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Chronic Kidney Disease (CKD) has emerged as a significant global public health concern, with membranous Nephropathy (MN) being the most prevalent pathological type of nephrotic syndrome in adults. MN is classified as an antibody-mediated autoimmune disease. There is a growing interest in the research of MN-related antigens. Furthermore, the treatment of MN predominantly relies on the administration of immunosuppressants, with traditional regimens such as corticosteroids and cyclophosphamide, which have significant side effects, and rituximab, having a 35-40% failure rate, highlighting the critical need for the development of specific and effective immunotherapy strategies. In this review, we summarized the research progress on newly discovered MN-related antigens, including exostosin 1/exostosin 2(EXT1/EXT2), Neural Cell Adhesion Molecule 1 (NCAM-1), Neural Epidermal Growth Factor-like 1 (NELL-1), Contactin 1 (CNTN1), Semaphorin 3B, High-Temperature Recombinant Protein A1 (HTRA1), protocadherin FAT atypical cadherin 1(FAT1) and Protocadherin 7(PCDH7). Among them, NELL-1 and HTRA1 primarily serve as target antigens for primary MN, and their serum antibody titers show a strong correlation with disease activity. While EXT1/EXT2, NCAM1, CNTN-1, and FAT1 mainly act as target antigens for secondary MN. In addition, we evaluated the clinical applications and efficacy of novel immunosuppressants and therapeutic approaches, including new anti-CD20 antibodies, proteasome inhibitors, anti-plasma cell therapies, belimumab, complement inhibitors, and immunoadsorption. The new anti-CD20 agents represented by obalimumab and obinutuzumab, along with anti-plasma cell therapies such as daratumumab, have emerged as ideal alternatives for patients with rituximab resistance. Other therapeutic approaches, including complement inhibitors, immunoadsorption, and belimumab, have also exhibited their unique advantages. Show less

Membranous nephropathy (MN) in very elderly patients frequently remains antigen-negative after routine testing, limiting diagnostic precision. Recently, serine protease high temperature requirement protein A1 (HTRA1) has been identified as a novel MN autoantigen. Here, we focused on patients 80 years and older with MN and sought to systematically evaluate this association. Three cohorts of patients with MN were examined under institutional approval, including 157 consecutive all-age series of PLA2R/THSD7A/NELL1/EXT1-negative patients with MN typed by mass spectrometry; 54 PLA2R-negative MN in patients aged 80 years and older assessed by paraffin immunofluorescence; and 45 PLA2R-negative malignancy-associated patients with MN. HTRA1 positivity was determined by paraffin immunofluorescence and/or mass spectrometry. Clinical and histopathologic features were reviewed where available. Proportions were compared using Fisher's exact test. HTRA1 positivity was identified in 1.9% of patients with PLA2R/THSD7A/NELL1/EXT-negative MN, 22.2% of patients 80 years and older, and 6.7% of patients with PLA2R-negative malignancy-associated MN. Compared with the all-age antigen-negative cohort, HTRA1 positivity was significantly enriched in patients aged 80 years (relative risk 11.6; 95% confidence interval 3.4- 39.7). Across all 18 HTRA1-positive cases, mean age was 81.5, 66.7% were male, and 83.3% had nephrotic-range proteinuria. HTRA1 is a common autoantigen in PLA2R-negative MN among very elderly patients, occurring in approximately one in five cases aged 80 years or more. These findings support inclusion of HTRA1 testing in diagnostic evaluation of antigen-negative MN in patients 80 years and older and suggest the existence of an age-linked MN subtype. Show less

