Adipose Tissue-Derived Mesenchymal Stem Cell Inhibits Osteoclast Differentiation through Tumor Necrosis Factor Stimulated Gene-6.

BACKGROUND: Mesenchymal stem cells (MSCs) have been highlighted as a potent therapeutic option for conditions with excessive osteoclast activity such as systemic and local bone loss in rheumatic disease. In addition to their immunomodulatory functions, MSCs also directly suppress osteoclast differentiation and activation by secreting osteoprotegerin (OPG) and IL-10 but the underlying mechanisms are still to be clarified. Tumor necrosis factor-stimulated gene-6 (TSG-6) is a potent anti-inflammatory molecule that inhibits osteoclast activation and has been shown to mediate MSC's immunomodulatory functions. In this study, we aimed to determine whether adipose tissue-derived MSC (ADMSC) inhibits the differentiation from osteoclast precursors to mature osteoclasts through TSG-6. METHODS: Human ADMSCs were co-cultured with bone marrow-derived monocyte/macrophage (BMMs) from DBA/1J or B6 mouse in the presence of osteoclastogenic condition (M-CSF 10 ng/mL and RANKL 10 ng/mL). In some co-culture groups, ADMSCs were transfected with siRNA targeting TSG-6 or OPG to determine their role in osteoclastogenesis. Tartrate-resistant acid phosphatase (TRAP) activity in culture supernatant and mRNA expression of osteoclast markers were investigated. TRAP+ multinucleated cells and F-actin ring formation were counted. RESULTS: ADMSCs significantly inhibited osteoclast differentiation under osteoclastogenic conditions. Suppression of TSG-6 significantly reversed the inhibition of osteoclast differentiation in a degree similar to that of OPG based on TRAP activity, mRNA expression of osteoclast markers, and numbers of TRAP+ multinucleated cell and F-actin ring formation. CONCLUSION: This study demonstrated that ADMSCs inhibit osteoclast differentiation through TSG-6 under osteoclastogenic conditions.

An Autopsy-proven Case-based Review of Autoimmune Encephalitis.

Autoimmune encephalitis (AIE) is a type of immunoreactive encephalitic disorder and is recognized as the most prevalent noninfectious encephalitis. Nevertheless, the rarity of definitive AIE diagnosis through biopsy or autopsy represents a significant hurdle to understanding and managing the disease. In this article, we present the pathological findings of AIE and review the literature based on a distinct case of AIE presenting as CD8+ T-lymphocyte predominant encephalitis. We describe the clinical progression, diagnostic imaging, laboratory data, and autopsy findings of an 80-year-old deceased male patient. The patient was diagnosed with pulmonary tuberculosis 6 months before death and received appropriate medications. A week before admission to the hospital, the patient manifested symptoms such as a tendency to sleep, decreased appetite, and confusion. Although the patient temporally improved with medication including correction of hyponatremia, the patient progressed rapidly and died in 6 weeks. The brain tissue revealed lymphocytic infiltration in the gray and white matter, leptomeninges, and perivascular infiltration with a predominance of CD8+ T lymphocytes, suggesting a case of AIE. There was no detectable evidence of viral infection or underlying neoplasm. The autopsy revealed that this patient also had Alzheimer's disease, atherosclerosis, arteriolosclerosis, and aging-related tau astrogliopathy. This report emphasizes the pivotal role of pathological examination in the diagnosis of AIE, especially when serological autoantibody testing is not available or when a patient is suspected of having multiple diseases.

Molecular imaging for evaluation of synovitis associated with osteoarthritis: a narrative review.

