The Role of Amphiregulin and Epidermal Growth Factor Receptor in First-Episode Psychosis: Exploring Links to Schizophrenia Pathophysiology.

Purpose Preeclampsia is a form of hypertensive disorders of pregnancy and defined as the presence of new-onset hypertension and proteinuria or other end organ damage occurring after 20-week gestation. Preeclampsia can be a destructive process that can cause maternal and infant mortality. The exact etiopathogenesis of preeclampsia is still undefined. We aimed to compare serum amphiregulin and cerebellin-1 levels of severe preeclampsia patients with healthy pregnant women and healthy control subjects. Materials and methods A total of 88 women were enrolled in this study. Patients diagnosed with severe preeclampsia were group 1 (n = 28), healthy non-pregnant normotensive women group 2 (n = 30), and healthy pregnant women group 3 (n = 30). The participants in each group were matched for age. Pregnant women in groups 1 and 3 were also matched for gestational age. Serum amphiregulin and cerebellin-1 levels were measured using ELISA. Results Serum amphiregulin levels were 3413 ± 1.38 ng/ml (1748–7739), 8510 ± 7213 ng/ml (2019–24,000), and 6580 ± 5360 ng/ml (2484–24,000) in preeclampsia patients, controls and healthy pregnant women, respectively. Amphiregulin levels were significantly lower in preeclampsia patients than healthy pregnant women (p=.008) and controls (p = .015). Amphiregulin levels were similar between healthy controls and healthy pregnant women (p = 1.00). Cerebellin-1 levels were 222.039 ± 92.681 pg/ml (138,580–557,757) in preeclamptic patients, 537.043 ± 525.117 pg/ml (150,432–1,600,000) in controls and 415.091 ± 436.580 pg/ml (137,284–1,600,000) in healthy pregnant women. Cerebellin-1 levels were similar among groups (p = .272). Serum amphiregulin and cerebellin-1 levels were significantly and positively correlated with each other in preeclampsia patients (r = 0.693, p < .001), controls (r = 0.882, p < .001), and healthy pregnant women (r = 0.591, p = .001). Serum level of amphiregulin ≤3590 pg/ml had a sensitivity of 67.9% and specificity of 63.3% in the diagnosis of preeclampsia (AUC: 0.751; p = .001). Conclusions Serum amphiregulin decreases in severe preeclampsia patients.

It has been emphasized for a long time that neurodevelopmental and neurodegenerative processes play an important role in the etiology of schizophrenia. In this study, brain magnetic resonance imaging (MRI) of 97 patients with schizophrenia (SCH), 42 first-episode psychosis (FEP) patients, and 70 healthy controls (HC) were analyzed, and abnormal findings on brain MRI were recorded. Participant's age, gender, and brain MRI findings were recorded retrospectively. Fazekas grades evaluated the distribution of white matter hyperintensities in the brain. The mean ages of FEP, SCH, and HC were 24.8±6.3, 36.9±11.5, and 36±10.5, respectively. Generalized cerebral atrophy was higher in SCH and HC than in FEP groups, and frontoparietal atrophy was higher in the SCH group than in HC and FEP groups (p<0.001). The percentage of Fazekas Grade-1 was higher in the SCH group than HC and FEP groups (p=0.006). Additionally, the cavum veli interpositi (CVI) rate was higher in FEP and SCH groups than in the HC group (p=0.042). Although there was no significant age difference between the SCH and HC groups, the higher prevalence of generalized cerebral atrophy in the SCH group may indicate the neurodegenerative process of schizophrenia. The fact that CVI, a congenital brain anomaly, was detected more frequently in the FEP and SCH groups may suggest that schizophrenia may be associated with neurodevelopmental process.