Osteomas are benign, slow-growing bony tumors that commonly develop in the craniofacial region; however, standardized diagnostic and treatment protocols remain limited. This study aimed to establish a systematic approach for the diagnosis, genetic evaluation, and surgical management of craniofacial osteomas, with emphasis on lesion distribution and gender prevalence. A retrospective review was conducted on 141 patients with craniofacial osteomas at Kyungpook National University Hospital between October 2011 and September 2025. All patients underwent clinical examinations and 3-dimensional computed tomography for diagnostic confirmation. Surgical excision was performed using direct, endoscopic, or bicoronal approaches based on lesion characteristics. Whole exome sequencing was performed in patients with multiple large osteomas to evaluate mutations in EXT1, EXT2, APC, MSH2, and MLH1 genes associated with Gardner syndrome. A total of 148 osteomas were identified. The frontal bone was the most common site (60.1%), followed by the parietal, mandibular, and occipital bones. Females accounted for 79.1% of cases. Genetic testing revealed no pathogenic variants related to Gardner syndrome, and no recurrences were observed during 6 months of follow-up. Craniofacial osteomas are benign, slow-growing lesions most frequently found in the frontal bone and are more prevalent among females. The integration of imaging-based diagnosis, tailored surgical techniques, and selective genetic testing allows for accurate evaluation, effective treatment, and favorable postoperative outcomes. Show less

Porcine enteric coronaviruses, including porcine deltacoronavirus (PDCoV), porcine epidemic diarrhea virus (PEDV), swine acute diarrhea syndrome coronavirus (SADS-CoV), and transmissible gastroenteritis coronavirus (TGEV), can cause acute diarrhea, vomiting, dehydration, and high mortality in suckling piglets. Recent studies revealing human PDCoV infections and the potential of SADS-CoV to penetrate human cell lines have heightened apprehensions about the zoonotic transmission risks of these viruses. While heparan sulfate (HS) serves as a receptor in PDCoV binding, the key host genes involved in HS biogenesis and the specific molecular mechanisms underlying this process have not been fully examined. Enzymes involved in HS biosynthesis, including SLC35B2, EXT1, and NDST1, were identified as critical host factors via the use of CRISPR-Cas9 knockout cells. Moreover, inhibition assays using heparin sodium, a competitive HS mimic, demonstrated dose-dependent reductions in PDCoV infection Show less

Acute respiratory distress syndrome (ARDS) has a high clinical mortality rate and continues to draw research attention regarding its mechanisms and potential treatments. Disruption of the endothelial barrier is a primary pathological feature, and glycocalyx degradation is a key factor contributing to this disruption. Human umbilical cord mesenchymal stem cells (hucMSCs) exhibit strong anti-inflammatory and immunomodulatory effects, making their application in ARDS treatment an area of increasing interest. Proteomic screening identified Cxcl12 as a protein secreted by hucMSCs. In male C57 mice and cell models, lipopolysaccharide (LPS) was used to induce injury, followed by interventions with hucMSCs or hucMSCs with silenced Cxcl12 to assess glycocalyx-related proteins SDC-1, HS, and the repair marker EXT-1. To evaluate downstream signaling, the CXCR4 receptor was inhibited and related indicators were examined. Silencing Cxcl12 reduced the therapeutic effect of hucMSCs on LPS-induced glycocalyx damage. Inhibition of CXCR4 also weakened the effect of Cxcl12. These findings indicate that hucMSCs alleviate LPS-induced glycocalyx damage in pulmonary vascular endothelial cells by secreting Cxcl12, which activates the downstream receptor CXCR4, providing a therapeutic effect for ARDS. Show less

Hereditary Multiple Osteochondromas (HMO) is a rare autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in EXT1 or EXT2, which encode glycosyltransferases essential for heparan sulfate (HS) biosynthesis. Whether haploinsufficiency alone suffices or biallelic inactivation is required for osteochondroma formation remains a central unresolved question. In this study, we employed CRISPR/Cas9 combined with PiggyBac transposon technology to introduce a second pathogenic mutation (c.1883+1G>T) into patient-derived induced pluripotent stem cells (iPSCs) carrying a heterozygous EXT1 c.1126C>T mutation. This approach enabled the generation of isogenic iPSC lines: wild-type (WT), single-mutant (SM), and double-mutant (DM). These iPSCs were differentiated through induced mesenchymal stem cells (iMSCs) into chondrocytes. Biallelic EXT1 mutation in DM cells led to significant upregulation of SOX9, COL2A1, and ACAN, elevated glycosaminoglycan (GAG) levels, and markedly reduced HS, whereas SM cells remained indistinguishable from WT. Three-dimensional (3D) chondrogenic organoid cultures revealed that DM organoids were enlarged and structurally disorganized, partially recapitulating key histopathological features of osteochondromas. Transcriptomic analysis identified the Wnt signaling pathway as the most significantly enriched pathway among differentially expressed genes following EXT1 loss. Collectively, these findings provide direct human cellular evidence that complete EXT1 inactivation-not haploinsufficiency-drives aberrant chondrogenesis, likely through impaired sequestration of morphogen ligands, thereby supporting the Two-hit pathogenic model. Show less