Recent evidence highlights the role of low-grade synovial inflammation in the progression of osteoarthritis (OA). Inflamed synovium of OA joints detected by imaging modalities are associated with subsequent progression of OA. In this sense, detecting and quantifying synovitis of OA by imaging modalities may be valuable in predicting OA progressors as well as in improving our understanding of OA progression. Of the several imaging modalities, molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) has an advantage of visualizing the cellular or subcellular events of the tissues. Depending on the radiotracers used, molecular imaging method can potentially detect and visualize various aspects of synovial inflammation. This narrative review summarizes the recent progresses of imaging modalities in assessing inflammation and OA synovitis and focuses on novel radiotracers. Recent studies about imaging modalities including ultrasonography (US), magnetic resonance imaging (MRI), and molecular imaging that were used to detect and quantify inflammation and OA synovitis are summarized. Novel radiotracers specifically targeting the components of inflammation have been developed. These tracers may show promise in detecting inflamed synovium of OA and help in expanding our understanding of OA progression.

Self-Powering Sensory Device with Multi-Spectrum Image Realization for Smart Indoor Environments.

The development of organic-based optoelectronic technologies for the indoor Internet of Things market, which relies on ambient energy sources, has increased, with organic photovoltaics (OPVs) and photodetectors (OPDs) considered promising candidates for sustainable indoor electronic devices. However, the manufacturing processes of standalone OPVs and OPDs can be complex and costly, resulting in high production costs and limited scalability, thus limiting their use in a wide range of indoor applications. This study uses a multi-component photoactive structure to develop a self-powering dual-functional sensory device with effective energy harvesting and sensing capabilities. The optimized device demonstrates improved free-charge generation yield by quantifying charge carrier dynamics, with a high output power density of over 81 and 76 µW cm-2 for rigid and flexible OPVs under indoor conditions (LED 1000 lx (5200 K)). Furthermore, a single-pixel image sensor is demonstrated as a feasible prototype for practical indoor operating in commercial settings by leveraging the excellent OPD performance with a linear dynamic range of over 130 dB in photovoltaic mode (no external bias). This apparatus with high-performance OPV-OPD characteristics provides a roadmap for further exploration of the potential, which can lead to synergistic effects for practical multifunctional applications in the real world by their mutual relevance.

Teratoma pathology and genomics in anti-NMDA receptor encephalitis.

INTRODUCTION: Ovarian teratoma is a common occurrence in patients with anti-NMDA receptor encephalitis (NMDARe), and its removal is crucial for a favorable prognosis. However, the initial pathogenesis of autoimmunity in the encephalitic teratoma remains unclear. In this study, we aimed to investigate the genomic landscape and microscopic findings by comparing NMDARe-associated teratomas and non-encephalitic control teratomas. MATERIALS AND METHODS: A prospective consecutive cohort of 84 patients with NMDARe was recruited from January 2014 to April 2020, and among them, patients who received teratoma removal surgery at Seoul National University Hospital were enrolled. We conducted a comparison of whole-exome sequencing data and pathologic findings between NMDARe-associated teratomas and control teratomas. RESULTS: We found 18 NMDARe-associated teratomas from 15 patients and compared them with 17 non-encephalitic control teratomas. Interestingly, the genomic analysis revealed no significant differences in mutations between encephalitic and non-encephalitic teratomas. Pathologic analysis showed no discrepancies in terms of the presence of neuronal tissue and lymphocytic infiltration between the encephalitic teratomas (n = 14) and non-encephalitic teratomas (n = 18). However, rituximab-naïve encephalitic teratomas exhibited a higher frequency of germinal center formation compared to non-encephalitic teratomas (80% vs. 16.7%, P = 0.017). Additionally, rituximab-treated encephalitic teratomas demonstrated a reduced number of CD20+ cells and germinal centers in comparison to rituximab-naïve encephalitic teratomas (P = 0.048 and 0.023, respectively). DISCUSSION: These results suggest that the initiation of immunopathogenesis in NMDARe-associated teratoma is not primarily attributed to intrinsic tumor mutations, but rather to immune factors present in the encephalitic patient group, ultimately leading to germinal center formation within the teratoma.

Methylation-based Subclassifications of Embryonal Tumor with Multilayered Rosettes in Not Just Pediatric Brains.