Objective To explore the diagnosis and prognosis effect of the serum vascular endothelial growth factor,platelet-derived growth factor and epidermal growth factor receptor in non-small cell lung cancer(NSCLC).Methods The sandwich enzyme-linked immunoabsorbent assay was used to detect serum VEGF,PDGF and EGFR in patients with NSCLC.Results Compared with healthy control group,the levels of serum VEGF.PDGF and EGFR in NSCLC patients were much higher.The serum VEGF,PDGF and EGFR levels were not correlated with pathological style.The serum VEGF,PDGF and EGFR levels in metastasis group were higher than those in group without metastasis.The serum VEGF level was positively correlated with the serum PDGF level and EGFR level.Conclusions The detection of serum VEGF and PDGF has very important value in estimating NSCLC diagnosis and prognosis. Key words: Vascular endothelial growth factor; Platelet-derived growth factor; Epidermal growth factor receptor:Non-small cell lung cancer

The association between cognitive deficits and depressive symptoms in at-risk mental state: A comparison with first-episode psychosis

Emotional recognition during the course of schizophrenia

Objective This study is aimed at investigating the clinical intervention effect of afatinib targeted therapy in patients with non-small-cell lung cancer. Methods The research object was a retrospective analysis of 86 patients with non-small-cell lung cancer who were admitted to our hospital from 1st January 2019 to 31st December 2021. The patients were divided into two groups. The patients in the two groups received conventional chemotherapy intervention, and the patients in group B received afatinib targeted therapy intervention on the basis of the treatment in group A. The clinical intervention effect, immune function, serum EGFR level, serum pro-GRP level, and incidence of adverse reactions were compared between the two groups of patients. Results After afatinib targeted therapy intervention, the total intervention effective rate of patients in treatment group B was significantly higher than that in patients in treatment group A. Compared with the treatment group A, the CD3+, CD4+, CD8+, and CD4+/CD8+ of the treatment group were significantly upregulated. After the intervention, the serum EGFR levels of patients in treatment groups A and B were significantly decreased, and the serum EGFR levels in patients in treatment group B were significantly lower than those in patients in treatment group A. The serum pro-GRP level in group B patients was significantly decreased. The overall incidence of adverse reactions in treatment group B was significantly lower than that in treatment group A. Conclusion Afatinib targeted therapy has a significant clinical intervention effect on patients with non-small-cell lung cancer, which not only helps to improve the immune function of patients but also effectively improves the serum EGFR and pro-GRP levels of patients.

