Epidermal Growth Factor-related Receptor Research Articles

Exploring causal correlations between inflammatory cytokines and Ménière's disease: a Mendelian randomization.

Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1β. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

Delta/Notch-like Epidermal Growth Factor-Related Receptor (DNER), a Potential Prognostic Marker of Gastric Cancer Regulates Cell Survival and Cell Cycle Progression.

Upregulation of the expression of Delta/notch-like epidermal growth factor-related receptor (DNER) and its oncogenic role have been reported in several cancers, including gastric, breast, and prostate cancers. This study aimed to investigate the oncogenic role of DNER and the mechanisms behind its oncogenic role in gastric cancer. Analysis of the RNASeq data of gastric cancer tissues obtained from the TCGA database revealed that the expression of DNER was associated with the pathology of advanced gastric cancer and the prognosis of patients. DNER expression was increased upon stem cell-enriching cancer spheroid culture. Knockdown of DNER expression inhibited cell proliferation and invasion, induced apoptosis, enhanced chemosensitivity, and decreased spheroid formation of SNU-638 gastric cancer cells. DNER silencing elevated the expression of p53, p21cip/waf, and p27, and increased G1 phase cells at the expense of S phase cells. Knockdown of p21cip/waf expression in the DNER-silenced cells partially restored cell viability and S phase progression. DNER silencing also induced the apoptosis of SNU-638 cells. While both cleaved caspases-8 and 9 were detected in adherent cells, only cleaved caspase-8 was found to have increased in spheroid-cultured cells, suggesting a distinct activation pattern of caspase activation depending on the growth condition. Knockdown of p53 expression rescued the DNER-silenced cells from apoptosis and partially restored cell viability. In contrast, overexpression of the Notch intracellular domain (NICD) decreased the expression of p53, p21cip/waf, and cleaved caspase-3 in DNER-silenced cells. Moreover, NICD expression fully reverted the cell viability reduction, arrest in the G1 phase, and elevated apoptosis caused by DNER silencing, thereby suggesting activation of Notch signaling by DNER. Expression of a membrane-unbound mutant of mDNER also decreased cell viability and induced apoptosis. On the other hand, TGF-β signals were found to be involved in DNER expression in both adherent and spheroid-cultured cells. DNER could therefore be a link connecting TGF-β signaling to Notch signaling. Taken together, DNER regulates cell proliferation, survival, and invasive capacity of the gastric cancer cells through the activation of Notch signaling, which may facilitate tumor progression into an advanced stage. This study provides evidences suggesting that DNER could be a potential prognostic marker, a therapeutic target, and a drug candidate in the form of a cell-free mutant.

Anti-Tr/DNER Paraneoplastic Cerebellar Degeneration with Marked Cerebellar and Psychological Symptoms Responsive to Plasma Exchange (P5-5.025)

