Effects of inflammation, childhood adversity, and psychiatric symptoms on brain morphometrical phenotypes in bipolar II depression.

BACKGROUND: The neuroanatomical alteration in bipolar II depression (BDII-D) and its associations with inflammation, childhood adversity, and psychiatric symptoms are currently unclear. We hypothesize that neuroanatomical deficits will be related to higher inflammation, greater childhood adversity, and worse psychiatric symptoms in BDII-D. METHODS: Voxel- and surface-based morphometry was performed using the CAT toolbox in 150 BDII-D patients and 155 healthy controls (HCs). Partial Pearson correlations followed by multiple comparison correction was used to indicate significant relationships between neuroanatomy and inflammation, childhood adversity, and psychiatric symptoms. RESULTS: Compared with HCs, the BDII-D group demonstrated significantly smaller gray matter volumes (GMVs) in frontostriatal and fronto-cerebellar area, insula, rectus, and temporal gyrus, while significantly thinner cortices were found in frontal and temporal areas. In BDII-D, smaller GMV in the right middle frontal gyrus (MFG) was correlated with greater sexual abuse (r = -0.348, q < 0.001) while larger GMV in the right orbital MFG was correlated with greater physical neglect (r = 0.254, q = 0.03). Higher WBC count (r = -0.227, q = 0.015) and IL-6 levels (r = -0.266, q = 0.015) was associated with smaller GMVs in fronto-cerebellar area in BDII-D. Greater positive symptoms was correlated with larger GMVs of the left middle temporal pole (r = 0.245, q = 0.03). CONCLUSIONS: Neuroanatomical alterations in frontostriatal and fronto-cerebellar area, insula, rectus, temporal gyrus volumes, and frontal-temporal thickness may reflect a core pathophysiological mechanism of BDII-D, which are related to inflammation, trauma, and psychiatric symptoms in BDII-D.

Interleukin-1ß moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression.

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1ß. Moreover, IL-1ß moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1ß may moderate the relationship between MFG-related connectivity and depressive symptoms.

Brain-derived subgroups of bipolar II depression associate with inflammation and choroid plexus morphology.

AIM: Elevated inflammation and larger choroid plexus (ChP) volume has been previously identified in mood disorders. Connections between inflammation, ChP, and clinical symptoms in bipolar II depression (BDII-D) are unclear. Data-driven clustering based on neuroanatomical phenotypes may help to elucidate neurobiological associations in BDII-D. METHODS: Inflammatory cytokines, clinical symptoms, and neuroanatomical features were assessed in 150 BDII-D patients. Sixty-eight cortical surface area (SA) and 19 subcortical volumes were extracted using FreeSurfer. The ChP volume was segmented manually using 3D Slicer. Regularized canonical correlation analysis was used to identify significantly correlated components between cortical SA and subcortical volumes (excluding the ChP), followed by k-means clustering to define brain-derived subgroups of BDII-D. Low-grade inflammation was derived by averaging the standardized z scores of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), which were computed to create a composite z-value score. Partial Pearson correlations followed by multiple comparison correction were conducted to explore associations between inflammation, clinical symptoms, and ChP volume. RESULTS: Subgroup I demonstrated smaller subcortical volume and cortical SA, higher inflammation, and larger ChP volume compared with subgroup II. Greater ChP volume was associated with a higher low-grade inflammation (mean r = 0.289, q = 0.003), CRP (mean r = 0.249, q = 0.007), IL-6 (left r = 0.200, q = 0.03), and TNF-α (right r = 0.226, q = 0.01), while greater IL-1ß was significantly associated with severe depressive symptoms in BDII-D (r = 0.218, q = 0.045). CONCLUSIONS: Neuroanatomically-derived subgroups of BDII-D differed in their inflammation levels and ChP volume. These findings suggest an important role of elevated peripheral inflammation and larger ChP in BDII-D.

Impact of marital status at diagnosis on the survival of patients with anal canal squamous cell carcinoma: a propensity score-matched analysis.