Hallucinations are considered one of the primary symptoms of psychosis; however, their neural basis remains unclear. Voxel-based morphometry (VBM)1 studies have associated hallucinations with gray matter (GM) volume reduction in the superior temporal gyrus in schizophrenia.2 Although hallucinations are associated with brain connectivity,3 few studies have investigated their relationship with white matter (WM) volume. Moreover, these studies have shown inconsistent results.4, 5 The chronicity of illness and long-term medications for schizophrenia may limit the interpretation of previous findings.2 Thus, hallucination studies in clinical high risk for psychosis (CHR) and first-episode psychosis (FEP) are required, with minimal effects of chronicity of illness and medication. However, no VBM study has examined the relationship between hallucinations and WM volume in CHR and FEP. Therefore, we aimed to investigate the regional GM and WM volumes associated with hallucinations in CHR and FEP. We enrolled 57 individuals with CHR, 50 individuals with FEP, and 33 healthy controls (HCs). The Comprehensive Assessment of At-Risk Mental States-Japanese version6 was used to confirm whether ultra-high risk criteria7 were met. Table S1 summarizes the demographic and clinical data of the patients. Hallucination severity was assessed using the Positive and Negative Syndrome Scale (PANSS)8 P3 score. Fig. S1 shows the distribution of the severity of hallucinations. Some of those with a PANSS P3 score of 3 or higher were classified as having CHR because of the low frequency and duration of hallucinations. Magnetic resonance imaging (MRI) data were acquired with a 1.5-T Philips scanner. We examined the association of GM and WM volume with hallucination severity in the group that combined patients with CHR and FEP (CHR/FEP combined group) and performed group comparisons of GM and WM volume between the CHR/FEP combined and HC groups. Age, sex, and intracranial volume were entered as nuisance covariates for each analysis. VBM analysis was conducted using DARTEL9 in SPM12 (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/) with standard smoothing of 8-mm full width at half maximum (FWHM). The initial statistical threshold was set at P < 0.001, uncorrected at the voxel level. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by SPM. Familywise error (FWE) correction at the cluster level (P < 0.05) was applied to identify significant clusters. Appendix S1 provides detailed information on these methods. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tohoku University Graduate School of Medicine and Tohoku University Hospital. Written informed consent was obtained from participants aged 18 years or older and from the parents of those under 18 years of age, with written assent from the participants. The anonymity of participants was preserved. WM volume was not significantly correlated with hallucination severity in the CHR/FEP combined group after FWE correction at the cluster level. Reanalysis with 15-mm or 20-mm FWHM filtering did not show significant associations. Additionally, there was no significant difference in the GM and WM volumes between the CHR/FEP combined and HC groups. No regional GM volume abnormalities were significantly correlated with hallucination severity in the CHR/FEP combined group. Appendix S1, Figs. S2–S5, and Tables S2–S5 provide uncorrected results and detailed information regarding these results. To the best of our knowledge, this is the first VBM study to investigate WM volume related to hallucinations in CHR and FEP. We found no significant correlation between WM volume and hallucination severity. In contrast to previous studies in schizophrenia,2, 4, 5 this study examined the brain volume association of hallucinations in CHR and FEP. CHR and FEP are heterogeneous groups in the early stages of mental illness and do not necessarily convert to schizophrenia. Our results indicate that brain disturbances involved in hallucinations in CHR and FEP may be more subtle and/or inconsistent with those in schizophrenia. Diffusion tensor imaging, a neuroimaging method applied to CHR,10 may be suitable for examining structural abnormalities in the development of hallucinations. This study has some limitations. First, information regarding hallucinations is not detailed. Second, the cross-sectional design limited the interpretation of our findings. Third, we used an MRI scanner with a lower field strength than that of recent studies.4 Fourth, there were significant age differences between the groups. Fifth, automatic quality assurance for MRI scans was not performed. In conclusion, advanced neuroimaging studies are needed to reveal the mechanism of hallucinations. This work was supported by JSPS KAKENHI (grant number 18K07586). We thank the participants, staff of the SAFE clinic, and radiological technologists. The authors declare no conflicts of interest. Appendix S1. Supporting information Figure S1. Distribution of hallucination severity. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; PANSS, Positive and Negative Syndrome Scale. Figure S2. Brain regions with lower gray matter volume in the CHR/FEP group compared to the HC group. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 117 based on the expected number of voxels per cluster provided by SPM. The full width at half maximum was set to 8-mm. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; SPM, Statistical Parametric Mapping Figure S3. Brain regions with lower white matter volume in the CHR/FEP group compared to the HC group. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 129 based on the expected number of voxels per cluster provided by SPM. The full width at half maximum was set to 8-mm. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; SPM, Statistical Parametric Mapping Figure S4. Positive correlation between gray matter volume and hallucination severity in the patients at clinical high risk for psychosis. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 101 based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. SPM, Statistical Parametric Mapping Figure S5. Negative correlation between white matter volume and hallucination severity in the patients at clinical high risk for psychosis. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 121 based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. SPM, Statistical Parametric Mapping Table S1. Demographic and clinical characteristics of the participants. †Educational level, CP-equivalent dose on MRI scan, PANSS positive, PANSS negative, PANSS general, PANSS total, PANSS P3: hallucinatory behavior, and days from enrollment to MRI scan were analyzed using the t-test. Age and intracranial volume were analyzed using one-way analysis of variance. Sex and antipsychotic use were analyzed using the chi-squared test. Significant results are shown in bold. CHR, clinical high risk for psychosis; CP-equivalent, chlorpromazine equivalent; FEP, first-episode psychosis; HC, healthy controls; PANSS, Positive and Negative Syndrome Scale. Table S2. Between-group comparison of regional gray matter volume. CHR/FEP < HC (extent threshold: 117 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S3. Between group comparison of regional white matter volume. CHR/FEP < HC (extent threshold: 129 voxels). † Uncorrected P-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S4. Correlation between gray matter volume and hallucination severity in the patients with CHR. Positive correlation (extent threshold: 101 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S5. Correlation between white matter volume and hallucination severity in the patients with CHR. Negative correlation (extent threshold: 121 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Epidermal growth factor receptor (EGFR, HER-1, and erbB1) is overexpressed in primary breast cancer and had been identified as a poor prognostic factor. Pretreatment serum EGFR levels were quantified by using an enzyme-linked immunoadsorbent assay in a Phase III first-line trial of letrozole and tamoxifen and were correlated with patient outcomes. Serum EGFR levels in a control group of 117 healthy, postmenopausal women measured 64.1 +/- 13.3 ng/mL (mean +/- standard deviation). Using a cutoff EGFR level of 44.1 ng/mL from the control group (5% nonparametric method), 53 of 535 patients (10%) had decreased serum levels of EGFR. Patients with decreased serum EGFR had no significant difference in objective response rate (ORR), clinical benefit rate (CBR), time to progression (TTP), or time to treatment failure (TTF); however, they did have significantly reduced survival compared with patients who had normal serum EGFR levels (median survival, 23.3 months vs. 30.9 months; P = .007). A combined analysis of pretreatment serum EGFR and HER-2 yielded no additional predictive information for ORR, CBR, TTP, or TTF compared to serum HER-2 alone. However, in the current analysis, a subgroup of patients who had decreased serum EGFR and normal serum HER-2 was identified (n = 39 of 535 patients; 7.3%) that had significantly reduced survival compared with patients who had normal serum levels of both EGFR and HER-2 (median survival, 23.5 months vs. 37.1 months; P = .005). In multivariate analysis, a decreased serum EGFR level remained a significant independent prognostic factor for decreased survival (hazards ratio, 1.58; P = .007). In patients who had metastatic breast cancer, decreased serum EGFR/normal serum HER-2 predicted shorter survival compared with patients who had normal levels of serum EGFR/HER-2. This patient subgroup deserves further study to assess their response to and selection for anti-EGFR-directed therapies.