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults and can be seen in association with other diseases, including malignancy, drugs, infections, or autoimmune diseases. Over the last decade, great progress has been made in understanding the pathogenesis of the disease, resulting from the discovery of several target antigens by use of laser microdissection/mass spectrometry methodology. This technique has proven to be the most sensitive method available and has the advantage of testing for all the target antigens at one time. The discovery of these target antigens has now shifted the classification of MN from primary versus secondary to classification based on the target antigen identified. Each target antigen has its own specific clinical characteristics and known associated diseases. Identification of the target antigen can help further identify the underlying cause for a more targeted approach in looking for associated diseases. Progress has also been made in the treatment of patients with MN, with more standard risk stratification of the patients and a shift in using anti-CD20 drugs as the first line for those with moderate and high risk of progression. Trials are ongoing to further investigate the role of anti-plasma cell, anticomplement, and CAR-T (chimeric antigen receptor T-cell) therapies. Show less

Heparan sulfate (HS), a linear sulfated polysaccharide attached to proteoglycans, modulates the availability and activity of growth factors and cytokines to regulate cell signaling, adhesion, and migration. Exostosin-1 (EXT1), a key glycosyltransferase for HS chain elongation, is increasingly implicated in cancer development and progression. Although originally identified as a tumor suppressor in hereditary multiple exostoses, EXT1 exhibits a complex, context-dependent role in cancer. The effects of EXT1 in cancer differ by cell and tumor type, exerting both tumor-suppressing and tumor-promoting effects. Notably, EXT1 also alters the tumor microenvironment via its expression in stromal fibroblasts and endothelial cells, further influencing tumor behavior. This review discusses the functions of HS and EXT1, emphasizing the roles of EXT1 in cancer and its microenvironment. A deeper understanding of these mechanisms may offer novel therapies targeting the HS biosynthetic pathway. Show less

Gallbladder adenosquamous carcinoma (GBASC) is an uncommon, highly aggressive neoplasm characterized by the coexistence of both glandular and squamous cells. Representing fewer than 5% of gallbladder malignancies, GBASC demonstrates a more aggressive behavior and has poorer prognosis, posing considerable challenges for early diagnosis and effective management. We present a case of GBASC in a 52-year-old woman who achieved long-term tumor-free survival by surgery, as well as targeted and immunotherapy after the operation. Targeted gene sequencing and bioinformatics analysis tools, including STRING, GeneMANIA, Metascape, TRRUST, Sangerbox, and cBioPortal, were used to analyze the biological functions and features of the mutated genes in GBASC. A total of 16 mutations ( Comparative analyses with other gallbladder carcinoma subtypes revealed GBASC to have distinct clinical phenotypes, molecular alterations, functional characteristics, and enriched signaling pathways. Moreover, there is an urgent need for standardized treatment protocols. Show less

To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families. Show less

Spinal osteochondromas develop from aberrant endochondral ossification of the vertebrae, which originate from the sclerotome of the paraxial mesoderm. These tumors typically involve the posterior elements, such as the spinous process, lamina, or pedicles. Spinal osteochondromas are rare, constituting less than 2% of all osteochondromas and under 4% of spinal tumors. A 7-year-old boy came to the clinic with a lump at the back of the neck and difficulty moving his head, which was diagnosed as osteochondroma at the fifth cervical vertebra (C5). The child also had a history of multiple hereditary exostoses affecting other parts of the body. Spinal osteochondromas account for a small percentage of cases, with the cervical spine being the most frequently affected. Diagnosis relies on computed tomography for precise visualization, aiding in preoperative planning. The etiology involves genetic mutations in EXT1 and EXT2, with additional mechanical factors possibly contributing to cervical spine involvement. This case contributes valuable insights into pediatric spinal osteochondromas, underscoring the need for timely diagnosis to prevent complications. Osteochondromas are considered the most common benign tumors. However, spinal osteochondromas are very rare, particularly in pediatric patients. This case underscores the importance of recognizing osteochondroma as a differential diagnosis for neck masses in children. Early diagnosis and surgical intervention can prevent complications and recurrence, highlighting the clinical significance of this rare condition. This report also emphasizes the necessity of vigilant postoperative follow-up to ensure complete recovery and monitor for potential complications. Show less

