Identification of a novel RNA transcript TISPL upregulated by stressors that stimulate ATF4.

Cells sense, respond, and adapt to environmental conditions that cause stress. In a previous study using HeLa cells, we isolated reporter cells responding to the endoplasmic reticulum (ER) stress inducers, thapsigargin and tunicamycin, using a highly sensitive promoter trap vector system. Splinkerette PCR and 5' rapid amplification of cDNA ends (5' RACE) identified a novel transcript that is upregulated by ER stress. Its endogenous expression increased approximately 10-fold in response to thapsigargin and tunicamycin within 1 h, but was down-regulated after 4 h. Because the transcript starts from an intron of a long noncoding RNA known as LINC-PINT, we designated the newly identified transcript TISPL (transcript induced by stressors from LINC-PINTlocus). TISPL was also expressed under several other stress conditions. It was particularly increased > 10-fold upon glucose starvation and 7-fold by arsenite exposure. Furthermore, in silico analyses, including a ChIP-atlas search, revealed that there is an ATF4-binding region with a c/ebp-Atf response element (CARE) downstream of the transcription start site of TISPL. Based on these results, we hypothesized that TISPL may be induced by the phospho-eIF2α and ATF4- axis of the integrated stress response pathway, which is known to be activated by the stress conditions listed above. As expected, knockout of ATF4 abolished the stress-induced upregulation of TISPL. Our results indicate that TISPL may be a useful biomarker for detecting stress conditions that activate ATF4. Our highly sensitive trap vector system proved beneficial in discovering new biomarkers.

Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.

Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.

Differentiation of ovarian serous carcinoma from ovarian clear cell carcinoma using a 10-gene signature selected by comprehensive gene expression analysis.

AIM: Ovarian serous carcinoma (OSC) and ovarian clear cell carcinoma (OCCC) are two major histological types of epithelial ovarian carcinoma (EOC), each with different biological features and clinical behaviors. Although immunostaining is commonly used for differential diagnosis between OSC and OCCC, correct identification of EOC with mixed-type histology is sometimes a diagnostic challenge. The aim of the present study was to explore candidate genes as potential diagnostic biomarkers that distinguish OSC from OCCC. METHODS: A total of 57 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery. Total RNAs were extracted from fresh-frozen tissues of EOC patients, and were used for comprehensive gene expression analysis using DNA microarray technology. RESULTS: Ten candidate genes, FXYD2, TMEM101, GABARAPL1, ARG2, GLRX, RBPMS, GDF15, PPP1R3B, TOB1, and GSTM3 were up-regulated in OCCC compared to OSC. All EOC patients were divided into two groups according to hierarchical clustering using a 10-gene signature. CONCLUSION: Our data suggest that the 10 candidate genes would be an excellent marker for distinguishing OSC from OCCC. Furthermore, the molecular signatures of the 10 genes may enlighten us on the differences in carcinogenesis, and provide a theoretical basis for OCCC's resistance to chemotherapy in the future.

Recent Status of Phase I Clinical Trials for Brain Tumors: A Regulatory Science Study of Exploratory Efficacy Endpoints.

BACKGROUND: Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. METHODS: Using Clarivate's Cortellis™, 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). RESULTS: Selected studies included a median of 1.5 PEs (range, 1-6) and 5 SEs (range, 0-19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B (p = 0.0039). CONCLUSIONS: Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.

Circularly polarized phosphorescence with a large dissymmetry factor from a helical platinum(II) complex.

A chiral platinum(II) complex with a helical Schiff-base [4]helicene ligand exhibits intense red circularly polarized phosphorescence (CPP) with a glum of 0.010 in the dilute solution state. The intense CPP was caused by a change in the electronic transition character based on the induction of the helical structure.

Multiple recombination events between endogenous retroviral elements and feline leukemia virus.