PURPOSE: Marital status has been shown to be an important psychosocial factor that plays an important role in the prognosis of various cancers. The effect of marital status on survival outcomes in anal canal squamous cell carcinoma has not been studied. The purpose of this study was to address this issue. METHODS: According to the established screening criteria, we obtained 2429 patients with anal canal squamous cell carcinoma from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and multivariate Cox regression analysis were used to analyze the survival of anal canal squamous cell carcinoma patients with different marital status. 1:1 propensity score matching (PSM) was used to match 979 unmarried patients with 979 married patients to further demonstrate the effect of marital status on the survival of patients with anal canal squamous cell carcinoma. RESULTS: The 5-year overall survival (OS) rates of married, divorced/separated, single, and widowed patients with anal canal squamous cell carcinoma were 75.6%, 69.7%, 62.2%, and 51.3%, respectively and the corresponding 5-year cancer-specific survival (CSS) rates were 80.7%, 79.6%, 70.1%, and 68.9%, respectively. Multivariate Cox regression analysis showed that marital status, sex, race, SEER stage, tumor size, regional nodes positive, primary site surgery, chemotherapy, and radiotherapy were independent prognostic factors for OS and CSS, and also demonstrated that the widowed patients suffered the highest risk mortality. Furthermore, married patients were found to have better OS and CSS than unmarried patients both before and after propensity score matching. CONCLUSION: This study found that married patients with anal canal squamous cell carcinoma had better survival outcomes, while widowed patients had the worst OS and CSS.

Common and distinct patterns of gray matter alterations in young adults with borderline personality disorder and major depressive disorder.

Young adults with borderline personality disorder (BPD) and major depressive disorder (MDD) have a relatively high comorbidity rate; however, whether they share a neurobiological basis remains controversial. Although previous studies have reported respective brain alterations, the common and distinct gray matter changes between two disorders are still inconsistent. We conducted a meta-analysis using anisotropic effect size-based algorithms (ASE-SDM) to identify consistent findings from whole-brain voxel-based morphometry (VBM) studies of gray matter volume (GMV) in 274 young adults (< 45 years old) with BPD and 1576 with MDD. Compared with healthy controls, the young adults with BPD showed GMV reduction mainly in the prefrontal cortex including the inferior frontal gyrus and superior frontal gyrus, medial temporal network, and insula, whereas the MDD showed GMV alteration in the visual network (fusiform gyrus and inferior temporal gyrus), sensorimotor network (bilateral postcentral gyrus (PoCG) and right cerebellum) and left caudate nucleus. The GMV differences between these two disorders were concentrated in the left orbitofrontal cortex, cingulate cortex, right insula, and cerebellum. The meta-regression of the MDD group showed a negative association between disease duration and the right middle cingulate gyrus as well as negative associations between depressive symptoms and brain regions of the right cerebellum and the left PoCG. Our results identified common and distinct patterns of GMV alteration between BPD and MDD, which may provide neuroimage evidence for the disorder comorbidity mechanisms and partly indicate the similar and different biological features in emotion regulation of the two disorders. This study was registered with PROSPERO (CRD42020212758).

Circular RNA hsa_circ_0053277 promotes the development of colorectal cancer by upregulating matrix metallopeptidase 14 via miR-2467-3p sequestration.

Colorectal cancer (CRC), a kind of human gastrointestinal cancer, has been reported to be one of the most common malignant tumors worldwide. Increasing evidence has indicated that circular RNAs exert significant effects on the development of multiple cancers. Nevertheless, whether hsa_circ_0053277 regulates the progression of CRC remains to be explored. In this study, our results showed that the expression of hsa_circ_0053277 was markedly upregulated in CRC tissues and cells. Knockdown of hsa_circ_0053277 inhibited cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process in CRC. miR-2467-3p had a binding site for hsa_circ_0053277. Molecular mechanism assays confirmed that hsa_circ_0053277 could bind with miR-2467-3p. In addition, hsa_circ_0053277 accelerated cell proliferation rate by acting as a sponge for miR-2467-3p in CRC. Matrix metalloproteinase 14 (MMP14) expression was notably upregulated in CRC cells and MMP14 was a downstream target gene of miR-2467-3p. Besides, hsa_circ_0053277 positively regulated MMP14 expression while miR-2467-3p negatively regulated MMP14 expression. Rescue assays verified that MMP14 knockdown countervailed the function of miR-2467-3p inhibitor on cell proliferation, migration, and EMT process in CRC. To sum up, hsa_circ_0053277 facilitated the development of CRC by sponging miR-2467-3p to upregulate MMP14 expression.

Long noncoding RNA HOTAIR knockdown inhibits autophagy and epithelial-mesenchymal transition through the Wnt signaling pathway in radioresistant human cervical cancer HeLa cells.