Membranous nephropathy (MN) is the cause of 3% of pediatric nephrotic syndrome, with increasing incidence in adolescents. It was historically divided into primary and secondary forms but is increasingly described by antigen. The direct clinical value of knowing the MN antigen often depends on the strength of association between antigen and various underlying conditions, prognostic potential, and the presence of commercially available serum antibody testing. In this case, we describe an adolescent with PLA2R-, NELL1-, THSD7A-, and EXT2-negative MN who responded to B-cell depleting therapy. Three years later, he developed proliferative lupus nephritis and ongoing membranous nephritis with newly detected EXT2-positive deposits on kidney biopsy. This discordant MN antigen result demonstrates (1) the potential for apparent change in MN antigen detection over time and (2) that EXT1/2 negativity does not exclude the possibility of later development of lupus nephritis in an adolescent with MN. Show less

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms. Show less

Most newly discovered membranous nephropathy (MN) antigens have been mutually exclusive, but there are rare cases of dual antigen MN based on immunohistochemistry (IHC)/immunofluorescence (IF) or serologic testing. Here, we searched for cases of dual antigen MN at Mayo Clinic and Arkana Laboratories with the diagnosis established by light/electron microscopy and IF. At Mayo Clinic, we performed laser capture microdissection of glomeruli followed by liquid chromatography tandem mass spectrometry (LC MS/MS) on paraffin-embedded kidney biopsy tissue to detect 12 MN antigens. Nine cases of dual antigen MN (four at Mayo Clinic, five at Arkana Laboratories) were confirmed by both LC MS/MS and IHC/IF. The detected antigens were NELL1 + CNTN1 (two cases), NCAM1 + EXT1/2 (two cases), and one case each NDNF + NELL1, NELL1 + PLA2R1, THSD7A + PLA2R1, PCDH7 + PLA2R1, and CNTN1 + PCDH7. Median age at diagnosis was 68 years (range 23-84). Eight patients presented with nephrotic syndrome and microscopic hematuria. Median serum creatinine at diagnosis was 1 mg/dL. The underlying conditions, when present, and serological characteristics, correlated with the involved antigens. The frequency at Mayo Clinic was 2.6% of PLA2R1-negative MN cases. Given that IHC/IF and LC MS/MS for MN antigen detection are typically not pursued in PLA2R1-associated MN, dual-antigen MN is likely underdiagnosed. Dual-antigen MN can involve a variety of MN antigens, including those that are podocyte-expressed, transmembrane, or secreted. Most patients with MN present with nephrotic syndrome and microscopic hematuria. Further studies are needed to understand the pathophysiology of dual-antigen MN and determine their role both in the therapeutic approach and clinical outcomes. Our findings suggest that LC MS/MS is a valuable methodology for detection of dual antigen MN. Show less

