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Background The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder (MDD). Each of these structures consists of several heterogeneous subfields. We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus–amygdala complex in medication-naïve patients with first-episode MDD. Methods High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode, medication-naïve, and noncomorbid MDD patients and 81 age-, sex-, and education level-matched healthy control participants (HCs). The structural covariance network (SCN) was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions; the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions, controlled for age, sex, education level, and intracranial volume. The global and nodal graph metrics were calculated and compared between groups. Results Compared with HCs, the SCN within the hippocampus–amygdala complex in patients with MDD showed a shortened mean characteristic path length, reduced modularity, and reduced small-worldness index. At the nodal level, the left hippocampal tail showed increased measures of centrality, segregation, and integration, while nodes in the left amygdala showed decreased measures of centrality, segregation, and integration in patients with MDD compared with HCs. Conclusion Our results provide the first evidence of atypical topologic characteristics within the hippocampus–amygdala complex in patients with MDD using structure network analysis. It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.

Background Cortical functional network alterations have been widely accepted as the neural basis of attention-deficit/hyperactivity disorder (ADHD). Recently, white matter has also been recognized as a novel neuroimaging marker of psychopathology and has been used as a complement to cortical functional networks to investigate brain–behavior relationships. However, disorder-specific features of white matter functional networks (WMFNs) are less well understood than those of gray matter functional networks. In the current study, we constructed WMFNs using a new strategy to characterize behavior-related network features in ADHD. Methods We recruited 46 drug-naïve boys with ADHD and 46 typically developing (TD) boys, and used clustering analysis on resting-state functional magnetic resonance imaging data to generate WMFNs in each group. Intrinsic activity within each network was extracted, and the associations between network activity and behavior measures were assessed using correlation analysis. Results Nine WMFNs were identified for both ADHD and TD participants. However, boys with ADHD showed a splitting of the inferior corticospinal–cerebellar network and lacked a cognitive control network. In addition, boys with ADHD showed increased activity in the dorsal attention network and somatomotor network, which correlated positively with attention problems and hyperactivity symptom scores, respectively, while they presented decreased activity in the frontoparietal network and frontostriatal network in association with poorer performance in response inhibition, working memory, and verbal fluency. Conclusions We discovered a dual pattern of white matter network activity in drug-naïve ADHD boys, with hyperactive symptom-related networks and hypoactive cognitive networks. These findings characterize two distinct types of WMFN in ADHD psychopathology.

Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder. Integrity of white matter microstructure plays a key role in the neural mechanism of ADHD presentations. However, the relationships between specific behavioural dimensions and white matter microstructure are less well known. This study aimed to identify associations between white matter and a broad set of clinical features across children and adolescent with and without ADHD using a data-driven multivariate approach.We recruited a total of 130 children (62 controls and 68 ADHD) and employed regularized generalized canonical correlation analysis to characterize the associations between white matter and a comprehensive set of clinical measures covering three domains, including symptom, cognition and behaviour. We further applied linear discriminant analysis to integrate these associations to explore potential developmental effects.We delineated two brain-behaviour dimensional associations in each domain resulting a total of six multivariate patterns of white matter microstructural alterations linked to hyperactivity-impulsivity and mild affected; executive functions and working memory; externalizing behaviour and social withdrawal, respectively. Apart from executive function and externalizing behaviour sharing similar white matter patterns, all other dimensions linked to a specific pattern of white matter microstructural alterations. The multivariate dimensional association scores showed an overall increase and normalization with age in ADHD group while remained stable in controls.We found multivariate neurobehavioral associations exist across ADHD and controls, which suggested that multiple white matter patterns underlie ADHD heterogeneity and provided neural bases for more precise diagnosis and individualized treatment.