The aim of this study is to investigate the genetic profiles and methylation-based classifications of Embryonal tumor with multilayered rosettes (ETMR), with a specific focus on differentiating between C19MC amplified and C19MC-not amplified groups, including cases with DICER1 mutations. To achieve this, next-generation sequencing using a targeted gene panel for brain tumors and methylation class studies using the Epic850K microarray were performed to identify tumor subclasses and their clinicopathological characteristics. The study cohort consisted of four patients, including 3 children (a 4-months/F, a 9-months/M, and a 2 y/F), and one adult (a 30 y/Male). All three tumors in the pediatric patients originated in the posterior fossa and exhibited TTYH1:C19MC fusion and C19MC amplification. The fourth case in the adult patient involved the cerebellopontine angle with biallelic DICER1 mutation. Histopathological examination revealed typical embryonal features characterized by multilayered rosettes and abundant neuropils in all cases, while the DICER1-mutant ETMR also displayed cartilage islands in addition to the classic ETMR pathology. All four tumors showed positive staining for LIN28A. The t-SNE clustering analysis demonstrated that the first three cases clustered with known subtypes of ETMR, specifically C19MC amplified, while the fourth case clustered separately to non-C19MC amplified subclass. During the follow-up period of 6~12 months, leptomeningeal dissemination of the tumor occurred in all patients. Considering the older age of onset in DICER1-mutant ETMR, genetic counseling should be recommended due to the association of DICER1 mutations with germline and second-hit somatic mutations in cancer.

Brain Tumor Classification by Methylation Profile.

The goal of the methylation classifier in brain tumor classification is to accurately classify tumors based on their methylation profiles. Accurate brain tumor diagnosis is the first step for healthcare professionals to predict tumor prognosis and establish personalized treatment plans for patients. The methylation classifier can be used to perform classification on tumor samples with diagnostic difficulties due to ambiguous histology or mismatch between histopathology and molecular signatures, i.e., not otherwise specified (NOS) cases or not elsewhere classified (NEC) cases, aiding in pathological decision-making. Here, the authors elucidate upon the application of a methylation classifier as a tool to mitigate the inherent complexities associated with the pathological evaluation of brain tumors, even when pathologists are experts in histopathological diagnosis and have access to enough molecular genetic information. Also, it should be emphasized that methylome cannot classify all types of brain tumors, and it often produces erroneous matches even with high matching scores, so, excessive trust is prohibited. The primary issue is the considerable difficulty in obtaining reference data regarding the methylation profile of each type of brain tumor. This challenge is further amplified when dealing with recently identified novel types or subtypes of brain tumors, as such data are not readily accessible through open databases or authors of publications. An additional obstacle arises from the fact that methylation classifiers are primarily research-based, leading to the unavailability of charging patients. It is important to note that the application of methylation classifiers may require specialized laboratory techniques and expertise in DNA methylation analysis.

Neuroepithelial tumor with EWSR1::PATZ1 fusion: A literature review.

We present the clinicopathological and molecular genetic characteristics of a neuroepithelial tumor (NET), EWSR1::PATZ1 fusion-positive with a literature review. This fusion has recently been discovered in rare central nervous system tumors and soft tissue sarcomas and was not included in the fifth edition of the WHO classifications. We identified this fusion in 2 NETs. The first case involved a 7-year-old girl and the second case occurred in a 53-year-old man; both presented with headaches and vomiting. The pediatric case initially showed an intermediate grade of the tumor, but upon recurrences, it transformed into a high-grade tumor with 2 relapses in 8.3 years. This case exhibited high mitotic activity (20/10 high-power fields), and a high Ki-67 index (21%). The TERT promoter (TERTp) mutation was present in both initial and recurrent tumors. In contrast, the adult case was a low-grade tumor with no mitotic activity or recurrence over 13.5 months after subtotal resection and gamma knife surgery. Interestingly, the pediatric case demonstrated a longer survival time compared to conventional glioblastoma. The TERTp mutation, similar to being a molecular signature in adult-type glioblastoma, could also be an indicator of high-grade behavior in PATZ1 fusion NET.

Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis.