2 Mitochondrial tumour suppressors: a genetic and biochemical link between metabolism and cancer

Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells

Brain-derived neurotropic factor (BDNF) is known to play a role in the pathogenesis of schizophrenia. However, the relationship between early onset schizophrenia and BDNF has not been extensively studied. The aim of the study was to compare the levels of BDNF between adolescent patients with first-episode psychosis (FEP) and the healthy control subjects. The study was conducted in the Department of Child Psychiatry at Dicle University. A total of 26 adolescent patients aged between 11 and 17 years who had not received previous therapy and whose conditions were diagnosed with psychosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and 26 age- and sex-matched healthy adolescent control subjects were included. Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version, and the Positive and Negative Symptom Scale were conducted with all participants. The clinical global impression was used to evaluate disease severity. The BDNF levels were measured in the serum by enzyme-linked immunosorbent assay method. The mean (SD) age was 14.6 (1.6) years in both FEP group (male/female, 11/15) and the control group (P > 0.05). The FEP group had significantly lower serum BDNF levels (2.0 ± 1.9 ng/mL) compared with the control group (3.4 ± 3.0 ng/mL, P = 0.03). There was no significant relationship between BDNF concentration and the Positive and Negative Symptom Scale (positive and negative scores) scores (r = -0.14, P = 0.74 and r = 0.49, P = 0.22, respectively). There was no significant relationship between the duration of untreated psychosis and serum BDNF levels (r = -0.22, P = 0.32). High incidence of schizophrenia in patients with FEP suggests a relationship between BDNF levels and the pathogenesis of schizophrenia. We suggest that BDNF may be a useful neurobiological marker of early onset schizophrenia.

