively . ADP ribosylases PARP1 and PARP2 reduce the DNAbinding activity of TERF2 .Genes encoding proteins involved in telomere replicationand/or capping: (1) enzymes RRM1 and TYMS involved insynthesis of deoxynucleoside triphosphates (dNTP) and thymidylatesrequired for DNA synthesis ; (2) helicases RTEL1 and MCM4; (3) RPA1 and RPA2, the subunitsof the RPA complex capable to unfold G-quadruplex structuresthat may block DNA replication ;(4) HNRNPA1 promoting telomere capping after DNA replication.Genes encoding proteins affecting the alternative telomerelengthening pathway. This telomerase-independentmechanism  includes the recombinationbetween telomeric regions of two DNA molecules. Three genes identified inGWA studies were attributed to this group . These genes encode SMC6 which activates ALT and its two inhibiting proteins: ATRX withchromatin remodeling activity and SLX4 endonuclease .Genes encoding DNA damage response proteins: (1) peptidaseSENP7 ; (2) chaperone protein BAG6; (3) DCAF4 interacting with CUL4-DDB1ligase ; (4) RFWD3 interacting withRPA protein (replication protein A) .Genes encoding subunits of RNA exosomes: EXOSC6,EXOSC9  and MPHOSPH6 . These proteins are functionally significant, becauseit is known that TERC may be subjected to 3ʹ-processing,and the RNA-exosomes are involved in this process .Human candidate genes identified in more than one studyAs mentioned above, we have analyzed 18 papers on identifyingtelomere length-associated human genome loci based onGWA studies and collected the data on 270 such genes . Notably, only 16 genes were identified inat least two studies .The most frequently identified genes were the ones encodingboth telomerase components (TERC and TERT ) and STN1encoding a component of the CST complex . Three genes POT1, TERF1,and TERF2 encoding components of the shelterin complexwere mentioned in 4, 3, and 2 publications, respectively.Three more genes DCAF4, RTEL1, and NAF1 controlling theDNA damageresponse, telomere replication, and telomerasebiogenesis were identified in four studies. ATM, PARP1,MPHOSPH6, RFWD3, SENP7, and TYMS were identifiedin 3 or 2 papers.Most of 16 genes listed above were identified in populationsamples of different ethnic origin: (1) TERC in three ethnicgroups, namely Europeans, Bangladeshis, and SingaporeanChinese; (2) DCAF4, MPHOSPH6, and TYMS in Europeansand as a result of the trans-ethnic meta-analyses (SingaporeanChinese+Europeans); (3) TERT, STN1, POT1, RTEL1, NAF1,TERF1, ATM, PARP1 in two ethnic groups, namely Europeansand Singaporean Chinese.Identification of the genes related to telomerelength regulation according to DAVIDUsing DAVID, we found the terms from the GOTERM_BP_DIRECT dictionary that were significantly (FDR < 0.05) associatedwith the list of 270 human genes presented in Suppl.Material 3. Sixteen terms indicating biological processes thatdirectly control telomere length are presented in Suppl. Material6, and the remaining fifteen terms are listed in Suppl.Material 7. There were 30 genes associated with the termsfrom the first group , with two of them (SIRT6 and TP53) previously not recognized as biologicallyinterpretable  without comment on their functional significance inthe context of telomere length regulation). The analysis ofscientific papers showed that proteins encoded by both genescan function in the subtelomeric regions of chromosomes, which means theycould be indirectly involved in telomere length regulationThen, the genes associated with the second group ofGOTERM_BP_DIRECT terms identified at FDR< 0.05  were analyzed. Among them, 29 geneswere found that had no biological interpretation .This group of 29 genes included the above mentioned SIRT6and TP53, as well as BRCA1, SAMHD1, and BRCC3 associatedwith the maximum number of GO terms . Apparently, the genes from the list thusobtained may also be of interest in the context of telomerelength regulation.Telomere length-associated genesfound in other animal speciesGenome-wide search for telomere length-associated loci andgenes was carried out in three animal species: cattle (Bostaurus), sparrows (Passer domesticus), and nematodes (Caenorhabditiselegans).A GWA study to investigate the species Bos taurus wascarried out on 702 animals of the Holstein–Friesian breed. The study of the DNA isolatedfrom the whole blood of cows sampled at birth showed sixtelomere length-associated polymorphic loci, and three additionalloci were identified when analyzing the DNA from bloodsamples at the first lactation. An analysis of the quantitativetrait loci (QTL) corresponding to the identified genetic variantsrevealed 14 candidate genes at birth and 9 at the first lactation. The authors wereunableto find any data on direct involvement of the identifiedgenes in processes associated with telomere length regulation.NUP93 nucleoporin gene encoding a nuclear pore componentwas considered a potential regulator, because it was shownearlier in yeast that nucleoporins facilitated silencing of genesin proximity of telomeric regions .The recently published results of GWA study  in house sparrow (Passer domesticus) nestlings madeit possible to identify 22 candidate genes . According to the authors, the genes ofinterest in the context of telomere length regulation seem tobe as follows: (1) WNT9B encoding a protein component ofWnt/ β-catenin signaling pathway due to β-catenin involvementin Tert activation in embryonic stem cells of mice; (2) CDCA4,GH, and GHRHR regulating cell proliferation, apoptosis, andbody growth; (3) RHOF involved in cytoskeletal organization;(4) RNF34 (E3 ubiquitin-protein ligase RNF34) regulatingubiquitination; (5) AQP1 due to involvement of aquaporinprotein in transport of nitrogen oxide and active forms ofoxygen,which increases oxidative stress which can in turnaffect telomerase activity; (6) SCN4A, because its expressionin human stem cells correlates with telomere length.Our analysis showed that none of the candidate genes identifiedin cattle (23 genes) and house sparrows (22 genes) (see theTable) had orthologs among the 270 genes identified based onGWA studies in humans and presented in Suppl. Material3.The study in C. elegans  produced9 candidate genes .One out of nine genes, pot-2, is orthologous to POT1 encodinga shelterin complex component in humans. The authorsassume that another gene ZK1127.4 may also be involved intelomere length regulation, because BCCIP encoded by anorthologous human gene interacts with BRCA2 involved inDNA replicationIn general, when comparing sets of candidate genes identifiedin humans and three other animal species, almost noorthologous genes are detected, which may be due to speciesspecificfeatures of telomere length regulation, some peculiaritiesof regulation at various ontogenetic stages, and differencesin sampled tissues or gender of the studied individuals.In the present paper, a compilation of telomere length-associatedgenes identified based on GWA studies and includingthe data on 270 human genes , as wellas 23, 22, and nine genes identified in cattle, house sparrow,and nematode (see the Table) is presented. The analysis offunctions of 52 human genes with functional interpretationavailable  showed that telomerelength may be affected by variants of genes encoding: (1) thestructural components of telomerase; (2) the protein componentsof telomeric chromosome regions (shelterin complexand CST complex); (3) the proteins involved in telomerasebiogenesis and regulating its activity; (4) the proteins regulatingfunctional activity of shelterin subunits; (5) the proteinsinvolved in telomere replication and/or capping; (6) the proteinscontrolling the alternative telomere lengthening pathway;(7) DNA damage response and repair proteins; (8) RNA exosomecomponentsCandidate human genes identified by several researchgroups in population samples of different ethnic origin aredetermined: genes encoding telomerase components (TERCand TERT ) and STN1 encoding a subunit of CST complex. It seems that polymorphic loci that affect thefunctions of these genes can potentially be the most reliablepredisposition markers for telomere length-associateddiseases.Comparison of the data obtained from GWA studies inhumans  with the results of similarexperiments obtained for other animal species  confirmed and expanded the understandingof the complex polygenic nature of telomere lengthregulation. In addition, a pair of orthologous genes encodinga shelterin protein (POT1 in humans and pot-2 in C. elegans)was identified; this finding demonstrates the high biologicalsignificance of this gene in various species.Systematized data on genes and their functions may lay thefoundation for development of prognostic criteria for humanpathologies explicitly associated with telomere length. 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Biomolecules.2020;10(10):1425. DOI 10.3390/biom10101425.Seeker L.A., Underwood S.L., Wilbourn R.V., Dorrens J., Froy H.,Holland R., Ilska J.J., Psifidi A., Bagnall A., Whitelaw B., CoffeyM., Banos G., Nussey D.H. Telomere attrition rates are associatedwith weather conditions and predict productive lifespan indairy cattle. Sci. Rep. 2021;11(1):5589. DOI 10.1038/s41598-021-84984-2.Sherman B.T., Hao M., Qiu J., Jiao X., Baseler M.W., Lane H.C.,Imamichi T., Chang W. DAVID: a web server for functional enrichmentanalysis and functional annotation of gene lists (2021 update).Nucleic Acids Res. 2022;50(W1):W216-221. DOI 10.1093/nar/gkac194.Snow B.E., Erdmann N., Cruickshank J., Goldman H., Gill R.M., RobinsonM.O., Harrington L. Functional conservation of the telomeraseprotein Est1p in humans. Curr. Biol. 2003;13(8):698-704.DOI 10.1016/s0960-9822(03)00210-0.Sobinoff A.P., Pickett H.A. Alternative lengthening of telomeres: DNArepair pathways converge. Trends Genet. 2017;33(12):921-932. 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Citrobacter braakii strain GW-Imi-1b1 was isolated from a hospital wastewater sample in Greifswald, Germany. The genome comprises one chromosome (5.09 Mb), one prophage (41.9 kb), and 13 plasmids (2 to 140.9 kb). The genome harbors 5,322 coding sequences, shows a high potential for genomic mobility, and includes genes encoding proteins for multiple drug resistances.The imipenem-resistant  Citrobacter strains thrive in soil, water, and gut microbiota of humans and animals. They cause nosocomial infections and show various degrees of antibiotic resistance  on Mueller-Hinton agar .sistance . CitrobaC. braakii GW-Imi-1b1 was extracted using the MasterPure complete DNA purification kit , from a strain that had been isolated by repeated streaking and regrowth in 10 mL Mueller-Hinton broth (Carl Roth GmbH & Co.) at 37°C. Illumina paired-end sequencing libraries were prepared with the Nextera XT DNA sample preparation kit  and sequenced using a MiSeq system and reagent kit v3 (2 × 300 cycles). Nanopore sequencing library preparation was performed with 1.5 μg high-molecular-weight DNA, a ligation sequencing kit 1D (SQK-LSK109), and the native barcode expansion kit (EXP-NBD104). Sequencing was performed for 72 h using a MinION Mk1B system with a SpotON R9.4.1 