This study aimed to find any ambiguous genetic outlier for "oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)" and "astrocytoma, IDH-mutant (A_IDH_mut)" and to redefine the genetic landscape and prognostic factors of IDH-mutant gliomas. Next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed for O_IDH_mut (n = 74) in 70 patients and for A_IDH_mut (n = 95) in 90 patients. 97.3% of O_IDH_mut and 98.9% of A_IDH_mut displayed a classic genomic landscape. Combined CIC (75.7%) and/or FUBP1 (45.9%) mutations were detected in 93.2% and MGMTp methylation in 95.9% of O_IDH_mut patients. In A_IDH_mut, TP53 mutations were found in 86.3% and combined ATRX (82.1%) and TERTp (6.3%) mutations in 88.4%. Although there were 3 confusing cases, NOS (not otherwise specified) category, based on genetic profiles, but they were clearly classified by combining histopathology and DKFZ methylation classifier algorithms. The patients with MYCN amplification and/or CDKN2A/2B homozygous deletion in the A_IDH_mut category had a worse prognosis than those without these gene alterations and MYCN-amplified A_IDH_mut showed the worst prognosis. However, there was no prognostic genetic marker in O_IDH_mut. In histopathologically or genetically ambiguous cases, methylation profiles can be used as an objective tool to avoid a diagnosis of NOS or NEC (not elsewhere classified), as well as for tumor classification. The authors have not encountered a case of true mixed oligoastrocytoma using an integrated diagnosis of histopathological, genetic and methylation profiles. MYCN amplification, in addition to CDKN2A/2B homozygous deletion, should be included in the genetic criteria for CNS WHO grade 4 A_IDH_mut.

Epigenetic Alteration of H3K27me3 as a Possible Oncogenic Mechanism of Central Neurocytoma.

Central neurocytoma (CN) is a low-grade neuronal tumor that mainly arises from the lateral ventricle (LV). This tumor remains poorly understood in the sense that no driver gene aberrations have been identified thus far. We investigated immunomarkers in fetal and adult brains and 45 supratentorial periventricular tumors to characterize the biomarkers, cell of origin, and tumorigenesis of CN. All CNs occurred in the LV. A minority involved the third ventricle, but none involved the fourth ventricle. As expected, next-generation sequencing performed using a brain-tumor-targeted gene panel in 7 CNs and whole exome sequencing in 5 CNs showed no driver mutations. Immunohistochemically, CNs were robustly positive for FGFR3 (100%), SSTR2 (92%), TTF-1 (Nkx2.1) (88%), GLUT-1 (84%), and L1CAM (76%), in addition to the well-known markers of CN, synaptophysin (100%) and NeuN (96%). TTF-1 was also positive in subependymal giant cell astrocytomas (100%, 5/5) and the pituicyte tumor family, including pituicytoma and spindle cell oncocytoma (100%, 5/5). Interestingly, 1 case of LV subependymoma (20%, 1/5) was positive for TTF-1, but all LV ependymomas were negative (0/5 positive). Because TTF-1-positive cells were detected in the medial ganglionic eminence around the foramen of Monro of the fetal brain and in the subventricular zone of the LV of the adult brain, CN may arise from subventricular TTF-1-positive cells undergoing neuronal differentiation. H3K27me3 loss was observed in all CNs and one case (20%) of LV subependymoma, suggesting that chromatin remodeling complexes or epigenetic alterations may be involved in the tumorigenesis of all CNs and some ST-subependymomas. Further studies are required to determine the exact tumorigenic mechanism of CN.

MYB/MYBL1::QKI fusion-positive diffuse glioma.