BackgroundInsomnia is a commonly seen symptom in adolescents with major depressive disorder (MDD). The suprachiasmatic nucleus (SCN), which is the circadian rhythm regulation center, plays a crucial role in the regulation of sleep-wake circulation. Nevertheless, how SCN function contributes to the exact neural mechanisms underlying the associations between insomnia and depressive symptoms has not been explored in adolescents. In the current study, we aimed to explore the relationship between SCN functional connectivity (FC) and insomnia symptoms in adolescents with MDD using a seed-based FC method.MethodsIn the current study, we recruited sixty-eight first-episode drug-naïve adolescents with MDD and classified them into high insomnia (MDD-HI) and low insomnia (MDD-LI) groups according to the sleep disturbance subscale of the Hamilton Depression Rating Scale (HAMD-S). Forty-three age/gender-matched healthy controls (HCs) were also recruited. SCN FC maps were generally for all subjects and compared among three groups using one-way ANOVA with age, gender and adjusted HAMD score as covariates. We used partial correlations to explore associations between altered FC and clinical symptoms, including sleep quality scores.ResultsAdolescents with MDD showed worse sleep quality, which positively correlated with the severity of depression. Compared to MDD-LI and HCs, MDD-HI adolescents demonstrated significantly decreased FC between the right SCN and bilateral precuneus, and there was no significant difference between the MDD-LI and HC groups. The HAMD-S scores were negatively correlated with bilateral SCN-precuneus connectivity, and the retardation factor score of HAMD was negatively correlated with right SCN-precuneus connectivity.ConclusionThe altered FC between the SCN and precuneus may underline the neural mechanism of sleep-related symptoms in depressive adolescents and provide potential targets for personalized treatment strategies.

Background Age of onset may be an important feature associated with distinct subtypes of obsessive-compulsive disorder (OCD). The amygdala joined neurocircuitry models of OCD for its role in mediating fear and regulating anxiety. The present study aims to identify the underlying pathophysiological specifics in OCD with different onset times by assessing amygdala subregional functional connectivity (FC) alterations in early-onset OCD (EO-OCD) and late-onset OCD (LO-OCD). Methods Resting-state functional magnetic resonance imaging data were acquired from 88 medication-free OCD patients (including 30 EO-OCD and 58 LO-OCD) and age- and sex-matched healthy controls (HC) for each patient group. Onset-by-diagnosis interactions were examined and comparisons between each OCD group and the corresponding HC group were performed regarding the FC of amygdala subregions including the basolateral amygdala (BLA), centromedial amygdala (CMA), superficial amygdala (SFA) and amygdalostriatal transition area (Astr). Results Significant onset-by-diagnosis interactions were found in FC between bilateral SFA, right CMA, left Astr and the cerebellum. EO-OCD patients showed abnormally increased BLA/SFA-cerebellum, BLA-precuneus and BLA/SFA-fusiform connectivity in addition to decreased BLA/SFA-orbitofrontal cortex connectivity. In contrast, LO-OCD patients exhibited increased CMA/Astr-precentral/postcentral gyrus and CMA-cuneus connectivity as well as decreased CMA/Astr-cerebellum and BLA-striatum connectivity. Limitations The exclusion of comorbidity may reduce the generalizability of our results. Conclusions These findings emphasized the different patterns of amygdala subregional connectivity alterations associated with EO-OCD and LO-OCD patients. These results provide unique insights into constructing evidence-based distinct OCD subtypes based on brain intrinsic connectivity and point to the need of specified management for EO-OCD and LO-OCD in clinical setting.

Widespread alterations in the corpus callosum (CC) microstructure and organization have been found in children with attention-deficit/hyperactivity disorder (ADHD); however, few studies have investigated the diffusion characteristics and volume of transcallosal fiber tracts defined by specific cortical projections in ADHD, which is important for identifying distinct functional interhemispheric connection abnormalities. In the current study, an automated fiber-tract quantification (AFQ) approach based on diffusion tensor imaging identified seven CC tracts according to their cortical projections and estimated diffusion parameters and volume among 76 drug-naïve ADHD patients (53 boys and 23 girls) and 37 typically developing children (TDC) (20 boys and 17 girls) matched for age, IQ, and handedness. We found significantly lower fractional anisotropy (FA) in the occipital and superior parietal tracts and higher mean diffusivity (MD) in the posterior, superior parietal and anterior frontal tracts in children with ADHD compared with TDC. In addition, lower FA and higher radial diffusivity (RD) in the occipital callosal tract were significantly associated with higher hyperactivity and impulsivity performance in ADHD. In addition, sex-by-diagnosis interactions were observed in the occipital, posterior and superior parietal tracts. Girls with ADHD showed decreased FA and volume in the occipital tract, which were significantly associated with increased impulsivity performance and poor response control, and increased MD in the posterior and superior parietal callosal tracts, which were significantly associated with increased inattention performance, whereas boys with ADHD merely showed decreased volume in the frontal tract. Our results elucidated that sex-specific alterations in the CC tracts potentially underlie ADHD symptomatology and further suggested a differential contribution of abnormalities in different CC tracts to impulsivity and inattention among girls with ADHD.