flow cell  and MinKNOW v22.05.5 and Guppy v6.2.1 (hac mode) software.The manufacturer’s recommendations were followed unless otherwise stated. Genomic DNA of NC_001422) leftovers. Furthermore, long reads were treated with Porechop v0.2.4 (https://github.com/rrwick/Porechop) and adjusted to 100× coverage with Filtlong v0.2.1 (https://github.com/rrwick/Filtlong), and chimeric reads were removed with unicycler_scrub of Unicycler v0.4.9 (C. braakii GW-Imi-1b1. Unicycler v0.5.0 (de novo hybrid assembly of plasmids (confirmed by BLAST)  . Finallyy BLAST)  and Polyy BLAST) , employihttps://figshare.com/articles/figure/Supplementary_Figure_1/22133567]), and 13 circular plasmids (0.2 to 140.9 kb). The coverages of all genetic entities were calculated with Qualimap v2.2.2 (Citrobacter braakii ASM207534v1 (GenBank accession number GCF_002075345.1), with a FastANI . Genome analysis with Resfams revealed the presence of 27 genes involved in antibiotic resistance, including resistance to β-lactams, aminoglycosides, quinolones, macrolides, nitroimidazoles, streptomycin, and chloramphenicol and efflux pumps .The genome contains one circular chromosome (5.1 Mbp), one circular (pro)phage . The whole-genome project of Citrobacter braakii GW-Imi-1b1 has been deposited in GenBank under the accession numbers CP115723 (chromosome), CP115737 (phage), CP115724 (plasmid 1), CP115729 (plasmid 2), CP115730 (plasmid 3), CP115731 (plasmid 4), CP115732 (plasmid 5), CP115733 (plasmid 6), CP115734 (plasmid 7), CP115735 (plasmid 8), CP115736 (plasmid 9), CP115725 (plasmid 10), CP115726 (plasmid 11), CP115727 (plasmid 12), and CP115728 (plasmid 13), with BioProject accession number PRJNA524094 and SRA accession numbers SRR23033312 (Oxford Nanopore Technologies MinION reads) and SRR23033313 (Illumina MiSeq reads).The assembled genomic entities , nucleotide and amino acid sequences, and GenBank records are accessible via Figshare (


Pseudomonas aeruginosa (PSA) is a common cause of acute pulmonary exacerbations in adult cystic fibrosis (CF) patients. In this setting, culture isolates are often multidrug resistant (MDR) or exhibit difficult-to-treat resistance (DTR) due to frequent antimicrobial exposure, resulting in the use of last-line or novel therapies  using a collection of clinical PSA isolates recovered from adult CF respiratory specimens.herapies . Cefiderherapies –7. TheA total of 31 adult CF PSA isolates were selected from an internal repository . These rin vitro potency compared with I-R, C-T, and CZA (50/MIC90 of CFDC was 0.25/16 µg/mL, respectively. The MIC50/MIC90 of I-R, C-T, and CZA was 2/32, 1/128, and 2/128 µg/mL, respectively (50 compared with the other novel agents (CFDC MIC50/MIC90 of 1/128 µg/mL; 75% susceptible per CLSI; Overall, CFDC retained the greatest  and CZA . The MICectively . Of notein vitro potency against PSA compared with C-T, CZA, and I-R. However, changes in target binding sites of PSA-derived AmpC β-lactamases may result in an increase in CFDC MICs (Antibiotic management of pulmonary exacerbations in the setting of CF is challenging as the etiologic agents often exhibit MDR. CFDC has enhanced activity against MDR PSA and is, therefore, an attractive option for intervention; albeit, CFDC resistance may occur , 13. TheFDC MICs . FurtherFDC MICs . Our stu


Response to NACT was evaluated using CA125 response and chemotherapy response score (CRS). Compared with the non-responders, the responders displayed a larger proportion of tumors showing increase in the infiltration of CD20+ cells (P = 0.046) and in the M1/M2 ratio (P = 0.038) as well as fewer tumors showing increase in the infiltration of CD56bright cells (P = 0.041). No association was found between pre-NACT TIME and response to NACT. Density of pre-NACT CD8+ cells was positively associated with longer progression-free survival (PFS) (P = 0.011) and overall survival (OS) (P = 0.048). Post-NACT CD20+ and CD163+ macrophages (M2) infiltrates were associated with prolonged (P = 0.005) and shortened PFS (P = 0.021), respectively. Increase in the density of CD4+ T cells was predictive for longer PFS (P = 0.022) and OS (P = 0.023). In the multivariate analysis, high density of CD8+ cells pre-NACT (P = 0.042) were independently associated with improved OS.Little is known about the association between efficacy of neoadjuvant chemotherapy (NACT)/survival and the dynamic change of tumor immune environment (TIME) during treatment in epithelial ovarian cancer (EOC). This study investigated the TIME landscape of treatment-naive EOC tumors using multiplex immunofluorescence and associated the TIME before and after platinum-based NACT with treatment efficacy and prognosis in 33 patients with advanced EOC. NACT significantly increased the density of CD8 Ovarian cancer is the most lethal gynecologic malignancy . Epithel+ cytotoxic cells, and CD3+ T cells] or deleterious  to ovarian cancer patients  of treatment-naïve tumor has allowed for identifying components of immune contexture that are beneficial . Serous carcinoma was the predominant histologic subtype , and most of the patients had FIGO stage III disease . Almost all the tumors were grade 3 . Approximately half of the patients had lymph node metastasis. The median CA125 level was 1632.0 U/mL at baseline. Seventy-six percent of patients received two cycles of NACT . CA125 response to 1 (57.6%) Table 1.