Feline leukemia virus (FeLV) is an exogenous retrovirus that causes malignant hematopoietic disorders in domestic cats, and its virulence may be closely associated with viral sequences. FeLV is classified into several subgroups, including A, B, C, D, E, and T, based on viral receptor interference properties or receptor usage. However, the transmission manner and disease specificity of the recombinant viruses FeLV-D and FeLV-B remain unclear. The aim of this study was to understand recombination events between exogenous and endogenous retroviruses within a host and elucidate the emergence and transmission of recombinant viruses. We observed multiple recombination events involving endogenous retroviruses (ERVs) in FeLV from a family of domestic cats kept in one house; two of these cats (ON-T and ON-C) presented with lymphoma and leukemia, respectively. Clonal integration of FeLV-D was observed in the ON-T case, suggesting an association with FeLV-D pathogenesis. Notably, the receptor usage of FeLV-B observed in ON-T was mediated by feline Pit1 and feline Pit2, whereas only feline Pit1 was used in ON-C. Furthermore, XR-FeLV, a recombinant FeLV containing an unrelated sequence referred to the X-region, which is homologous to a portion of the 5'-leader sequence of Felis catus endogenous gammaretrovirus 4 (FcERV-gamma4), was isolated. Genetic analysis suggested that most recombinant viruses occurred de novo; however, the possibility of FeLV-B transmission was also recognized in the family. This study demonstrated the occurrence of multiple recombination events between exogenous and endogenous retroviruses in domestic cats, highlighting the contribution of ERVs to pathogenic recombinant viruses.IMPORTANCEFeline leukemia virus subgroup A (FeLV-A) is primarily transmitted among cats. During viral transmission, genetic changes in the viral genome lead to the emergence of novel FeLV subgroups or variants with altered virulence. We isolated three FeLV subgroups (A, B, and D) and XR-FeLV from two cats and identified multiple recombination events in feline endogenous retroviruses (ERVs), such as enFeLV, ERV-DC, and FcERV-gamma4, which are present in the cat genome. This study highlights the pathogenic contribution of ERVs in the emergence of FeLV-B, FeLV-D, and XR-FeLV in a feline population.

Additive impact of soy protein dietary intake and exercise on visceral fat mass reduction and mitochondrial complex I activation in skeletal muscle.

Soy protein has shown remarkable effectiveness in reducing fat mass compared with other protein sources, and exercise has the potential to further enhance this fat loss effect. Previous studies have demonstrated that soy protein intake leads to decreased fatty acid synthesis, which contributes to its fat-loss properties. However, the exact mechanism by which these lipids are consumed remains unclear. To investigate this, we conducted a comprehensive study using C57/BL6 male mice, comparing the effects of soy and casein proteins with and without exercise (Casein-Sed, Casein-Ex, Soy-Sed, and Soy-Ex groups) under high- and low-protein conditions (14% or 40% protein). Our findings revealed that combining soy protein intake with exercise significantly reduced epididymal white adipose tissue (eWAT) weight, particularly in the high-protein diet group. Further analysis revealed that exercise increased the expression of lipid oxidation-regulatory proteins, including mitochondrial oxidative phosphorylation protein (OXPHOS) complexes, in the plantaris muscle regardless of the protein source. Although soy protein intake did not directly affect muscle mitochondrial protein expression, the activity of OXPHOS complex I was additively enhanced by exercise and soy protein under the 40% protein condition. Notably, complex I activity inversely correlated with eWAT weight in the soy protein diet group. These results highlight the potential link between improved complex I activity induced by soy protein and fat mass reduction, which emphasizes the promising benefits of combining soy protein with exercise in promoting fat loss.NEW & NOTEWORTHY The findings revealed that soy protein intake combined with exercise resulted in reduced adipose tissue weight compared with that obtained with casein protein intake. Furthermore, the joint impact of exercise and soy protein consumption resulted in enhanced activity of oxidative phosphorylation protein (OXPHOS) complex I in fast-twitch muscles, which appears to be associated with fat mass reduction. These findings elucidate the potential additive effects of soy protein and exercise on body weight management.

Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to liver steatosis, fibrosis, and hepatocellular carcinoma (HCC). Despite the accumulation of clinical data showing the impact of amino acid substitutions at positions 70 (R70Q/H) and/or 91 (L91M) in the HCV core protein in progressive liver diseases, including HCC, the underlying mechanisms have not been elucidated. We analyzed 72 liver biopsy specimens from patients with chronic HCV genotype 1b (HCV-1b) infection prior to antiviral treatment. Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor erythroid 2-related factor 2 (NRF2) in the nucleus were quantified using liver tissue immunohistochemistry. The effects of amino acid substitutions in the HCV core region on hepatocellular oxidative stress were investigated using wild-type or double-mutant (R70Q/H+L91M) HCV-1b core transfection and stable expression in human hepatoma HuH-7 cells. Overall, 24, 19, 11, and 18 patients had the wild-type, R70Q/H, L91M, and R70Q/H+L91M genotypes, respectively, in the HCV core. A significantly higher accumulation of hepatocellular 8-OHdG and a lower NRF2/8-OHdG ratio were observed in patients with R70Q/H+L91M than in those with the wild-type disease. Increased levels of intracellular superoxide and hydrogen peroxide in the cytoplasm and mitochondria, mRNA expression of enzymes generating oxidative stress, and nuclear expression of nicotinamide adenine dinucleotide phosphate oxidase 4 were augmented in cells treated with R70Q+L91M. HCV core proteins harboring either or both substitutions of R70Q/H or L91M enhanced hepatocellular oxidative stress in vivo and in vitro. These amino acid substitutions may affect HCC development by enhancing hepatic oxidative stress in patients with chronic HCV-1b infection.

Circularly Polarized Luminescence from Schiff-base [4]Helicene Boron Complexes.

Boron complexes with Schiff-base [4]helicene ligands were synthesized. These complexes were characterized by NMR spectroscopy and their helical molecular structures were unequivocally established by X-ray diffraction (XRD) analysis. The helical boron complexes exhibited efficient photoluminescence under UV irradiation, and the circularly polarized luminescence (CPL) properties were investigated for optically pure samples. Density functional theory (DFT) calculations were conducted to further understand their photophysical properties including chiroptical responses.

RNA and Single-Stranded DNA Phages: Unveiling the Promise from the Underexplored World of Viruses.

RNA and single-stranded DNA (ssDNA) phages make up an understudied subset of bacteriophages that have been rapidly expanding in the last decade thanks to advancements in metaviromics. Since their discovery, applications of genetic engineering to ssDNA and RNA phages have revealed their immense potential for diverse applications in healthcare and biotechnology. In this review, we explore the past and present applications of this underexplored group of phages, particularly their current usage as therapeutic agents against multidrug-resistant bacteria. We also discuss engineering techniques such as recombinant expression, CRISPR/Cas-based genome editing, and synthetic rebooting of phage-like particles for their role in tailoring phages for disease treatment, imaging, biomaterial development, and delivery systems. Recent breakthroughs in RNA phage engineering techniques are especially highlighted. We conclude with a perspective on challenges and future prospects, emphasizing the untapped diversity of ssDNA and RNA phages and their potential to revolutionize biotechnology and medicine.

Idiopathic Normal Pressure Hydrocephalus With Multiple Sulcus Enlargements but No Ventricular Enlargement Resembling Brain Atrophy Over a Long Period Before Diagnosis: A Case Report.

The most common imaging findings in idiopathic normal pressure hydrocephalus (iNPH) are disproportionately enlarged subarachnoid space hydrocephalus, i.e., enlarged ventricles (Evans index >0.3), narrowing of the superior arcuate and median sulci, widening of the Sylvian fissure, and focal widening of the sulci of the brain. In the present study, we encountered an interesting case of a 73-year-old woman with iNPH with characteristic imaging findings of cerebral atrophy-like features and no prominent ventricular enlargement. Many cases might be difficult to diagnose as iNPH because of atypical imaging findings such as no prominent ventricular enlargement and so on. Even in cases with multiple atrophic sulcus openings without any prominent ventricular enlargement, the callosal angle and posterior commissure-level brain-ventricle ratio (BVR) could be helpful in the diagnosis, and bilateral opening of the occipitoparietal sulcus might be a key imaging finding.