Cervical cancer is one of the most common female malignancies around the world, and radiation resistance is a major obstacle to cancer therapy. Previously, overexpression of the long noncoding ribonucleic acid (RNA) (lncRNA) HOX transcript antisense RNA (HOTAIR) has been found to be associated with the invasion and metastasis capacities of several epithelial cancers, including cervical cancer. To gain insights into the molecular mechanisms of HOTAIR in cervical cancer resistance to radiotherapy, we investigated cellular autophagy and epithelial-to-mesenchymal transition (EMT) in radioresistant human cervical cancer HeLa cells when HOTAIR was suppressed. HOTAIR levels were quantified in cancerous and noncancerous cervical tissues obtained from 108 patients with cervical cancer. Next, we inhibited HOTAIR by RNA interference and activated the Wnt signaling pathway by LiCl in radioresistant HeLa cells to investigate the regulatory mechanisms for the HOTAIR mediating Wnt signaling pathway. We determined that the upregulated HOTAIR may contribute to cervical cancer progression. We found that the short interfering ribonucleic acid (siRNA)-mediated knockdown of HOTAIR disturbed the Wnt signaling pathway, reduced autophagy, inhibited EMT, decreased cell proliferation, and induced apoptosis in radioresistant HeLa cells. It is worthy to note that the combination treatment of siRNA-HOTAIR and LiCl demonstrated that the activation of the Wnt signaling pathway is responsible for the beneficial effect of HOTAIR knockdown in enhancing sensitivity to radiotherapy in radioresistant HeLa cells. Together, our results revealed an important role of HOTAIR in regulating cervical cancer resistance to radiotherapy. Functional suppression of HOTAIR could enhance sensitivity to radiotherapy by reduction of autophagy and reversal of EMT through the suppression of the Wnt signaling pathway.

Mismatch repair gene MSH6 correlates with the prognosis, immune status and immune checkpoint inhibitors response of endometrial cancer.

Objective: Many patients treated with immune checkpoint inhibitors (ICIs) developed primary or secondary drug resistance for unknown reasons. This study investigates whether mismatch repair (MMR) genes are responsible for this therapeutic restriction. Methods: We obtained the transcriptional, clinical and single nucleotide polymorphism data for endometrial cancer (EC) from The Cancer Genome Atlas and the immunophenoscore data of EC from The Cancer Immunome Atlas, then analyzed in R to evaluate the relationship between MMR genes and clinicopathological features, prognosis, immune infiltration, immune checkpoint expression and responsiveness to ICIs in EC. We used differentially expressed genes in the MSH6 high and low expression groups to conduct GO and KEGG analyses to explore the impact of MSH6 on the biological functions of EC. Finally, we verified the bioinformatics results with in vitro experiments. Results: Our analyses showed that compared with the high MSH6 expression group, the low MSH6 expression group had better survival outcomes and less aggressive clinicopathological features. In the multivariate Cox analysis, MSH6 was the only independent risk factor that could predict the prognosis of EC. Besides, the low MSH6 expression group also had a higher immune score, more active immune infiltration and higher immune checkpoint expression, resulting in better responsiveness to ICIs treatment, consistent with the enrichment of GO terms and KEGG pathways related to immune response in this group. Meanwhile, the GO and KEGG enrichment results of the MSH6 high expression group were associated with cell cycle, DNA damage repair and tumorigenesis. To exclude the influence of MSH6 mutations, we performed the previous analyses on the MSH6 wild-type tumor samples and obtained consistent results. In vitro experiments also confirmed that after knocking down MSH6 in endometrial cancer cells, their proliferation, migration and invasion abilities were weakened, while the expression levels of PD-L1 and PD-L2 were elevated. In comparison, overexpression of MSH6 showed an opposite trend. Conclusion: Reduced MSH6 expression could serve as a potential biomarker for predicting better prognosis, active immune status, higher immune checkpoint expression level and better responsiveness to ICIs treatment in EC. MSH6 may become a potential target for treating solid tumors.

Non-invasive brain stimulation for treating catatonia: a systematic review.

Background: Non-invasive brain stimulation (NIBS) techniques offer new therapeutic options for modifying pathological neuroplasticity and have been proven to be beneficial in the treatment of neuropsychiatric disorders. Objective: This study aimed to investigate the role of NIBS in treating catatonia. Materials and methods: We conducted a systematic search to identify meta-analyses or systematic reviews on electroconvulsive therapy (ECT) and studies on the effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on patients with catatonia from the PubMed, Web of Science, Embase, China National Knowledge Internet, Wanfang, and China Science and Technology Journal databases from inception until 31 July 2022. The methodological quality of the included studies was assessed with the AMSTAR2 or Joanna Briggs Institute Critical Appraisal tools. Paired t-tests and Wilcoxon signed-rank tests were used to compare changes in catatonia symptom scores after rTMS or tDCS. Results: A total of 13 systematic reviews and one meta-analysis on ECT, two systematic reviews and 12 case reports on rTMS, and seven studies of 14 cases applying tDCS were identified. Systematic reviews of ECT consistently described improvement in catatonia symptoms across catatonia types and patient age groups. After treatment with rTMS (t = 4.489, p = 0.006) and tDCS (z = -3.065, p = 0.002), patients exhibited significant improvement. Conclusion: ECT, rTMS, and tDCS were effective in treating catatonia. Early intervention with NIBS techniques may help improve catatonia symptoms in patients with schizophrenia. It may be advantageous to use rTMS or tDCS to maintain this improvement. NIBS techniques may thus represent a promising treatment for catatonia, but additional high-quality randomized controlled trials are needed.