<h3>Objective:</h3> We present a patient who developed cerebellar degeneration and severe psychological symptoms leading to the diagnosis of Hodgkin’s disease and detection of anti-Tr/DNER antibodies. The patient failed to respond methylprednisolone, intravenous immunoglobulin G, rituximab, and tumor treatment but had significant improvement with plasma exchange (PLEX). <h3>Background:</h3> Paraneoplastic cerebellar degeneration accompanying Hodgkin’s disease may have its onset prior to detection of the underlying malignancy, during its course, or following treatment. The major associated autoantibody, anti-Tr, is reactive with neuronal delta/notch-like epidermal growth factor-related receptors (DNER), an autoantibody not included in all paraneoplastic testing screens. The condition characterized by progressive cerebellar injury, and response to immunosuppressive therapy and tumor treatment is generally poor. <h3>Design/Methods:</h3> <h3>Case Presentation:</h3> A 60-year-old male presented with diplopia, progressive loss of balance, and ataxia, with impaired short-term memory, confusion, and anger outbursts. Initial commercial screen for paraneoplastic autoantibodies was negative. Two months following his initial presentation he developed inguinal lymphadenopathy. He was diagnosed as having Hodgkin’s Lymphoma Stage 1B and found by a second laboratory to have anti-TR/DNER antibodies (Titer 1:3480; Reference range &lt;1:240), an antibody not included in the initial testing panel. CSF analysis was notable for a protein of 92mg/dL. MRI demonstrated normal findings for age. <h3>Results:</h3> Treatment with Doxorubicin-Bleomycin-Vinblastine-Dacarbazine (ABVD), pulse methylprednisolone, and intravenous immunoglobulin did not affect progression of neurological symptoms. Plasma exchange (PLEX), however, resulted in marked improvement. Symptoms worsened during subsequent treatment with intravenous immunoglobulins and rituximab but improved with further plasma exchange. <h3>Conclusions:</h3> Although Hodgkin’s disease is an important malignancy in paraneoplastic cerebellar degeneration, its most common associated autoantibody is not necessarily included in commercial paraneoplastic autoantibody screens, potentially leading to delay in diagnosis. Our patient’s dramatic improvement with PLEX suggests that PLEX should be considered early in treatment, or where there is poor response to other treatment modalities. <b>Disclosure:</b> Dr. Crane has nothing to disclose. Dr. Wynn has nothing to disclose. Dr. DeWitt has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Greenlee has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Medlink. Dr. Greenlee has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Sommers Schwartz Law Offices. Dr. Greenlee has received publishing royalties from a publication relating to health care. Dr. Greenlee has received publishing royalties from a publication relating to health care.

DNER-IgG screening of 3290 cerebral spinal fluid samples: Two autoimmune cerebellar ataxia cases without tumors in long-term follow-up

BackgroundThis study aimed to retrospectively report the findings of delta/notch-like epidermal growth factor-related receptor (DNER)-immunoglobin G (IgG) in cerebral spinal fluid (CSF) in two cases with cerebellar ataxia. Methods: CSF samples were collected from 3290 patients with possible autoimmune encephalitis. The immunofluorescence pattern was reviewed using a tissue-based assay. Results: An immunofluorescence pattern with a specific IgG-binding pattern in the cytoplasm of cerebellar Purkinje cells, as well as a fine-dotted pattern in the molecular layer, was found in two samples (0.06%, 2/3290), each from one patient. DNER-IgG was confirmed by cell-based assays. Both of the patients were male and did not have tumors. This suggests that cerebellar ataxia was the main manifestation. Brain magnetic resonance imaging showed non-specific lesions in both patients. One patient responded well to steroid treatment, but the other patient demonstrated a weak response to treatment. During the two-year follow-up period, both patients were stable, and no tumors developed in either patient. ConclusionThe DNER-IgG antibody is rarely found in patients with possible autoimmune encephalitis, and therefore it is not necessarily associated with tumors.

Anti-Tr/DNER Paraneoplastic Cerebellar Degeneration with Marked Cerebellar and Psychological Symptoms Responsive to Plasma Exchange

Objective We present a patient who developed cerebellar degeneration and severe psychological symptoms leading to the diagnosis of Hodgkin's disease and detection of anti-Tr/DNER antibodies. The patient failed to respond methylprednisolone intravenous immunoglobulin G, rituximab, and tumor treatment but had significant improvement with plasma exchange (PLEX). Background Paraneoplastic cerebellar degeneration accompanying Hodgkin's disease may have its onset prior to detection of the underlying malignancy, during its course, or following treatment. The associated autoantibody, anti-Tr, is reactive with neuronal delta/notch-like epidermal growth factor-related receptors (DNER), an autoantibody not included in all paraneoplastic testing screens. The condition characterized by progressive cerebellar injury, and response to immunosuppressive therapy and tumor treatment is generally poor. Design/Methods Case Presentation: A 60-year-old male presented with diplopia, progressive loss of balance, and ataxia, with impaired short-term memory, confusion, and anger outbursts. Initial commercial screen for paraneoplastic autoantibodies was negative. Two months following his initial presentation he developed inguinal lymphadenopathy. He was diagnosed as having Hodgkin's Lymphoma Stage 1B and found by a second laboratory to have anti-TR/DNER antibodies (Titer 1:3480; Reference range &lt;1:240), an antibody not included in the initial testing panel. CSF analysis was notable for a protein of 92 mg/dL. MRI demonstrated normal findings for age. Results Treatment with Doxorubicin-Bleomycin-Vinblastine-Dacarbazine (ABVD), pulse methylprednisolone, and intravenous immunoglobulin did not affect disease progression. Plasma exchange PLEX resulted in marked improvement. Symptoms worsened during subsequent treatment with intravenous immunoglobulins and rituximab but improved with further plasma exchange. Conclusions Although Hodgkin's disease is an important malignancy in paraneoplastic cerebellar degeneration, its associated autoantibody is not necessarily included in commercial paraneoplastic autoantibody screens, potentially leading to delay in diagnosis. Our patient's dramatic improvement with PLEX suggests that PLEX should be considered early in treatment, or where there is poor response to other treatment modalities.