A New Hyper-Heuristic Multi-Objective Optimisation Approach Based on MOEA/D Framework.

A multi-objective evolutionary algorithm based on decomposition (MOEA/D) serves as a robust framework for addressing multi-objective optimization problems (MOPs). However, it is widely recognized that the applicability of a fixed offspring-generating strategy in MOEA/D can be limited, despite its foundation in the MOEA/D methodology. Consequently, hybrid algorithms have gained popularity in recent years. This study proposes a novel hyper-heuristic approach that integrates the estimation of distribution (ED) and crossover (CX) strategies into the MOEA/D framework based on the view of successful replacement rate (SSR) and attempts to explain the potential reasons for the advantages of hybrid algorithms. The proposed approach dynamically switches from the differential evolution (DE) operator to the covariance matrix adaptation evolution strategy (CMA-ES) operator. Simultaneously, certain subproblems in the neighbourhood denoted as B(i) employ the Improved Differential Evolution (IDE) operator to generate new individuals for balancing the high evaluation costs associated with CMA-ES. Numerical experiments unequivocally demonstrate that the suggested approach offers distinct advantages when applied to a three-objective test suite. These experiments also validate a significant enhancement in the efficiency (SRR) of the DE operator within this context. The perspectives and experimental findings, with a focus on the Success Rate Ratio (SRR), have the potential to provide valuable insights and inspire further research in related domains.

Tyrosine Kinase Inhibitor Profiling Using Multiple Forskolin-Responsive Reporter Cells.

We have developed a highly sensitive promoter trap vector system using transposons to generate reporter cells with high efficiency. Using an EGFP/luciferase reporter cell clone responsive to forskolin, which is thought to activate adenylate cyclase, isolated from human chronic myelogenous leukemia cell line K562, we found several compounds unexpectedly caused reporter responses. These included tyrosine kinase inhibitors such as dasatinib and cerdulatinib, which were seemingly unrelated to the forskolin-reactive pathway. To investigate whether any other clones of forskolin-responsive cells would show the same response, nine additional forskolin-responsive clones, each with a unique integration site, were generated and quantitatively evaluated by luciferase assay. The results showed that each clone represented different response patterns to the reactive compounds. Also, it became clear that each of the reactive compounds could be profiled as a unique pattern by the 10 reporter clones. When other TKIs, mainly bcr-abl inhibitors, were evaluated using a more focused set of five reporter clones, they also showed unique profiling. Among them, dasatinib and bosutinib, and imatinib and bafetinib showed homologous profiling. The tyrosine kinase inhibitors mentioned above are approved as anticancer agents, and the system could be used for similarity evaluation, efficacy prediction, etc., in the development of new anticancer agents.

Brain Abscess Due to Dental Sinusitis: A Case Report on Incomplete Infection Defense Associated With a Post-Fusion Linear Skull Fracture.

Brain abscess is a pyogenic disease secondary to a bacterial, tuberculous, or fungal infection of the brain; thus, early detection and treatment are of crucial importance. Herein, we present a case of a brain abscess arising from dental sinusitis due to an incomplete infection defense mechanism linked to a post-fusion linear skull fracture. The patient initially presented with a persistent headache, which was diagnosed as frontal sinusitis. Consequently, antibiotic treatment was started. However, due to a refractory response to antibiotics, MRI was performed, which revealed a brain abscess in the frontal lobe adjacent to the right frontal sinus measuring 40 mm in diameter. This abscess was surgically drained and cultured. Initially, the patient was treated with three antibiotics, which were eventually de-escalated. The cultures revealed nasal commensal bacteria, suggesting a direct spillover from sinusitis leading to a brain abscess. A tooth with root inflammation, which had been left untreated and resulted in bone melting of the maxillary sinus wall, was extracted. After more than eight weeks of antimicrobial therapy, improvement in the clinical and imaging findings was noted, and the patient was discharged. Brain abscesses may develop from sinusitis even after linear fractures have healed due to a continued incomplete infection defense mechanism. Moreover, root and sinus infections should undergo evaluation, including the upper dental crown using coronal computed tomography, and treatment should be initiated promptly.