The MYB/MYBL1::QKI fusion induces the protooncogene, MYB, and deletes the tumor suppressor gene, QKI. MYB/MYBL1::QKI rearrangement was previously reported only in angiocentric glioma (AG) and diffuse low-grade glioma. This report compares 2 tumors containing the MYB/MYBL1::QKI fusion: a diffuse pediatric-type high-grade glioma (DPedHGG) in an 11-year-old boy and an AG in a 46-year-old woman. We used immunohistochemistry, next-generation sequencing, and methylation profiling to characterize each tumor and compare our findings to the literature on AG and tumors with the MYB/MYBL1::QKI rearrangement. Both tumors were astrocytic with angiocentric patterns. The MYB::QKI fusion-positive DPedHGG, which recurred once, was accompanied by TP53 mutation and amplification of CDK6 and KRAS, suggesting malignant transformation secondary to additional genetic aberrations. The second case was the adult AG with MYBL1::QKI fusion, which mimicked ependymoma based on histopathology and its dot- and ring-like epithelial membrane antigen positivity. Combined with a literature review, our results suggest that MYB/MYBL1 alterations are not limited to low-grade gliomas, including AG. AG is most common in the cerebra of children and adolescents but exceptional cases occur in adults and the acquisition of additional genetic mutations may contribute to high-grade glioma. These cases further demonstrate that molecular characteristics, morphologic features, and clinical context are essential for diagnosis.

Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.

Molecular subtyping of ependymoma and prognostic impact of Ki-67.

Although ependymomas (EPNs) have similar histopathology, they are heterogeneous tumors with diverse immunophenotypes, genetics, epigenetics, and different clinical behavior according to anatomical locations. We reclassified 141 primary EPNs from a single institute with immunohistochemistry (IHC) and next-generation sequencing (NGS). Supratentorial (ST), posterior fossa (PF), and spinal (SP) EPNs comprised 12%, 41%, and 47% of our cohort, respectively. Fusion genes were found only in ST-EPNs except for one SP-EPN with ZFTA-YAP1 fusion, NF2 gene alterations were found in SP-EPNs, but no driver gene was present in PF-EPNs. Surrogate IHC markers revealed high concordance rates between L1CAM and ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs. The 7% cut-off of Ki-67 was sufficient to classify EPNs into two-tiered grades at all anatomical locations. Multivariate analysis also delineated that a Ki-67 index was the only independent prognostic factor in both overall and progression-free survivals. The gain of chromosome 1q and CDKN2A/2B deletion were associated with poor outcomes, such as multiple recurrences or extracranial metastases. In this study, we propose a cost-effective schematic diagnostic flow of EPNs by the anatomical location, three biomarkers (L1CAM, H3K27me3, and EZHIP), and a cut-off of a 7% Ki-67 labeling index.

Adult-onset Still's Disease after BNT162b2 mRNA COVID-19 Vaccine.

The coronavirus disease 2019 (COVID-19) pandemic is being overcome by widespread inoculation with various COVID-19 vaccines, but concerns about the safety of the vaccines are a major hurdle to widespread vaccination. We report the first case of adult-onset Still's disease (AOSD) developing in a 36-year-old, previously healthy woman after the first dose of BNT162b2 mRNA COVID-19 vaccine (Pfizer). She visited our hospital due to high spiking fever and sore throat that developed 10 days after vaccination. Based on thorough investigations and changes in symptoms and signs after admission, she was diagnosed with AOSD and treated with high dose steroids and tocilizumab. This report suggests the possibility that AOSD could be triggered by COVID-19 vaccines through activation of the innate immune system.

Revisiting vimentin: a negative surrogate marker of molecularly defined oligodendroglioma in adult type diffuse glioma.

Vimentin is a marker of epithelial-mesenchymal transformation and indicates poor prognosis in various cancers, but its role in diffuse gliomas remains unknown. We investigated the vimentin expression of diffuse gliomas according to the upcoming 2021 WHO classification, its variations due to mutational status, and its prognostic effects. We analyzed vimentin immunohistochemistry in 315 gliomas: a test set (n = 164) and a validation set (n = 151). RNA-seq and mutational information from The Cancer Genome Atlas (TCGA, n = 422) were also used for validation. Vimentin was diffusely positive in astrocytic tumors but negative in oligodendroglial tumors (ODGs) and its expression was significantly higher in isocitrate dehydrogenase (IDH) wild-type tumors. High vimentin expression was correlated with poor prognosis (hazard ratio [HR]: 5.99), but it was dependent on the new WHO grade which reflects both histologic features and genetics (HR: 1.28). Using the significant difference in vimentin expression between ODGs and astrocytic tumors, the positive and negative predictive values of the vimentin-based diagnosis for ODGs were 93.5% and 97.8% in the validation set. Along with additional alpha-thalassemia/mental retardation, X-linked (ATRX) immunohistostaining, the values were 98.3% and 97.8%, respectively. Vimentin is a useful ancillary marker for identifying ODGs when combined with routine histochemistry markers.