Role of Delta/Notch-like epidermal growth factor-related receptor in gastric cancer patients and cells and its clinical significance.

Gastric cancer (GC) is a common digestive system malignancy. The aim of this study was to explore the role of Delta/Notch-like epidermal growth factor-related receptor (DNER) in GC patients and cells. Gene expression omnibus data base public databases were used to analyze the DNER expression in GC patient. A total of 30 cases of GC and adjacent tissue samples were retrospectively obtained to analyze the DNER expression. MTT assay was conducted to measure the cell viability. The apoptosis rate of GC cells was determined by flow cytometry. The migration and invasion were detected by transwell assay. Real-time polymerase chain reaction and western blot were performed to measure the DNER expression. Bioinformatics tools exhibited that DNER expression is significantly upregulated in the GC, which was also found in GC tissues and cells. The high levels of DNER were closely related the tumor size, sex and lymph node metastasis. Additionally, the survival rate of patients with high DNER expression is decreased. Furthermore, knockdown of DNER inhibits the proliferation, migration and invasion, and induces the apoptosis rate of the GC cells. DNER was upregulated in GC and knockdown of DNER inhibits the growth and metastasis of DNER. DNER may be a potential prognostic biomarker and therapeutic target of GC patients.

Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response.

The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase-signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) >3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P < 0.001). Marked (>20%) and statistically significant (P < 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (>50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.

Delta and Notch-like epidermal growth factor-related receptor suppresses human glioma growth by inhibiting oncogene TOR4A.

Delta and Notch-like endothelial growth factor-related receptor (DNER) is a transmembrane protein that mediates signal communication between neurons and glial cells. This study was performed to elucidate the specific mechanism by which DNER inhibits human glioma growth. RNA sequencing was used to detect differentially expressed genes after DNER inhibition in glioma cells. The functions of the Torsin family 4 member A (TOR4A) gene were explored through cell proliferation and clonogenic assays, flow cytometric analysis, in vitro cell migration and invasion assays, in vivo glioma transplantation, and human glioma tissue analysis using the Chinese Glioma Genome Atlas database. Protein expression levels were determined using the western blot assay. We found that TOR4A was highly expressed after the inhibition of DNER in glioma cells. The prognosis of patients with gliomas that expressed high levels of TOR4A was worse than those with low levels of the protein. TOR4A promoted the proliferation of glioma cells and inhibited their apoptosis, likely by enhancing the expression of phosphorylated protein kinase B (p-AKT) and inhibiting that of antiapoptotic proteins. We confirmed that TOR4A is an oncogene and that DNER acts as a tumor suppressor gene by inhibiting TOR4A and its functions of promoting p-AKT and inhibiting antiapoptotic protein expression.

Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction.