To investigate whether W' in the extreme-intensity domain is smaller, yet linked to the W' predicted by the severe-intensity time series. Twelve recreationally active participants (four females) completed 1) three extreme-intensity and three severe-intensity constant-power output (PO) trials to establish the PO duration series and to obtain W' within their respective domains (W'EXT and W'SVR, respectively); 2) two decremental protocols from extreme-to-severe (EXT1→SVR3) and from severe-to-severe POs (SVR2→SVR3); 3) one extreme- and one severe-intensity constant-PO trial preceded by priming exercise (EXT1P and SVR2P, respectively); and 4) control extreme- and severe-intensity constant-PO trials. Peak values for oxygen uptake (V̇O2peak), blood lactate concentration ([La-]b-peak), and minute ventilation (V̇Epeak) were also analyzed. W'EXT was significantly smaller than W'SVR (P < 0.001). There was no difference in W' between the composite EXT1→SVR3 and SVR2→SVR3 and SVR3 alone (all P > 0.05). Priming-induced increase in W'EXT and W'SVR was not different (P = 0.401). V̇O2peak, V̇Epeak, and [La-]b-peak were all greater in EXT1P compared with EXT1 (all P < 0.05). We showed that W'EXT is smaller than W'SVR during cycling. Following task failure during EXT1, more work could be performed at SVR3 until complete depletion of W'SVR. Additionally, heavy-intensity priming exercise increased W'EXT and W'SVR by a similar magnitude. Collectively, these findings suggest that performance within the extreme-intensity domain is limited by mechanisms, at least in part, different from those that limit performance within the severe-intensity domain. Show less

Long-term antigen-specific data in PMN among Chinese populations remain limited. This study evaluated six target antigens and their clinical significance during extended follow-up. We retrospectively analyzed 132 treatment-naïve PMN patients diagnosed by biopsy (2010-2018) and followed for a median of 62.9 months. Renal tissue expression of PLA2R, THSD7A, NELL-1, PCDH7, EXT1, and EXT2 was assessed by immunohistochemistry, and serum anti-PLA2R antibodies were measured by ELISA. Associations between antigen profiles and 5-year outcomes (remission, renal survival, malignancy) were evaluated. PLA2R was the predominant antigen (84.1%), followed by THSD7A (5.3%) and NELL-1 (0.76%); no PCDH7, EXT1, or EXT2 positivity was detected. PLA2R-negative patients were more often female (71.4% vs. 36.0%, This >5-year Chinese PMN cohort provides the first comprehensive analysis of six target antigens. PLA2R remains predominant, while PLA2R-negative patients distinct immunopathologic features yet favorable long-term outcomes. A population-specific anti-PLA2R cutoff showed good diagnostic performance for predicting tissue antigen deposition. Rare antigens were infrequent and their malignancy associations require cautious interpretation. These findings provide long-term antigen-specific data supporting antigen-guided, population-adapted precision management of PMN. Show less

Hepcidin, a liver-derived hormone, is the central regulator of systemic iron homeostasis. Elevated hepcidin levels contribute to iron-refractory iron deficiency anemia (IRIDA) and anemia of inflammation, both characterized by restricted iron availability. Current treatments, such as parenteral iron infusions, are often ineffective and pose risks of adverse reactions, underscoring the need for alternative therapeutic strategies targeting hepcidin. We previously identified a novel hepcidin regulatory pathway involving liver heparan sulfate (HS) proteoglycans (HSPGs), which modulate receptor-ligand interactions through their sulfated HS chains. Recently, we found that halofuginone impairs HS biosynthesis and considered whether it could be used as a hepcidin modulator. Here, we demonstrate that in human hepatoma (Hep3B) cells, halofuginone inhibits both basal and BMP6-induced hepcidin expression and p-SMAD1 signaling in a dose- and time-dependent manner. Consistently, Hep3B cells lacking HS (EXT1-/-) show no hepcidin suppression in response to halofuginone. In vivo administration of halofuginone reduces hepcidin expression in an iron-overload mouse model (8.3 g/kg carbonyl iron). This effect was absent in mice with impaired liver HS sulfation (Ndst1f/fAlbCre+), confirming that halofuginone suppresses hepcidin via HSPG-mediated mechanisms. Additionally, halofuginone decreased hepcidin expression in mice subjected to acute inflammation. These findings establish halofuginone as a potential therapeutic for mitigating hepcidin-driven iron restriction in anemic disorders. Show less

Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric skeletal disorder characterized by osteochondromas that form along the growth plates. These benign tumors can cause skeletal deformities, joint dysfunction, chronic pain and other health problems. Most HMO patients are born with a heterozygous mutation in EXT1 or EXT2 that encode Golgi enzymes responsible for heparan sulfate synthesis. However, prior studies have established that these mutations alone are insufficient to trigger osteochondroma formation, but additional genetic changes are needed. Loss-of-heterozygosity (LOH) has been invoked in some cases, but the full genomic landscape of osteochondromas remains unclear. Here, we carried out a proof-of-principle study and asked whether gene variants occur in osteochondromas in addition to EXT mutations, whether the variants are shared by osteochondromas in same or different patients and what putative pathogenic roles they may have. A total of 8 tumors from 4 patients were subjected to whole exome sequencing (WES) along with saliva DNA from the 4 patients and 3 parents that was used as specific reference. WES identified over 1,600 somatic single nucleotide variants or insertion/deletions that were only partially shared amongst the tumors and were absent in the saliva DNA. Six genes were commonly mutated, including PABC1, TDG and ANKRD36. These genes exert action which could directly or indirectly influence chondrogenesis, the first differentiation step in osteochondroma formation. The study reveals that osteochondromas do possess gene variants distinguishing them in the same or different patients. These traits could modulate their tumorigenic character and add complexity to HMO pathogenesis. Clinical Significance: This study provides insights into the genomic landscape of osteochondromas, potentially leading to development of disease diagnostic and prognostic tools. Show less

This study aimed to explore the genotype and phenotype correlation of patients with multiple osteochondroma (MO), and validate phenotypic differences in ATDC5 cell model with Mutation analysis was employed in 27 families with MO using polymerase chain reaction (PCR)-Sanger sequencing and targeted next-generation sequencing (t-NGS). ATDC5 cell model with A total of 27 pathogenic mutations were identified in Clinical research identified nine novel mutations in Show less

An 88-year-old man was referred with peripheral edema, pleural effusion and nephrotic syndrome that had developed 3 months prior. Based on a kidney biopsy, the majority of glomeruli exhibited capillary wall thickening and the slight area of glomeruli exhibited spike formations and bubbly appearances. Fluorescent immunostaining showed global deposition of neural epidermal growth factor-like 1 (NELL-1), immunoglobulin (Ig) G1 and complement (C) 3c within the glomerular capillary wall. Electron microscopy showed the presence of unique subepithelial electron-dense deposits distributed in a ribbon-like manner along more than 75% of glomerular capillary walls. Fluorescent immunostaining showed no positivity for other recently identified antigens associated with membranous nephropathy, including M-type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), and exostosin 1 (EXT1). A comprehensive medical examination for malignant diseases yielded negative results, and there was no discernible change in κ/λ staining. Additionally, serum complement levels were within the normal range. The patient was therefore diagnosed with NELL-1-positive membranous nephropathy and has been refractory to the treatment with prednisolone, cyclosporine (CyA) and rituximab for 10 months. According to previous reports, segmental or incomplete IgG capillary loop staining have been observed in 93.4% of cases of NELL-1-positive membranous nephropathy. Diffuse and global ribbon-like deposits, as observed in this case, are exceedingly rare. Show less

A chimeric protein of heparanase and Ig-Fc was designed as a novel tool to expand the detection of structurally heterogeneous heparan sulfate (HS) and related glycosaminoglycans. The whole mouse heparanase gene was combined with the gene segment encoding the mouse IgG1 hinge-Fc domain. A point mutation E335A was inserted to disable putative HS degradation activity. Chimeric proteins consisted of the latent form of the enzyme devoid of HS degradation activity. The chimeric proteins bound to heparin, Show less

Here, we identified a type of hypothetical T7SS effector in This alternative strategy facilitates effectors' delivery, even for fragmented substrates, highlighting its importance in ensuring the functionality of T7SS. Show less

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant skeletal disorder resulting from loss-of-function variants in the We aimed to comprehensively review the literature for reported cases of non-skeletal malignancies in individuals with HME and evaluate a potential association with hematologic cancers, particularly in the pediatric population. An extensive literature search was conducted in the PubMed database up to August 2025 using search terms related to HME and malignancy. Eligible reports included case descriptions of non-skeletal cancers occurring in patients with confirmed or suspected HME. Extracted data included patient age, sex, cancer type, and available genetic or molecular findings. Thirteen cases of non-skeletal malignancies associated with HME were identified. Fewer than half underwent molecular genetic testing. Six cases occurred in pediatric patients, four of which involved hematologic malignancies, three leukemias and one Burkitt lymphoma. In adults, malignancies affected a range of organ systems, including respiratory, gastrointestinal, nervous, and endocrine. A marked male predominance was observed (11 males vs. 2 females). Although a definitive causal relationship cannot be established, hematologic malignancies in pediatric HME patients appear to be disproportionately represented among reported cases. This finding highlights the need for further investigation through large-scale, population-based studies incorporating both clinical and genetic data. Show less