Background The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder (MDD). Each of these structures consists of several heterogeneous subfields. We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus-amygdala complex in medication-naïve patients with first-episode MDD. Methods High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode, medication-naïve and non-comorbid MDD patients and 81 age-, sex- and education level -matched healthy controls (HCs). The structural covariance network (SCN) was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions; the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions, controlled for age, sex, education level and intracranial volume. The global and nodal graph metrics were calculated and compared between groups. Results Compared with HCs, the SCN within the hippocampus-amygdala complex in patients with MDD showed a shortened mean characteristic path length, reduced modularity, and reduced small-worldness index. At the nodal level, the left hippocampal tail showed increased measures of centrality, segregation and integration, while nodes in the left amygdala showed decreased measures of centrality, segregation and integration in patients with MDD compared with HCs. Conclusion Our results provide the first evidence of atypical SCN within the hippocampus-amygdala complex in patients with MDD, suggesting a potentially disrupted feedback or/and feedforward systems between the hippocampus and amygdala that underlying dysregulated emotional memory process in MDD.

Background The function of the insula has been increasingly mentioned in neurocircuitry models of obsessive-compulsive disorder (OCD) for its role in affective processing and regulating anxiety and its wide interactions with the classic cortico-striato-thalamo-cortical circuit. However, the insular resting-state functional connectivity patterns in OCD remain unclear. Therefore, we aimed to investigate characteristic intrinsic connectivity alterations of the insula in OCD and their associations with clinical features. Methods We obtained resting-state functional magnetic resonance imaging data from 85 drug-free OCD patients and 85 age- and sex-matched healthy controls (HCs). We performed a general linear model to compare the whole-brain intrinsic functional connectivity maps of the bilateral insula between the OCD and HC groups. In addition, we further explored the relationship between the intrinsic functional connectivity alterations of the insula and clinical features using Pearson or Spearman correlation analysis. Results Compared with HCs, patients with OCD exhibited increased intrinsic connectivity between the bilateral insula and bilateral precuneus gyrus extending to the inferior parietal lobule and supplementary motor area. Decreased intrinsic connectivity was only found between the right insula and bilateral lingual gyrus in OCD patients relative to HC subjects, which was negatively correlated with the severity of depression symptoms in the OCD group. Conclusion In the current study, we identified impaired insular intrinsic connectivity in OCD patients and the dysconnectivity of the right insula and bilateral lingual gyrus associated with the depressive severity of OCD patients. These findings provide neuroimaging evidence for the involvement of the insula in OCD and suggest its potential role in the depressive symptoms of OCD.

Alterations in resting-state functional connectivity (rsFC) of hippocampus and orbitofrontal cortex (OFC) have been highly implicated in major depressive disorder (MDD) and the researches have penetrated to the subregional level. However, relatively little is known about the intrinsic connectivity patterns of these two regions in adolescent MDD (aMDD), especially that of their functional subregions. Therefore, in the current study, we recruited 68 first-episode drug-naive aMDD patients and 43 matched typically developing controls (TDC) to characterize the alterations of whole-brain rsFC patterns in hippocampus and OFC at both regional and subregional levels in aMDD. The definition of specific functional subregions in hippocampus and OFC were based on the prior functional clustering-analysis results. Furthermore, the relationship between rsFC alterations and clinical features was also explored. Compared to TDC group, aMDD patients showed decreased connectivity of the left whole hippocampus with bilateral OFC and right inferior temporal gyrus at the regional level and increased connectivity between one of the right hippocampal subregions and right posterior insula at the subregional level. Reduced connectivity of OFC was only found in the subregion of left OFC with left anterior insula extending to lenticula in aMDD patients relative to TDC group. Our study identifies that the aberrant hippocampal and orbitofrontal rsFC was predominantly located in the insular cortex and could be summarized as an altered hippo-orbitofrontal-insular circuit in aMDD, which may be the unique features of brain network dysfunction in depression at this particular age stage. Moreover, we observed the distinct rsFC alterations in adolescent depression at the subregional level, especially the medial and lateral OFC.

Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance.