AimsLittle information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex‐specific proteomic profiles associated with CMD in patients with HFpEF.Methods and resultsUsing the prospective multinational PROMIS‐HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high‐throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non‐overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy‐associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin‐like growth factor‐binding protein 1, phage shock protein D, CUB domain‐containing protein 1, prostasin, decorin, FMS‐like tyrosine kinase 3, ligand growth differentiation factor 15, spondin‐1, delta/notch‐like epidermal growth factor‐related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation‐mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13‐kinase and transforming growth factor‐beta signalling pathway among women with HFpEF.ConclusionWhile the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women.

Anti-Tr/DNER Antibody–Associated Cerebellar Ataxia: a Systematic Review

Rapidly progressive cerebellar ataxia is a classical paraneoplastic neurological syndrome associated with different autoantibodies and typical demographic characteristics, extracerebellar signs, tumor association, and prognosis. Anti-Tr/anti-Delta/Notch-like epidermal growth factor-related receptor (DNER) antibody is one of the associated antibodies. Given the rarity of this condition, our current knowledge is based on case reports and small case series. In order to improve our understanding of these conditions, we conducted a systematic review of the literature. Our study followed the PRISMA reporting guidelines. Studies of patients with the presence of anti-Tr/DNER antibodies in serum or cerebrospinal fluid (CSF) were included. We extract data information related to study characteristics, demographics, clinical symptoms, tumor association, neuroimaging, and cerebrospinal fluid analysis. Out of 131 records, we analyzed 17 papers, including a total of 85 patients with anti-Tr/DNER antibody-associated cerebellar ataxia. We confirmed that this disease occurred mostly in middle-aged males. Isolated cerebellar ataxia was the most common presentation. Extracerebellar features were rare (8%). Ninety-one percent of the patients presented an associated tumor, being Hodgkin lymphoma the most common. Abnormal neuroimaging patterns included cerebellar atrophy (19%) and cerebellar hypersignal (6%). Cerebrospinal fluid was inflammatory in 64% of the patients. Oncological response was complete in 88%, but neurological prognosis was poor with only 41% of the patients presenting significant neurological improvement at the last follow up. Anti-Tr/DNER antibodies should be tested in rapid progressive cerebellar ataxia. Oncological response is excellent; however, many patients do not improve from their cerebellar ataxia.

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia.

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia.

A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM)

BackgroundAntibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. Trastuzumab that targets the human epidermal growth factor related receptor 2 (HER2) is one of the greatest success stories in this field. For decades, trastuzumab based treatment regimens are significantly improving the prognosis of HER2-positive breast cancer patients both in the metastatic and the (neo-) adjuvant setting. Nevertheless, ≥ 50% of trastuzumab treated patients experience de-novo or acquired resistance. Therefore, an enhanced anti-HER2 targeting with improved treatment efficiency is still aspired.MethodsHere, we determined cellular and molecular mechanisms involved in the treatment of HER2-positive BC cells with a new rabbit derived HER2 specific chimeric monoclonal antibody called “B100″. We evaluated the B100 treatment efficiency of HER2-positive BC cells with different sensitivity to trastuzumab both in vitro and in the presence of a human immune system in humanized tumor mice.ResultsB100 not only efficiently blocks cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed equivalent HER2 internalization and recycling capacity, similar Fc receptor signaling, but different HER2 epitope recognition with high binding and treatment efficiency. In trastuzumab resistant SK-BR-3 based humanized tumor mice the B100 treatment eliminated the primary tumor but even more importantly eradicated metastasized tumor cells in lung, liver, brain, and bone marrow.ConclusionOverall, B100 demonstrated an enhanced anti-tumor activity both in vitro and in an enhanced preclinical HTM in vivo model compared to trastuzumab or pertuzumab. Thus, the use of B100 is a promising option to complement and to enhance established treatment regimens for HER2-positive (breast) cancer and to overcome trastuzumab resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Inflammation biomarker discovery in Parkinson\u2019s disease and atypical parkinsonisms