+ T cells, significantly increased    . No significant difference was found in the density of other immune cell subsets, including CD3+, CD4+Foxp3+, CD4+, CD68+CD163- and PD-1+CD8+ . We also observed a significant increase in the infiltrates of PD-1+ cells (P = 0.048), PD-L1+CD68+ macrophages (P = 0.017), CD20+ B cells (P = 0.033), and CD56dim (P = 0.022) , PD-1+ cells (P = 0.011), PD-L1+CD68+ macrophages (P = 0.023) and PD-1+CD8+ cells (P = 0.035) in the stoma of CRS2 responders (+Foxp3+ Treg cells (P = 0.036) and PD-L1+CD68+ macrophages (P = 0.022) in the stroma and decreased M1/M2 ratio (P = 0.016) in the tumor of CRS1 non-responders (+ cells (P = 0.046) and in the M1/M2 ratio (P = 0.038) as well as fewer tumors showing increase in the infiltration of CD56bright cells (P = 0.041)  and M2 macrophages  in the tumor  and PFS   (P = 0.034) (Data not shown), and lower density of CD68+CD163+ M2 macrophages  in the post-NACT tumor were found to predict better PFS  and OS (log-rank P = 0.023) , and OS  and tumoral CD8+ pre-NACT  were independently associated with improved OS. The difference in PFS between pre-NACT CD8high and pre-NACT CD8low patients was marginally significant (P = 0.054)  Table 3.+ T cell, CD20+ B cells, and PD-L1+CD68+ macrophages. The biopsies pre-NACT from patients with good response to NACT had significantly increased infiltration of CD8+ T cells and CD20+ B cells compared with tumor specimens post-NACT. Infiltrates of CD8+ T cells pre-NACT, CD20+ B cells and CD163+ macrophages post-NACT, and marked change in CD4+ T cells during NACT are associated with prolonged survival.In the current study, we reported that the infiltration of immune cells in the tumor lesions pre-NACT and post-NACT was associated with response to NACT and long-term survival benefits. With mIF, we analyzed multiple immune cell subsets closely associated with cancer dissemination in a cohort of patients with paired pre-NACT and post-NACT specimens. We show that NACT altered the balance of immune cell subsets of T cells, B cells, and macrophages, showing significantly elevated density of CD8+ T cells, CD3+ T cells, CD20+ B cells, and PD-1+ cells  were associated with prolonged and shortened PFS, respectively. There is evidence that a high M1:M2 ratio post-NACT is predictive of improved PFS and OS  for the publication of any potentially identifiable images or data included in this article.GC: Acquisition of data, writing-review and editing. DH: Methodology, writing-review and editing. JL: Data curation, formal analysis, writing-review and editing. XZ: Data curation, formal analysis, writing-review and editing. ZZ: Data curation, formal analysis, writing-review and editing. BZ: Data curation, formal analysis, writing-review and editing. TB: Writing–original draft, writing–review and editing. LC: Conceptualization, resources, supervision, writing–review and editing. SC: Conceptualization, resources, supervision, writing–review and editing. SW: Resources, data curation, writing-review and editing. LZ: Conceptualization, resources, supervision, methodology, project administration, writing–review and editing. All authors contributed to the article and approved the submitted version.


Correction: Arthritis Res Ther 25, 143 (2023)https://doi.org/10.1186/s13075-023-03129-0Following publication of the original article , the autThe sentence currently reads:17 studies were included , indicating that multiple sclerosis patients are more likely to suffer from periodontal diseases and TMD [7]. TMD and periodontal disease might be the first symptoms of several rheumatic diseases [8].The sentence should read:Unilateral mastication due to PD could induce pain and structural changes in the temporomandibular joint [7]. In addition to clinical observational studies, two symptoms often occur together in many diseases, such as rheumatic diseases  and multiple sclerosis [10].Updated references:J Periodontal Implant Sci 2017, 47(4):211-218.7. Jeon HM, Ahn YW, Jeong SH, Ok SM, Choi J, Lee JY, Joo JY, Kwon EY: Pattern analysis of patients with temporomandibular disorders resulting from unilateral mastication due to chronic periodontitis. Journal of clinical medicine 2018, 8(1).8. Gualtierotti R, Marzano AV, Spadari F, Cugno M: Main Oral Manifestations in Immune-Mediated and Inflammatory Rheumatic Diseases. Reumatol Clin (Engl Ed) 2020, 16(4):262-271.9. González-Chávez SA, Pacheco-Tena C, Campos Torres RM, Quiñonez-Flores CM, Reyes-Cordero G, Caraveo Frescas TJ: Temporomandibular and Odontological Abnormalities in Patients with Rheumatoid Arthritis. Evidence-based dentistry 2021, 22(1):44-45.10. Al-Ansari A: Is there an association between multiple sclerosis and oral health? The original article  has been


Predictors of SOF/VEL/VOX failure were genotype 3, active HCC, baseline cirrhosis, and prior SOF/VEL. Baseline RAS mutation and ribavirin supplementation were not associated with higher SVR12. Treatment discontinuation because of drug-related adverse events was uncommon . In summary, SOF/VEL/VOX is efficacious and safe for retreatment in DAA-experienced CHC patients, even with RAS mutation. Our findings support SOF/VEL/VOX as a first-line rescue treatment for DAA-experienced CHC patients. About 5% of chronic hepatitis C (CHC) patients experienced treatment failure with direct-acting antiviral (DAA) treatment. The global data on the practice and treatment outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) in DAA-experienced CHC patients remains sparse. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of SOF/VEL/VOX as a salvage treatment in DAA-experienced CHC patients. We searched five electronic databases from inception to 31 January 2023. The study outcomes were SVR12 and treatment-related adverse effects, with subgroup analysis performed based on genotype, cirrhosis, HCC, prior SOF/VEL exposure, and region. We identified and analyzed data from 24 studies (2877 DAA-experienced CHC patients); 17.2% had prior SOF/VEL exposure, 25% received ribavirin with SOF/VEL/VOX, and 42% had pre-treatment resistance-associated substitution (RAS) testing performed. Eastern Mediterranean had a higher pooled SVR12 than the America and Europe regions ( Chronic hepatitis C (CHC) infection affects 56.8 million people globally, with about 1.5 million new infections every year, resulting in 400,000 deaths each year . VirologTreatment options remain limited in DAA-experienced CHC patients who fail to achieve SVR12. Retreatment of CHC patients with DAA failure could be challenging because of the emergence of resistance-associated substitution (RAS). Current guidelines recommend Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) as a salvage treatment for DAA-experienced CHC patients who failed to achieve SVR12 . SOF/VELThe global data on practice and treatment outcomes of SOF/VEL/VOX remained lacking, especially in regions such as Asia and Africa. Although some studies reported a lower SVR12 among CHC patients with liver cirrhosis or genotype 3, which is prevalent in south Asia ,10, suchWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for data extraction and reporting . With thWe included all studies that met one of the following inclusion criteria, regardless of publication dates and publication status. Our inclusion criteria were as follows: (1) DAA-experienced, adult CHC patients (age > 18 years old) treated with 12 weeks of SOF/VEL/VOX, with or without Ribavirin, and (2) reported data on either SVR12 or adverse events. Our exclusion criteria were (1) paediatric CHC patients; (2) animal studies; (3) studies that did not report study outcomes; (4) case reports or case series with less than 10 patients; (5) reviews, editorials, or guidelines; and (6) clinical trials. Three authors  independently performed the initial screening of the title and abstract identified in the primary search for eligibility. Any discrepancy in the article selection was resolved by discussion and consensus with the senior author (W.Y.J.). The data from each study were independently extracted using a standardized form. We contacted the corresponding author to verify any missing information. The data extracted included demographics of the study participants (age and genotype of hepatitis C virus), location, sample size, RAS testing at baseline, SVR12, concurrent use of ribavirin (RBV), and treatment-related adverse events requiring discontinuation of treatment.The outcomes studied were as follows: (1) SVR12 (both the intention-to-treat (ITT) and per-protocol (PP) analysis) and (2) frequency of adverse events leading to treatment discontinuation. The ITT analysis included all subjects treated with SOV/VEL/VOX, while the PP analysis only included SOF/VEL/VOX-treated CHC patients with available SVR12 results. Subgroup analysis was performed based on region, HCV genotype, baseline cirrhosis status, prior SOF/VEL exposure, hepatocellular carcinoma, RAS mutation, and concurrent use of ribavirin. p-value of less than 0.05 was considered to be statistically significant. Study heterogeneity was assessed by the 2I% statistics. We used Review Manager Software version 5.3  to perform our meta-analysis. The effect measures were estimated using the odds ratio (OR) for categorical outcomes and mean difference (MD) for continuous outcomes together with the respective 95% confidence interval (95%CI). The meta-analysis was performed using the random-effects model. A The quality of all included studies was independently assessed by three authors using the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool (non-randomized studies)  and the . Most studies had either a low risk [From an initial total of 522 citations identified using our search strategy, 92 full texts were reviewed. We excluded 68 citations for the following reasons: clinical trial (n = 41), treatment-naïve CHC patients (n = 8), case report or study with less than 10 patients n = 17), and missing data (n = 2). Finally, a total of 24 studies were included for analysis . Most st, and mislow risk ,21,22,23low risk ,31,32,33A total of 2887 DAA-experienced CHC patients from 24 studies were included. All patients received 12 weeks of SOF/VEL/VOX, with or without ribavirin. The patient characteristics of the included studies are summarised in p = 0.0006), Western Pacific region (five studies: 94.7% (95%Cl: 91.3–97.1%), p = 0.019), and Europe region (nine studies: 95.8% (95%Cl: 94.5–96.7%), p = 0.04) (p < 0.001) and GT3 infection . The real-world studies had a lower pooled SVR12 than the clinical trials (87.7% (95%CI: 86.4–89.2%) vs. 98.2% (95%CI: 95.9–99.2%), p < 0.0001). The overall SVR12 for DAA-experienced CHC patients treated with SOF/VEL/VOX based on PP and ITT analysis was 95% (95%CI: 94.0–95.8%) and 88% (95%CI: 86.7–89.5%), respectively. The SVR12 in the Eastern Mediterranean region (two studies: 98.2% (95%Cl: 96.0–99.3%)) was significantly higher than the region of Americas ,  = 0.04) . The higI2 = 7%)  and non-GT3 DAA-experienced CHC patients treated with SOF/VEL/VOX was 86.1% (95%CI: 82.3–89.3%) and 94.9% (95%CI: 93.4–96.1%), respectively. GT3 HCV infection was associated with a lower odds of SVR12  .I2 = 0%) (I2 = 3%)  and 97.7% (95%CI: 95.5–99.0%), respectively. Liver cirrhosis was associated with a lower odds