DNA-translocation-independent role of INO80 remodeler in DNA damage repairs.

Chromatin remodelers utilize ATP hydrolysis to reposition histone octamers on DNA, facilitating transcription by promoting histone displacements. Although their actions on chromatin with damaged DNA are assumed to be similar, the precise mechanisms by which they modulate damaged nucleosomes and their specific roles in DNA damage response (DDR) remain unclear. INO80-C, a versatile chromatin remodeler, plays a crucial role in the efficient repair of various types of damage. In this study, we have demonstrated that both abasic sites and UV-irradiation damage abolish the DNA translocation activity of INO80-C. Additionally, we have identified compromised ATP hydrolysis within the Ino80 catalytic subunit as the primary cause of the inhibition of DNA translocation, while its binding to damaged nucleosomes remains unaffected. Moreover, we have uncovered a novel function of INO80-C that operates independently of its DNA translocation activity, namely, its facilitation of apurinic/apyrimidinic (AP) site cleavage by the AP-endonuclease 1 (APE1). Our findings provide valuable insights into the role of the INO80-C chromatin remodeler in DDR, thereby advancing our understanding of chromatin remodeling during DNA damage repairs.

A multilocus sequence typing method of Staphylococcus aureus DNAs in a sample from human skin.

The skin and mucous membranes are the primary sites of Staphylococcus aureus colonization, particularly those of health care personnel and patients in long-term care centers. We found that S. aureus colonized with a higher abundance ratio on skins which had recovered from pressure injury (PI) than on normal skins in our earlier research on the skin microbiota of bedridden patients. Multilocus sequence typing (MLST) is a useful tool for typing S. aureus isolated from clinical specimens. However, the MLST approach cannot be used in microbiota DNA owing to the contamination from other bacteria species. In this study, we developed a multiplex-nested PCR method to determine S. aureus MLST in samples collected from human skins. The seven pairs of forward and reverse primers were designed in the upstream and downstream regions, which were conserved specifically in S. aureus. The first amplifications of the seven pairs were conducted in a multiplex assay. The samples were diluted and applied to conventional PCR for MLST. We confirmed that the method amplified the seven allele sequences of S. aureus specifically in the presence of untargeted DNAs from human and other skin commensal bacteria. Using this assay, we succeeded in typing sequence types (STs) of S. aureus in the DNA samples derived from the skins healed from PI. Peaks obtained by Sanger sequencing showed that each sample contained one ST, which were mainly categorized into clonal complex 1 (CC1) or CC5. We propose that this culture-free approach may be used in detecting S. aureus in clinical specimens without isolation.

Empirical Myoelectric Feature Extraction and Pattern Recognition in Hemiplegic Distal Movement Decoding.

In myoelectrical pattern recognition (PR), the feature extraction methods for stroke-oriented applications are challenging and remain discordant due to a lack of hemiplegic data and limited knowledge of skeletomuscular function. Additionally, technical and clinical barriers create the need for robust, subject-independent feature generation while using supervised learning (SL). To the best of our knowledge, we are the first study to investigate the brute-force analysis of individual and combinational feature vectors for acute stroke gesture recognition using surface electromyography (EMG) of 19 patients. Moreover, post-brute-force singular vectors were concatenated via a Fibonacci-like spiral net ranking as a novel, broadly applicable concept for feature selection. This semi-brute-force navigated amalgamation in linkage (SNAiL) of EMG features revealed an explicit classification rate performance advantage of 10-17% compared to canonical feature sets, which can drastically extend PR capabilities in biosignal processing.