BackgroundParkinson’s disease (PD) and atypical parkinsonisms (APD) have overlapping symptoms challenging an early diagnosis. Diagnostic accuracy is important because PD and APD have different prognosis and response to treatment. We aimed to identify diagnostic inflammatory biomarkers of PD and APD in cerebrospinal fluid (CSF) using the multiplex proximity extension assay (PEA) technology and to study possible correlations of biomarkers with disease progression.MethodsCSF from a longitudinal cohort study consisting of PD and APD patients (PD, n = 44; multiple system atrophy (MSA), n = 14; vascular parkinsonism (VaP), n = 9; and PD with VaP, n = 7) and controls (n = 25) were analyzed.ResultsConcentrations of CCL28 were elevated in PD compared to controls (p = 0.0001). Five other biomarkers differentiated both MSA and PD from controls (p < 0.05) and 10 biomarkers differentiated MSA from controls, of which two proteins, i.e. beta nerve growth factor (β-NGF) and Delta and Notch like epidermal growth factor-related receptor (DNER), were also present at lower levels in MSA compared to PD (both p = 0.032). Two biomarkers (MCP-1 and MMP-10) positively correlated with PD progression (rho > 0.650; p < 0.01).ConclusionsPEA technique identified potential new CSF biomarkers to help to predict the prognosis of PD. Also, we identified new candidate biomarkers to distinguish MSA from PD.

Delta/notch-like epidermal growth factor-related receptor promotes stemness to facilitate breast cancer progression

DNER, Delta/Notch-like epidermal growth factor (EGF)-related receptor, is a neuron-specific transmembrane protein carrying extracellular EGF-like repeats. The function of DNER in breast cancer has not been evaluated. The present study demonstrates that the expression of DNER in breast cancer tissue is significantly higher than its expression in breast benign disease and is associated with poor recurrence-free survival (RFS) of breast cancer patients. It demonstrated that DNER could enhance the proliferation and metastasis of breast cancer cells in vitro and significantly increases tumor growth in vivo. Our study uncovered that DNER can promote breast cancer cells proliferation and metastasis by activating Girdin/PI3K/AKT signaling and subsequently regulating several key genes involving the characters of cancer stem cells. Taken together, DNER promotes breast cancer growth and metastasis, which provided a theoretical basis for future applications of DNER inhibitors in the treatment of breast cancer.

Neurochondrin Antibody Serum Positivity in Three Cases of Autoimmune Cerebellar Ataxia

To report three cases of autoimmune ataxia patients with positive neurochondrin (NCDN) antibodies. Patients with unknown cerebellar ataxia were screened for autoimmune cerebellar ataxia (ACA)-related antibodies, including glutamic acid decarboxylase 65 (GAD65), delta/notch-like epidermal growth factor-related receptor (Tr/DNER), zinc finger protein 4 (ZIC4), inositol 1,4,5-triphosphate receptor 1 (ITPR1), Homer protein homologue 3 (Homer-3), neurochondrin (NCDN), Purkinje cell antibody 2 (PCA-2) and carbonic anhydrase-related protein VII (CARPVII). The antibodies were assessed by indirect immunofluorescence using transfected cells (cell-based assay, CBA) and monkey cerebellum (tissue-based assay, TBA) with the multi-antigen co-plate biochip mosaic technique. Patients with positive antibodies received immunotherapy and were followed up in the clinic. Clinical characteristics, laboratory data, and outcomes of antibody-positive patients were described, analysed and compared with previously reported cases. The NCDN antibody was positive in three male patients in whom the onset ages were four years and 11months, two years and seven months and 67years old. Serum antibody titres were 1:32, 1:100 and 1:320. Cerebral ataxia was the most prominent presentation. Cerebellar atrophy was found in one of the patients. Immunotherapy was effective in all three patients. The NCDN antibody is associated with autoimmune ataxia, and it has been suggested that the NCDN antibody should be tested in patients with cerebellar ataxia who are negative for routine ACA antibodies. Early immunotherapy may have a beneficial impact on prognosis.

Proximity extension assay testing reveals novel diagnostic biomarkers of atypical parkinsonian syndromes

ObjectiveThe high degree of clinical overlap between atypical parkinsonian syndromes (APS) and Parkinson’s disease (PD) makes diagnosis challenging. We aimed to identify novel diagnostic protein biomarkers of APS using multiplex...