Pure membranous lupus nephritis (pMLN, ISN/RPS-class V) is a rare form of lupus nephritis (LN). Despite being associated with significant comorbidities, it has traditionally been considered a less aggressive subtype. Emerging data challenges this perception, highlighting its potential for chronic kidney disease progression and kidney failure. pMLN is pathologically defined by subepithelial immune-complex deposits and typically presents with nephrotic syndrome, preserved renal function, and fewer systemic/immunologic manifestations compared to proliferative LN (ISN/RPS-classes III/IV). Repeat biopsies reveal frequent histological class switching from pMLN to proliferative and mixed LN forms, underscoring the dynamic nature of the disease and the limitations of clinical markers in reflecting histological activity. While the ISN/RPS kidney biopsy classification provides important prognostic insight, it does not fully capture underlying molecular heterogeneity. Recent advances in precision medicine, including proteomic and biomarker studies (e.g., EXT1/2, NCAM1), offer promising tools for patient stratification and tailored treatments. International guidelines now recommend immunosuppressive therapy for pMLN, aligning treatment strategies more closely with those for proliferative and mixed LN. Overall, pMLN should be considered a distinct but clinically relevant LN subtype requiring personalized management based on clinical, histological and molecular features. Long-term monitoring is essential, as baseline presentation does not reliably predict treatment response or disease trajectory. Show less

The pathogenesis of hereditary multiple exostoses is mainly related to genetic variants and often requires surgical resection when it causes clinical symptoms. This case report describes a variant in the We present the case of an 11-year-old boy who developed hereditary multiple exostoses. The patient presented with multiple bone swellings throughout his body and difficulty squatting due to a swelling in his right thigh. Genetic testing showed that the child had a heterozygous variant in the The diagnosis of hereditary multiple exostoses relies on a clinical examination and genetic testing. Surgical resection is indicated for symptomatic cases with functional impairments. To prevent vascular injuries such as femoral artery rupture, meticulous surgical technique is essential, including thorough smoothing of the resected bone surface and a careful intraoperative assessment of the adjacent neurovascular structures. In cases of postoperative bleeding or suspected pseudoaneurysm, prompt imaging and surgical exploration are critical for timely vascular repair. Show less

Non-syndromic cleft lip with or without cleft palate (ns-CL/P) is one of the most common craniofacial anomalies with a multifactorial etiology. To investigate the contribution of rare variants to disease risk, we performed whole-exome sequencing (WES) in 58 patients with ns-CL/P from a homogeneous Polish population, excluding from analysis 423 previously investigated cleft candidate genes. After stringent filtering, prioritization, and segregation analysis, we identified 31 likely pathogenic (LP) variants across 30 genes, significantly enriched in categories related to developmental processes. Notably, 29% of variants occurred in genes not previously linked to clefting, including Show less

Hereditary multiple osteochondromas (HMO) is an autosomal dominant disorder caused by heterozygous deleterious variants in the EXT1 or EXT2 genes. While the clinical core phenotype is well established and mainly consists of bone deformities, limb length discrepancies, multiple benign bone neoplasms, and increased risk of chondrosarcoma, the association of HMO with malignancies remains undefined. Only two cases have been reported to date. We report a third patient with HMO and leukemia. New research suggests that EXT1 and EXT2 genes may influence leukemogenesis through several mechanisms, including protein-protein interactions with leukemia-associated genes and modulation by specific microRNAs (miRNAs). Dysregulation of heparan sulfate biosynthesis, a pathway involving exostosin proteins, may disrupt the bone marrow microenvironment, impacting hematopoietic cell growth and differentiation. Show less