A comparative study of gray matter volumetric alterations in adults with attention deficit hyperactivity disorder and bipolar disorder type I.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and bipolar disorder type I (BD-Ι) share great overlapping symptoms and are highly comorbid. We aimed to compare and obtain the common and distinct gray matter volume (GMV) patterns in adult patients. METHOD: We searched four databases to include whole-brain voxel-based morphometry studies and compared the GMV patterns between ADHD and healthy controls (HCs), between BD-I and HCs, and between ADHD and BD-I using anisotropic effect-size signed differential mapping software. RESULTS: We included 677 ADHD and 452 BD-Ι patients. Compared with HCs, ADHD patients showed smaller GMV in the anterior cingulate cortex (ACC) and supramarginal gyrus but a larger caudate nucleus. Compared with HCs, BD-Ι patients showed smaller GMV in the orbitofrontal cortex, parahippocampal gyrus, and amygdala. No common GMV alterations were found, whereas ADHD showed the smaller ACC and larger amygdala relative to BD-Ι. Subgroup analyses revealed the larger insula in manic patients, which was positively associated with the Young Mania Rating Scale. The decreased median cingulate cortex (MCC) was positively associated with the ages in ADHD, whereas the MCC was negatively associated with the ages in BD-Ι. LIMITATIONS: All included data were cross-sectional; Potential effects of medication and disease course were not analyzed due to the limited data. CONCLUSIONS: ADHD showed altered GMV in the frontal-striatal frontal-parietal circuits, and BD-Ι showed altered GMV in the prefrontal-amygdala circuit. These findings could contribute to a better understanding of the neuropathology of the two disorders.

Vascular Normalization: A New Window Opened for Cancer Therapies.

Preclinical and clinical antiangiogenic approaches, with multiple side effects such as resistance, have not been proved to be very successful in treating tumor blood vessels which are important targets for tumor therapy. Meanwhile, restoring aberrant tumor blood vessels, known as tumor vascular normalization, has been shown not only capable of reducing tumor invasion and metastasis but also of enhancing the effectiveness of chemotherapy, radiation therapy, and immunotherapy. In addition to the introduction of such methods of promoting tumor vascular normalization such as maintaining the balance between proangiogenic and antiangiogenic factors and targeting endothelial cell metabolism, microRNAs, and the extracellular matrix, the latest molecular mechanisms and the potential connections between them were primarily explored. In particular, the immunotherapy-induced normalization of blood vessels further promotes infiltration of immune effector cells, which in turn improves immunotherapy, thus forming an enhanced loop. Thus, immunotherapy in combination with antiangiogenic agents is recommended. Finally, we introduce the imaging technologies and serum markers, which can be used to determine the window for tumor vascular normalization.

Dysfunction of Resting-State Functional Connectivity of Amygdala Subregions in Drug-Naïve Patients With Generalized Anxiety Disorder.

Objective: Although previous studies have reported on disrupted amygdala subregional functional connectivity in generalized anxiety disorder (GAD), most of these studies were conducted in GAD patients with comorbidities or with drug treatment. Besides, whether/how the amygdala subregional functional networks were associated with state and trait anxiety is still largely unknown. Methods: Resting-state functional connectivity of amygdala subregions, including basolateral amygdala (BLA) and centromedial amygdala (CMA) as seed, were mapped and compared between 37 drug-naïve, non-comorbidity GAD patients and 31 age- and sex-matched healthy controls (HCs). Relationships between amygdala subregional network dysfunctions and state/trait anxiety were examined using partial correlation analyses. Results: Relative to HCs, GAD patients showed weaker functional connectivity of the left BLA with anterior cingulate/medial prefrontal cortices. Significantly increased functional connectivity of right BLA and CMA with superior temporal gyrus and insula were also identified in GAD patients. Furthermore, these functional connectivities showed correlations with state and trait anxiety scores. Conclusions: These findings revealed abnormal functional coupling of amygdala subregions in GAD patients with regions involved in fear processing and emotion regulation, including anterior cingulate/medial prefrontal cortex and superior temporal gyrus, which provide the unique biological markers for GAD and facilitating the future accurate clinical diagnosis and target treatment.