of SVR12  A. DecompI2 = 3%) B.I2 = 54%)  and 91.7% (95%CI: 90.0–93.5%), respectively. Prior SOF/VEL exposure was associated with a lower odds of SVR12  A. I2 = 0%)  and 92.8% (95%CI: 90.3–95.3%), respectively. Active HCC during SOF/VEL treatment was associated with a lower odds of SVR12  B.I2 = 34%)  and 91.6% (95%CI: 85.1–98.1%), respectively. The odds of SVR12 were similar among DAA-experienced CHC patients receiving SOF/VEL/VOX, with or without baseline RAS testing  .I2 = 55%)  and 96.2% (95%CI: 94.0–98.5%), respectively. The odds of SVR12 were similar among DAA-experienced CHC patients receiving SOF/VEL/VOX, with or without ribavirin  .From a total of 1283 DAA-experienced CHC patients received SOF/VEL/VOX, the pooled risk of severe adverse events that occurred during SOF/VEL/VOX treatment was 1.94% (95%CI: 1.2–2.8%). The types of serious adverse events are summarised in In this meta-analysis, we found that SOF/VEL/VOX is an efficacious and safe salvage therapy among DAA-experienced CHC patients. The pooled SVR12 was high and treatment discontinuation due to treatment-related SAE was uncommon. Predictors for a lower SVR12 rate by SOF/VEL/VOX were genotype 3, active HCC, baseline cirrhosis, decompensated cirrhosis, and prior SOF/VEL exposure. Meanwhile, the presence of baseline RAS mutation and addition of ribavirin to SOF/VEL/VOX was not associated with higher SVR12. The higher overall SVR12 among the Eastern Mediterranean studies is likely attributed to a lower proportion of patients with GT3 infection and liver cirrhosis. SOF/VEL/VOX, being a protease-inhibitor based DAA, was discouraged in patients with decompensated cirrhosis because of potential toxicity from delayed drug clearance. Among 34 decompensated CHC patients treated with SOF/VEL/VOX in five different studies ,31,32,33Current EASL guidelines recommend the use of RBV with SOF/VEL/VOX in patients with a higher risk of treatment failure; however, the benefits of routine addition of RBV remain unclear . We founThis meta-analysis provides a comprehensive global perspective on the effectiveness and safety of SOF/VEL/VOX among DAA-experienced CHC patients. Prior to this, information on practice and treatment outcomes of SOF/VEL/VOX use among Asian and African population was limited. We acknowledge that there are limitations when interpreting our findings. Most studies did not report the compliance and potential drug interaction among patients receiving SOF/VEL/VOX. The number of patients within subgroups of decompensated cirrhosis was small because the current guidelines discourage the use of SOF/VEL/VOX in these patients. Nevertheless, the results of this meta-analysis provide important data to support the recommendation of using SOF/VEL/VOX as a first-line option among DAA-experienced CHC patients and could be considered level 1 evidence. To conclude, SOF/VEL/VOX is a well-tolerated and highly effective rescue therapy among DAA-experienced CHC patients who failed to achieve SVR12. Predictors of treatment failure include GT3, liver cirrhosis, and active HCC. Safety data of SOF/VEL/VOX among decompensated cirrhosis patients should be investigated in further studies.


Cryptosporidium spp. are important zoonotic agents of bovine diarrhea. However, little is known about microbiota and short-chain fatty acids (SCFAs) changes in yaks infected with Cryptosporidium spp. Therefore, we performed 16S rRNA sequencing and detected the concentrations of SCFAs in Cryptosporidium-infected yaks. Results showed that over 80,000 raw and 70,000 filtered sequences were prevalent in yak samples. Shannon (p<0.01) and Simpson (p<0.01) were both significantly higher in Cryptosporidium-infected yaks. A total of 1072 amplicon sequence variants were shared in healthy and infected yaks. There were 11 phyla and 58 genera that differ significantly between the two yak groups. A total of 235 enzymes with a significant difference in abundance (p<0.001) were found between healthy and infected yaks. KEGG L3 analysis discovered that the abundance of 43 pathways was significantly higher, while 49 pathways were significantly lower in Cryptosporidium-infected yaks. The concentration of acetic acid (p<0.05), propionic acid (p<0.05), isobutyric acid (p<0.05), butyric acid (p<0.05), and isovaleric acid was noticeably lower in infected yaks, respectively. The findings of the study revealed that Cryptosporidium infection causes gut dysbiosis and results in a significant drop in the SCFAs concentrations in yaks with severe diarrhea, which may give new insights regarding the prevention and treatment of diarrhea in livestock.Diarrhea is a severe bovine disease, globally prevalent in farm animals with a decrease in milk production and a low fertility rate.  