P53-negative status and gross total resection as predictive factors for autologous tumor vaccine treatment in newly diagnosed glioblastoma patients.

Background: Among primary brain tumors, glioblastoma (GBM) is the most common and aggressive in adults, with limited treatment options. Our previous study showed that autologous formalin-fixed tumor vaccine (AFTV) contributed to prognostic improvements in newly diagnosed GBM patients. However, some patients died early despite the treatment. The discovery of predictive factors in the treatment was warranted for efficient patient recruitment and studies to overcome resistance mechanisms. Identifying prognostic factors will establish AFTV guidelines for patients who may respond to the therapy. Methods: Data from 58 patients with newly diagnosed GBM, including 29 who received standard therapy plus AFTV (AFTV group) and 29 who received standard treatment (control group) were analyzed. Several data including patient age, sex, the extent of removal, and various cell immunohistochemistry (IHC) parameters were also included in the analysis. Results: Both univariate and multivariate analyses revealed that gross total resection (GTR) and negative p53 were associated with a better prognosis only in the AFTV group. In the IHC parameters, CD8 staining status was also one of the predictive factors in the univariate analysis. For blood cell-related data, lymphocyte counts of 1100 or more and monocyte counts of 280 or more before chemo-radiotherapy were significant factors for good prognosis in the univariate analysis. Conclusions: A p53-negative status in IHC and GTR were the predictive factors for AFTV treatment in newly diagnosed GBM patients. Microenvironment-targeted treatment and pretreatment blood cell status may be key factors to enhance therapy effects.

[Sixteen Cases of Appendiceal Mucinous Neoplasm].

Appendiceal mucinous neoplasm is a relatively rare disease. It is classified as mucinous adenocarcinoma(MACA)and low- grade appendiceal mucinous neoplasm(LAMN). We retrospectively evaluated 16 cases of appendiceal mucinous neoplasm (LAMN: 13 cases, MACA: 3 cases)that were surgically resected in our hospital between January 2010 and July 2021. There were 7 men and 9 women, with a median age of 61 years(27-85 years). The most common chief complaint was abdominal pain(12 patients), while 3 cases were incidental findings following medical checkups for other diseases and without a chief complaint. Colonoscopy was performed for 9 cases. Of these, 5 revealed abnormal findings. The preoperative diagnosis was appendicitis in 7 patients and appendiceal tumor in 8 patients. The surgical procedures were planned for 8 cases and performed as emergencies in 8 cases. The procedures included laparoscopic surgery(n=6)and laparotomy(n=10). The resection range included appendectomy(n=9), partial cecal resection(n=4), and ileocecal resection(n=3). Surgical margins were negative in all cases. Metastases were not observed in patients who underwent lymph node dissections (2 patients with MACA and 1 patient with LAMN). The median follow-up was 17 months(1-43 months). Recurrence including peritoneal pseudomyxoma was not detected in any of the patients.

Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts.

Retrograde menstruation is a widely accepted cause of endometriosis. However, not all women who experience retrograde menstruation develop endometriosis, and the mechanisms underlying these observations are not yet understood. Here, we demonstrated a pathogenic role of Fusobacterium in the formation of ovarian endometriosis. In a cohort of women, 64% of patients with endometriosis but <10% of controls were found to have Fusobacterium infiltration in the endometrium. Immunohistochemical and biochemical analyses revealed that activated transforming growth factor-ß (TGF-ß) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)-positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. Fusobacterium inoculation in a syngeneic mouse model of endometriosis resulted in a marked increase in TAGLN-positive myofibroblasts and increased number and weight of endometriotic lesions. Furthermore, antibiotic treatment largely prevented establishment of endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model. Our data support a mechanism for the pathogenesis of endometriosis via Fusobacterium infection and suggest that eradication of this bacterium could be an approach to treat endometriosis.