Functional connectivity of the hippocampus in predicting early antidepressant efficacy in patients with major depressive disorder.

BAKGROUD: The hippocampus is involved in the pathophysiology of major depressive disorder (MDD), and its structure and function have been reported to be related to the antidepressant response. This study aimed to identify relationships between hippocampal functional connectivity (FC) and early improvement in patients with MDD and to further explore the ability of hippocampal FC to predict early efficacy. METHODS: Thirty-six patients with nonpsychotic MDD were recruited and underwent resting-state functional magnetic resonance imaging scans at baseline. After two weeks of treatment with escitalopram, patients were divided into subgroups with early improved depression (EID, n= 19) and nonimproved depression (NID, n=17) . A voxelwise FC analysis was performed with the bilateral hippocampus as seeds, two-sample t-tests were used to compare hippocampal FC between groups. Receiver operating characteristic (ROC) curves were constructed to determine the best FC measures and optimal threshold for differentiating EID from END. RESULTS: The EID group showed significantly higher FC between the left hippocampus and left inferior frontal gyrus and precuneus than the END group. And the left hippocampal FC of these two regions were positively correlated with the reduction ratio of the depressive symptom scores. The ROC curve analysis revealed that summed FC scores for these two regions exhibited the highest area under the curve, with a sensitivity of 0.947 and specificity of 0.882 at a summed score of 0.14. LIMITATIONS: The sample used in this study was relatively small. CONCLUSIONS: These findings demonstrated that FC of the left hippocampus can predict early efficacy of antidepressant.

Illness Severity Moderated Association Between Trait Anxiety and Amygdala-Based Functional Connectivity in Generalized Anxiety Disorder.

Trait anxiety is considered a vulnerability factor for the development of generalized anxiety disorder (GAD). The amygdala is related to both trait anxiety and GAD. Thus, we investigated amygdala-based functional connectivity (FC) in drug-naive non-comorbid GAD patients and explored its associations with personality, symptoms, and illness severity. FC analyses using the bilateral amygdala as seeds were performed with resting-state functional MRI data from 38 GAD patients and 20 matched healthy controls (HCs). Clinical characteristics were correlated with FC Z-scores from regions showing significant group differences. Furthermore, moderation analyses were used to explore the conditional effect of illness severity measured by the Clinical Global Impression-Severity (CGI-S) scale on the relationship between FC and trait anxiety. Relative to HCs, GAD patients showed hypoconnectivity between the amygdala and the rostral anterior cingulate cortex (rACC), inferior frontal gyrus (IFG), parahippocampal gyrus, and cerebellum and hyperconnectivity between the amygdala and the superior temporal gyrus (STG), insula, and postcentral gyrus. In GAD patients, amygdala-rACC connectivity was negatively associated with symptom severity and trait anxiety, and amygdala-IFG connectivity was positively associated with symptom severity. Moreover, CGI-S scores moderated the negative correlation between trait anxiety and amygdala-rACC FC. We demonstrate that there is extensive amygdala-based network dysfunction in patients with GAD. More importantly, amygdala-rACC connectivity plays a key role in the neural pathology of trait anxiety. Finally, the more severe the illness, the stronger the negative association between trait anxiety and amygdala-rACC FC. Our results emphasize the importance of personalized intervention in GAD.

miR-152 is involved in the proliferation and metastasis of ovarian cancer through repression of ERBB3.

MicroRNAs (miRNAs) participate in post-transcriptional regulation by targeting the 3' untranslated region of target genes that are involved in diverse biological processes. To the best of our knowledge, the association between miR­152 and ERBB3 in ovarian cancer remains unclear. In the present study, a negative correlation between miR­152 and ERBB3 in ovarian cancer was observed. The luciferase reporter gene assay results demonstrated that miR­152 negatively regulated ERBB3 in SKOV3 and OVCAR3 ovarian cancer cells. Furthermore, our results revealed that miR­152 suppressed the ability of ovarian cancer cell proliferation, migration and invasion, and promoted apoptosis through inhibiting ERBB3 in vitro. Therefore, in the present study, miR­152 was found to be involved in the proliferation and metastasis of ovarian cancer cells through repression of ERBB3 expression. Therefore, miR­152 may be a potential therapeutic target for the treatment of ovarian cancer.