The long-haired ruminant yak is a plateau bovine species living in the 3000-5000 m high-altitude regions and is mostly found on the Qinghai Tibet plateau . DiarrheEscherichia coli, Salmonella spp., and Cryptosporidium spp. have been commonly observed in infected cattle  with equal number of negative samples (n=4) were sequenced and divided into infected (INF) and healthy (H) groups, respectively.Fecal samples (n=40) were collected from free-ranged yaks in Xining, Qinghai  and examined for sted PCR  and posiThe extraction of total genomic DNA was performed by utilizing a commercial TIANamp Stool DNA Kit (Tiangen Biotech (Beijing) Co., Ltd, China) according to the product’s specifications. Fecal DNA concentration, purification, and quality examination were performed through NanoDrop 2000 UV-Vis spectrophotometer  and 1.2% agarose gel electrophoresis, respectively. Then the hypervariable regions of bacterial 16S rRNA gene (V3-V4) were amplified using primers 338F and 806R as described in a previous study . All PCR® OnePot II DNA Library Prep Kit for Illumina®  according to the product’s instructions, and sequenced through the Illumina NovaSeq platform . Quality control of sequencing data was performed by employing QIIME2 (https://docs.qiime2.org/2019.1/) to generate amplicon sequence variant (ASV) (p<0.05 and log2 (FoldChange) > 2), clustering heatmap (with Z-score > 0.5 or < -0.5) and evolutionary tree (p<0.05) methods to reveal differences in bacterial abundance among yak samples   and taxont (ASV) . Analysi samples . Microbi samples , and parpost-hoc test to measure the individual differences in microbial function between the yak groups with a p<0.05 as statistically significant.The potential KEGG Ortholog (KO) functional profiles of yak microbiota was predicted with PICRUSt  by annotvia t-test.The concentrations of SCFAs in fecal samples were detected by employing GC-MS , and theP values < 0.05 were considered as statistically significant.The differences between different yak groups were calculated by the chi-square test piloting IBM SPSS Statistics (SPSS 22.0). p<0.01) and Simpson (p<0.01) were both significantly higher in group INF than in group H , Proteobacteria (8.97%), and Actinobacteria (8.72%) in group H, while Firmicutes (56.38%) and Bacteroidetes (29.83%) were the main phyla in group INF (Clostridia (51.13%) and Bacilli (17.28%) were the primary classes in healthy yaks, while Clostridia (51.13%) and Bacteroidia (29.83%) were the major classes in infected yaks , Lactobacillales (8.20%), and Bacillales (8.10%) were the primary orders in healthy yaks, while Clostridiales (51.04%) and Bacteroides (29.83%) were the main orders in infected yaks (Ruminococcaceae and Lachnospiraceae in groups H and INF (Pseudomonadaceae Pseudomonas (6.13%), and Lactobacillus (6.00%) were the dominating genera in healthy yaks, while unclassified (69.25%), Prevotellaceae Prevotella (5.13%) and Arthrobacter (2.45%) were the main genera in infected yaks (Veronii (6.11%), and Alactolyticus (1.66%), while unclassified (95.15%), Flavefaciens (1.50%) and Veronii (1.12%) were the main bacteria in group INF  and evolutionary tree (top 50 abundance) with heat map analysis were plotted. The results revealed that at the order level, infected yaks showed an abundance of Bacteroidia and Deltaproteobacteria, while healthy animals showed abundance of Bacilli, Erysipelotrichi, Betaproteobacteria, Alphaproteobacteria, and Nitriliruptoria as expressed in the clustering heatmap. The evolutionary tree also showed an obvious abundance difference in Betaproteobacteria, Fibrobacteria, SJA_176, 4C0d_2, Nitriliruptoria, Clostridia, and Bacilli between groups H and INF , Bacteroidetes (p<0.0001), Armatimonadetes (p<0.0001), Fibrobacteres (p<0.01), and Synergistetes (p<0.01) were visibly higher in infected yaks, while Cyanobacteria (p<0.0001), Proteobacteria (p<0.0001), Armatimonadetes (p<0.0001), Euryarchaeota (p<0.0001), Actinobacteria (p<0.01), Firmicutes (p<0.01), and Elusimicrobia (p<0.05) were significantly lower (p<0.0001), Prevotellaceae_Prevotella (p<0.0001), CF231 (p<0.0001), L7A_E11 (p<0.0001), BF311 (p<0.0001), Desulfovibrio (p<0.0001), Succiniclasticum (p<0.0001), Desemzia (p<0.0001), Anaerovorax (p<0.0001), Pseudobutyrivibrio (p<0.0001), Acinetobacter (p<0.0001), Fibrobacter (p<0.0001), Ruminococcaceae_Ruminococcus (p<0.0001), Anaerorhabdus (p<0.0001), Treponema (p<0.0001), Selenomonas (p<0.001), Clostridium (p<0.001), Shuttleworthia (p<0.001), Dehalobacterium (p<0.001), TG5 (p<0.01), unclassified (p<0.01), Anaerostipes (p<0.01), Syntrophomonas (p<0.01), Brachymonas (p<0.01), Pyramidobacter (p<0.01), SHD_231 (p<0.05), Butyrivibrio (p<0.05), Desulfobulbus (p<0.05), RFN20 (p<0.05), and Anaerofustis (p<0.05) were significantly higher in infected yaks, while Turicibacter (p<0.0001), Lactobacillus (p<0.0001), Sporosarcina (p<0.0001), Ralstonia (p<0.0001), Akkermansia (p<0.001), Streptococcus (p<0.001), Methylobacterium (p<0.01), Adlercreutzia (p<0.01), Faecalibacterium (p<0.01), Roseburia (p<0.01), Paenibacillus (p<0.01), Methanosphaera (p<0.01), Pseudomonadaceae_Pseudomonas (p<0.01), Peptostreptococcaceae_Clostridium (p<0.01), Slackia (p<0.01), Cupriavidus (p<0.01), Halomonas (p<0.01), Gemmiger (p<0.01), Dietzia (p<0.01), Blautia (p<0.05), Agrobacterium (p<0.05), Nesterenkonia (p<0.05), Sanguibacter (p<0.05), Phascolarctobacterium (p<0.05), Actinomycetospora (p<0.05), Bifidobacterium (p<0.05), SMB53 (p<0.05), and Dorea (p<0.05) were significantly lower in infected animals  were found between healthy and infected yaks, with 119 higher and 116 lower abundance enzymes in INF yaks , propionic acid (p<0.05), isobutyric acid (p<0.05), butyric acid (p<0.05) and isovaleric acid was significantly lower in infected yaks, respectively, while there was no significant difference of valeric acid and caproic acid between H and INF groups  and Simpson (p<0.01)   can be found below: The animal study was reviewed and approved by ethics committee of Nanjing Agricultural University.KL and QW, research idea and methodology. HD, XC, XZ, and CZ, reagents, materials, and analysis tools. KL, writing-original draft and preparation. KM, MF-E-A, ZB, QW, JZ, SN, and KL, writing-review and editing. KL, JZ, and QW, visualization and supervision. All authors contributed to the article and approved the submitted version.