Varicella zoster virus (VZV)-specific immunity and subclinical VZV reactivation in patients with autoimmune diseases.

BACKGROUND/AIMS: The risk of herpes zoster (HZ) is increased in patients with autoimmune diseases (AID), probably due to immunosuppressive therapy. METHODS: This prospective cross-sectional study investigated varicella zoster virus (VZV)-specific immunity in relation to subclinical VZV reactivation in 48 AID patients and 48 healthy controls (HCs). We assessed humoral immunity (serum VZV immunoglobulin g [IgG], IgA, and IgM) and cell-mediated immunity (interferon-γ [IFNγ]-releasing assay) to VZV as well as salivary VZV DNA status. Subclinical VZV reactivation was confirmed by detecting VZV DNA in saliva or VZV IgM in serum in the absence of typical HZ symptoms. RESULTS: Median IgA levels were higher in the AID group than in the HC group, while VZV IgG and IgM levels were comparable between the groups. AID patients showed fewer IFNγ spot-forming cells (SFCs) upon VZV stimulation than HCs (58.2 vs. 122.0 SFCs/106 peripheral blood mononuclear cells [PBMCs], p < 0.0001). Subclinical VZV reactivation was more frequent in AID patients than in HCs (12.5% vs. 0%, p = 0.01). AID patients with VZV reactivation received prednisolone more frequently and at a higher dose than AID patients without reactivation. VZV-specific IFNγ SFCs were significantly lower in patients with VZV reactivation among AID patients (26.3 vs. 62.6 SFCs/106 PBMCs, p < 0.0001). CONCLUSION: Results suggest that poor cellular response against VZV might cause clinical and subclinical reactivation of VZV in AID patients.

Targeting metastatic breast cancer with peptide epitopes derived from autocatalytic loop of Prss14/ST14 membrane serine protease and with monoclonal antibodies.

BACKGROUND: In order to develop a new immunotherapeutic agent targeting metastatic breast cancers, we chose to utilize autocatalytic feature of the membrane serine protease Prss14/ST14, a specific prognosis marker for ER negative breast cancer as a target molecule. METHODS: The study was conducted using three mouse breast cancer models, 4 T1 and E0771 mouse breast cancer cells into their syngeneic hosts, and an MMTV-PyMT transgenic mouse strain was used. Prss14/ST14 knockdown cells were used to test function in tumor growth and metastasis, peptides derived from the autocatalytic loop for activation were tested as preventive metastasis vaccine, and monoclonal and humanized antibodies to the same epitope were tested as new therapeutic candidates. ELISA, immunoprecipitation, Immunofluorescent staining, and flow cytometry were used to examine antigen binding. The functions of antibodies were tested in vitro for cell migration and in vivo for tumor growth and metastasis. RESULTS: Prss14/ST14 is critically involved in the metastasis of breast cancer and poor survival rather than primary tumor growth in two mouse models. The epitopes derived from the specific autocatalytic loop region of Prss14/ST14, based on structural modeling acted as efficient preventive metastasis vaccines in mice. A new specific monoclonal antibody mAb3F3 generated against the engineered loop structure could reduce cell migration, eliminate metastasis in PyMT mice, and can detect the Prss14/ST14 protein expressed in various human cancer cells. Humanized antibody huAb3F3 maintained the specificity and reduced the migration of human breast cancer cells in vitro. CONCLUSION: Our study demonstrates that Prss14/ST14 is an important target for modulating metastasis. Our newly developed hybridoma mAbs and humanized antibody can be further developed as new promising candidates for the use in diagnosis and in immunotherapy of human metastatic breast cancer.