General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort.

To investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator. This study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62-81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations. After a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor-related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker. General and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association.

DNER modulates the length, polarity and synaptogenesis of spiral ganglion neurons via the Notch signaling pathway.

The Delta/Notch-like epidermal growth factor-related receptor (DNER) serves an important role in the developing central nervous system. However, the actions of DNER in the development of the spiral ganglion in the inner ear have yet to be elucidated. Wild-type C57BL/6 mice were housed and time-mated for use in the present study. Primary neuronal cultures were prepared using spiral ganglion progenitors isolated from the modiolus of postnatal day 1 (P1) mice. DNER recombinant lentiviral vectors were constructed and transfected into the cultured primary neurons. The relative proportion of differentiated neurons and the length of their neurites were evaluated using microscopy. The results of the present study demonstrated that DNER was expressed in spiral ganglion neurons (SGNs) that exhibited significant polarity in the early differentiation stages; DNER expression gradually decreased until the polarity was lost on week 35. The in vitro expression of DNER was revealed to be similar to that in vivo. When DNER expression was silenced using RNA interference, the polarity of the differentiated neurons was altered and they exhibited significantly reduced dendritic length. In addition, the proportion of bipolar neurons was decreased compared with the control group. Furthermore, the expression of α-synuclein and the GluR2/3 subunits of the α-amin-o-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor were also reduced in cultured neurons in which DNER was silenced. Notch1 was co-expressed with DNER in SGNs isolated from P1 mice. The indirect Notch inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester also affected the polarity and the formation of protrusions, and reduced the expression of DNER and glial fibrillary acidic protein in SGNs. In conclusion, the present study demonstrated that DNER was expressed in SGNs and appeared to be involved in the mechanisms underlying neuronal polarity and neuritogenesis, via a Notch-dependent signaling pathway.

Microtubule-associated protein 1B: Novel paraneoplastic biomarker.

To report the identification of microtubule-associated protein (MAP) 1B as the antigen of the previously described Purkinje cell cytoplasmic antibody type 2 (PCA-2) antibody, its frequency, and clinical, oncological, and serological associations. Archival serum or cerebrospinal fluid (CSF) specimens were available from 96 of 118 consecutive PCA-2-IgG-seropositive patients identified during 1993-2016. The autoantigen, defined in mouse brain lysate by Western blot and mass spectrometry, was confirmed by dual immunohistochemical staining using commercial antibodies. The major antigenic region was defined by Western blot using recombinant protein fragments. IgG in 95 of 96 patients' serum or CSF (but in none of 98 healthy or disease control subjects' serum specimens) bound to recombinant MAP1B. A minority (17.5%) of patients' IgG also bound to MAP1A. PCA-2 was often accompanied by additional neural autoantibody markers of small-cell carcinoma, including collapsin response-mediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA-1) IgG (also known as anti-Hu; 13%). Neurological manifestations in 95 patients were (in decreasing frequency): peripheral neuropathy, 53%; cerebellar ataxia, dysmetria, or dysarthria, 38%; and encephalopathy, 27%. Cancer (majority small-cell lung carcinoma [SCLC]) was detected in 66 of 84 evaluated patients (79%). The MAP1B (PCA-2) autoantibody detection rate, among approximately 70,000 patients undergoing service neural autoantibody evaluation in 2015, was 0.024%, equaling amphiphysin IgG (0.026%) and more common than ANNA-2 (also known as anti-Ri; 0.016%) and PCA-Tr (also known as delta/notch-like epidermal growth factor-related receptor [DNER]; 0.006%). MAP1B, the PCA-2 autoantigen, represents a novel target in paraneoplastic neurological disorders and has high predictive value for SCLC. Its relatively high prevalence, compared with other recognized paraneoplastic neural autoantibodies, justifies its testing in comprehensive paraneoplastic neural autoantibody evaluation. Ann Neurol 2017;81:266-277.