L265P and MYD88other.This study aims to investigate the clinical and molecular differences between diffuse large B-cell lymphoma (DLBCL) patients with MYD88L265P and MYD88other were investigated.DLBCL patients with MYD88 variations were collected from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CHCAMS), and Suzhou Municipal Hospital from February 6th, 2007 to May 20th, 2022. Clinicopathological parameters and treatment outcomes between MYD88L265P, while 54 were MYD88other. MYD88L265P was more common in non-GCB subtype than MYD88other . Besides, MYD88L265P was significantly related to higher proportion of testicle/ central nervous system involvement , PIM1 mutation , and PIM1 hypermutation , compared with MYD88other. Compared with MYD88L265P, MYD88other were more likely to have higher percentage of advanced stage , extranodal site ≥ 2 , elevated LDH , positive CD10 expression , BCL-6 translocation , and NOTCH pathway gene alteration . In non-GCB DLBCL subtype, patients with MYD88other were significantly associated with worse progression free survival (PFS) than those with MYD88L265P when treated initially with R-CHOP/R-CHOP-like regimen (P = 0.010).A total of 132 patients with MYD88 variations from a cohort of 475 DLBCL patients were included, among which, 78 were MYD88L265P and MYD88other are likely to be two subgroups with different clinical and molecular characteristics. The survival of patients with MYD88other is not superior than those with MYD88L265P, even poorer when focusing on the non-GCB subtype.The findings of this study indicate that DLBCL patients with MYD88The online version contains supplementary material available at 10.1007/s00432-023-04714-1. A total of 132 patients with MYD88 variations were included for analysis. The inclusion criteria were as follows: (1) patients were histologically diagnosed with DLBCL based on the World Health Organization classification of Tumors of Hematopoietic and Lymphoid Tissue (2008)  performance status (PS), number of extranodal involvement sites, lactate dehydrogenase (LDH) level, International Prognostic Index (IPI) score, bulky disease, B symptoms, primary site, testicle/central nervous system (CNS) involvement, relapse, bone marrow/peripheral blood involvement, cell of origin (COO) type, first-line therapy, protein expression of CD5, CD10, CD20, BCL-2, BCL-6, c-MYC, MUM-1, Ki-67, and PD-L1, genetic alteration of CD79, TP53, BCL-2, BCL-6, c-MYC, PIM1, SGK1, cell cycle-related genes , NOTCH pathway-related genes , JAK-STAT pathway-related genes , PI3K pathway-related genes , immune-related genes , epigenetics-related genes , RAS pathway-related genes . Any gene occurred alteration in the pathway will be defined as “pathway gene alteration”.Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from included patients. The protein expression of CD5, CD10, CD20, BCL-2, BCL-6, c-MYC, MUM-1, and Ki-67 were evaluated by immunohistochemistry (IHC) using associated antibodies . The Programmed death-ligand 1 (PD-L1) expression was detected using the 22C3 anti-PD-L1 rabbit monoclonal antibody . The COO classification was confirmed according to the Hans algorithm  was performed on three-micrometer-thick FFPE tumor tissues using Vysis LSI CMYC/BCL2/BCL6 Dual Color Break Apart Rearrangement Probe  according to the manufacturer’s instructions. Assessment of FISH signals was performed using Zeiss Axio Imager M2 epifluorescence microscope . Fifty tumor cells were counted, and the percentage of tumor cells with split-signal over 15% indicated the translocation of c-MYC, BCL-2, or BCL-6.Genomic DNA was extracted from the collected FFPE DLBCL tissues using the QIAamp DNA FFPE tissue kit . DNA concentration was quantified using Qubit dsDNA HS Assay Kit . DNA fragmentation was conducted using Covaris S2 Ultrasonicator . Fragments of 200–250 bp were selected by AMPure beads . End repair, phosphorylation, adaptor ligation, hybridization with capture-probe baits, hybrid selection with magnetic beads, and polymerase chain-reaction amplification were subsequently processed. Two capture panels were adopted, one consisted of 112 commonly altered genes in lymphoma and hematologic malignancies, the other covering 413 frequently mutated genes in DLBCL. There were 101 overlapping genes between the two panels. Capture-based targeted sequencing was performed on a Next Seq500 Sequencer  with pair-end reads at Geneplus-Beijing  or Burning Rock Biotech . Detailed sequencing procedure was performed as our previous study described .Chi-squared test or Fisher’s exact test when appropriated was adopted for the comparisons between categorical variables. Kaplan–Meier survival curve and log-rank test were performed for comparing the PFS and OS. L265P, while 41% (54/132) were MYD88other. Among patients with MYD88other, the p.S219C (14/54), p.L273P (10/54), and p.S243N (6/54) were the top three frequently occurred mutations . Among the patients with MYD88 variation, 59% (78/132) occurred MYD88L265P and MYD88other variants . A total of 21 patients eventually occurred death. No statistically significance was observed in PFS and OS between MYD88L265Pand MYD88other   , which is consistent with previous reports  domain, which is the same domain as MYD88L265P resides. As regards the ability to activate NF-κB, MYD88wild−type presents modest activity, MYD88L265P has strong activity, as does MYD88M232T and MYD88S243N, while MYD88S222R and MYD88T294P exert intermediate effect. Their results suggested MYD88other can contribute to the constitutive NF-κB activation in ABC DLBCL as with MYD88L265P  and NFKB2/p52  Below is the link to the electronic supplementary material.


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