Comparison of renoprotective effects of febuxostat and allopurinol in hyperuricemic patients with chronic kidney disease.

PURPOSE: This study aimed to compare the renoprotective effect between febuxostat and allopurinol in hyperuricemic patients with chronic kidney disease (CKD), about which limited data are available. METHODS: 141 patients with stage 3 CKD and hyperuricemia were followed from June 2005 to April 2018. Thirty patients received febuxostat, 40 allopurinol and 71 conventional CKD management only (control group). We compared the mean serum uric acid levels, estimated glomerular filtration rate (eGFR) changes over time and renal survival time free from predefined renal disease progression among these 3 groups. RESULTS: Overall, mean age was 62.6 ± 13.3 years, baseline eGFR 42.1 ± 8.8 mL/min/1.73 m2, and serum uric acid 8.6 ± 1.5 mg/dL without intergroup difference. During the observation period (55.9 ± 31.8 months), febuxostat group, compared to both allopurinol and control group, had significantly lower mean serum uric acid levels (5.7 ± 1.0 vs. 7.1 ± 1.2 vs. 8.0 ± 0.8 mg/dL, p < 0.001) and maintained significantly higher mean eGFR values consistently for 4 years. Febuxostat group had significantly longer renal survival time free from renal disease progression than allopurinol and control group (87.7 (95% CI 71.2-104.2) vs. 77.6 (95% CI 60.2-94.9) vs. 48.7 (95% CI 39.3-58.1) months, respectively, p < 0.001). Cox proportional hazard model analysis adjusting for potent confounders revealed that febuxostat, with control group as reference, significantly reduced the risk of renal disease progression by 74.3% (hazard ratio 0.257 (95% CI 0.072-0.912), p = 0.036), while allopurinol showed insignificant result. CONCLUSIONS: Febuxostat seems to reduce serum uric acid level and to retard renal disease progression more effectively than allopurinol in hyperuricemic patients with CKD.

Correction: Clinical management of seronegative and seropositive rheumatoid arthritis: A comparative study.

[This corrects the article DOI: 10.1371/journal.pone.0195550.].

Clinical management of seronegative and seropositive rheumatoid arthritis: A comparative study.

Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) are associated with poor radiologic outcomes in patients with rheumatoid arthritis (RA). In general, RA patients positive for RF or ACPA (SPRA) are considered to manifest an aggressive disease course compared with seronegative RA patients (SNRA). However, the relationship between seropositivity and measures of disease severity other than radiologic outcome is disputed. In this study, we sought to compare the clinical presentations and treatment outcomes of SNRA and SPRA patients. A total of 241 patients diagnosed with DMARD-naïve RA under either 1987 American College of Rheumatology (ACR) criteria or 2010 ACR/European League Against Rheumatism (EULAR) criteria were identified (40 with SNRA and 201 with SPRA). We investigated the disease activity measures including ESR, CRP, patient VAS, 28 tender/swollen joint count (28 TJC, 28 SJC) and DAS28 as well as radiologic outcomes at baseline, 1 and 2 years after conventional treatment with DMARD. Age, sex and disease duration were similar between SNRA and SPRA. However, the baseline 28 TJC (4.7±2.9 vs. 3.3±2.7, p = 0.004), 28 SJC (4.3±3.0 vs. 2.9±2.3, p = 0.001) and DAS28 (5.1±1.0 vs. 4.7±1.0, p = 0.043) components were significantly higher in SNRA than in SPRA. Over 2 years of similar treatment with DMARDs, all disease activity measures significantly improved in both groups. Comparison among populations matched for baseline disease activity showed that ΔDAS28 at 1 year was greater in SNRA than in SPRA (-2.84±1.32 vs. -3.70±1.29, p = 0.037) in high disease activity population (DAS28-ESR>5.1). Radiologic outcomes at baseline and at 1- or 2-year follow-up were similar between the 2 groups. In conclusion, SNRA patients manifested more active disease at baseline, but showed a better response to treatment compared with SPRA. SNRA does not appear to be a benign subtype of RA.