Investigating the correlation of the number of diagnostic criteria to serum adiponectin, leptin, resistin, TNF-alpha, EGFR levels and abdominal adipose tissue

Proteomic profiling in the progression of psychosis: Analysis of clinical high-risk, first episode psychosis, and healthy controls

Amphiregulin (AREG) is a ligand of epidermal growth factor receptor (EGFR), which plays an important role in injury-induced kidney fibrosis. However, the clinical significance of serum soluble AREG in chronic kidney disease (CKD) is unclear. In this study, we elucidated the clinical significance of serum soluble AREG in CKD by analyzing the association of serum soluble AREG levels with renal function and other clinical parameters in patients with CKD. In total, 418 Japanese patients with CKD were enrolled, and serum samples were collected for the determination of soluble AREG and creatinine (Cr) levels, and other clinical parameters. Additionally, these parameters were evaluated after 2 and 3years. Moreover, immunohistochemical assay was performed ate AREG expression in the kidney tissues of patients with CKD. Soluble AREG levels were positively correlated with serum Cr (p < 0.0001). Notably, initial AREG levels were positively correlated with changes in renal function (ΔCr) after 2 (p < 0.0001) and 3years (P = 0.048). Additionally, soluble AREG levels were significantly higher (p < 0.05) in patients with diabetic nephropathy or primary hypertension. Moreover, AREG was highly expressed in renal tubular cells in patients with advanced CKD, but only weakly expressed in patients with preserved renal function. Serum soluble AREG levels were significantly correlated with renal function, and changes in renal function after 2 and 3years, indicating that serum soluble AREG levels might serve as a biomarker of renal function and renal prognosis in CKD.

Background: It is well documented that the hippocampal volume is reduced in schizophrenia. Latest studies suggest that the reduction is more robust in certain hippocampal subfields in patients with chronic schizophrenia. It remains unclear whether these differences are already present during first-episode of psychosis.Furthermore, the clinical correlates of these brain abnormalities have remained elusive. Since impaired glucose tolerance has known detrimental effect on the central nervous system, we tested if glucose metabolism could underlie the changes seen in the hippocampus. Methods: We recruited 58 first-episode psychosis (FEP) patients and 54 matched randomly selected general population controls. Patient sample included both non-affective and affective psychoses (DSM-IV). Hippocampal subfield volumes were measured using a novel segmentation protocol in FreeSurfer6. A general linear model was used to test for group differences in hippocampal subfield volumes. All tests were corrected for age, sex, body mass index, and total intracranial volume, and test within the FEP group were also corrected for antipsychotic medication. After excluding subjects with diabetes, we tested associations between fasting glucose (<6.2 mmol/l), insulin, HOMA-index, clinical symptoms, and the subfield volumes. Results: We found that several hippocampal subfields (ROI) were significantly smaller in FEP than in controls (ROI × Group P = .010, Partial η2 .039). In FEP patients particularly molecular layer (P = .001, left β = −38.95, right β = −27.81), subiculum (P = .028, left β = −19.71, right β = −13.35), CA1 (P = .016, left β = −29.73, right β = −28.58) and presubiculum (P = .004, left β = −14.01, right β = −13.92) were smaller than in the controls.Blood fasting glucose-dependent group interaction was found between FEP and control group (Group × Glucose P = .038). Glucose correlated positively with hippocampal volumes in the controls but not in the FEP. In FEP group, fasting glucose levels correlated negatively with volumes in right subiculum (P = .033, β = −25.13), left presubiculum (P = .004, β = −29.31) and right presubiculum (P = .038, β = −21.04). Cognitive tests or symptom severity were not associated with the hippocampal subfield volumes. Conclusion: We showed that hippocampal subregions are differently affected already in the first episode of psychosis. We found that several hippocampal subfields were differently associated with blood glucose levels in FEP and control group. The findings do not provide evidence for causal relationships but suggest that hippocampal subregions are differently involved in the regulation of glucose metabolism in FEP and control group. The results suggest FEP patients are susceptible to the negative effects of impaired glucose metabolism.