Anxiety and depressive symptoms may predispose individuals to sleep disturbance. Understanding how these emotional symptoms affect sleep quality, especially the underlying neural basis, could support the development of effective treatment. The aims of the present study were therefore to investigate potential changes in brain morphometry associated with poor sleep quality and whether this structure played a mediating role between the emotional symptoms and sleep quality. One hundred and forty-one healthy adults (69 women, mean age = 26.06 years, SD = 6.36 years) were recruited. A structural magnetic resonance imaging investigation was performed, and self-reported measures of anxiety, depressive symptoms and sleep quality were obtained for each participant. Whole-brain regression analysis revealed that worse sleep quality was associated with thinner cortex in left superior temporal sulcus (STS). Furthermore, the thickness of left STS mediated the association between the emotional symptoms and sleep quality. A subsequent commonality analysis showed that physiological component of the depressive symptoms had the greatest influence on sleep quality. In conclusion, thinner cortex in left STS may represent a neural substrate for the association between anxiety and depressive symptoms and poor sleep quality and may thus serve as a potential target for neuromodulatory treatment of sleep problems.

Repetitive transcranial magnetic stimulation (rTMS) benefits adults with depression while its efficacy and safety in children and adolescents with major depressive disorder (MDD) remain unclear. We conducted a preliminary meta-analysis here to objectively appraise rTMS in the youth with MDD to inform future research and clinical practice.We searched Pubmed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials from their inception to December 1, 2021. Studies with a control group or self-controlled designs and evaluating the Hamilton Depression Scale (HAM-D) or the Children's Depression Rating Scale-Revised (CDRS-R) at baseline and post-rTMS treatment were included. Two reviewers independently selected eligible studies, retrieved data in a structured fashion and assessed studies' quality. Hedges'g with 95 % confidence intervals and withdrawal rate with 95 % confidential intervals were separately used to evaluate the efficacy and safety of rTMS.Thirteen studies with six datasets (165 patients, 61.8 % female, age range from 10 to 25 years old) were included and our meta-analysis found children and adolescents with MDD benefited from rTMS treatment (Hedges'g 1.37, 95 % CI 0.85 to 1.90, P = 0.001). In addition, 4 % of patients (95 % CI 0.02 to 0.09) withdrew during rTMS treatment for reasons including fear, mood swings, suicide ideation and adverse events.This conclusion is tempered by a small number of studies included and a potentially existing placebo effect.Our findings suggest rTMS could benefit children and adolescents with MDD in a relatively safe manner, and this result may help guide clinical practice.

A precise understanding of amygdala-centered subtle networks may help refine neurocircuitry models of obsessive-compulsive disorder (OCD). We applied connectivity-based parcellation methodology to segment the amygdala based on resting-state fMRI data of 92 medication-free OCD patients without comorbidity and 90 matched healthy controls (HC). The amygdala was parcellated into two subregions corresponding to basolateral amygdala (BLA) and centromedial amygdala (CMA). Amygdala subregional functional connectivity (FC) maps were generated and group differences were evaluated with diagnosis-by-subregion flexible factorial ANOVA. We found significant diagnosis × subregion FC interactions in insula, supplementary motor area (SMA), midcingulate cortex (MCC), superior temporal gyrus (STG) and postcentral gyrus (PCG). In HC, the BLA demonstrated stronger connectivity with above regions compared to CMA, whereas in OCD, the connectivity pattern reversed to stronger CMA connectivity comparing to BLA. Relative to HC, OCD patients exhibited hypoconnectivity between left BLA and left insula, and hyperconnectivity between right CMA and SMA, MCC, insula, STG, and PCG. Moreover, OCD patients showed reduced volume of left BLA and right CMA compared to HC. Our findings characterized disorganized functional architecture of amygdala subregional networks in accordance with structural defects, providing direct evidence regarding the specific role of amygdala subregions in the neurocircuitry models of OCD.

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Background Exploring white matter (WM) microstructural alterations is a momentous step for gaining insights about underlying mechanisms of obsessive-compulsive disorder (OCD) and improving the efficacy of therapies for this condition. Many tract-based spatial statistics (TBSS) studies have revealed abnormalities of fractional anisotropy (FA; an index of WM integrity) in OCD. However, research works have not drawn robust conclusions. Therefore, we integrated the findings of TBSS studies to identify the most consistent FA changes in OCD using meta-analytical approach. Methods Online databases were systematically searched for all TBSS studies comparing FA between patients with OCD and controls. A coordinate-based meta-analysis was performed using anisotropic effect size version of the seed-based d mapping software. Meanwhile, meta-regression was used to explore the potential association of clinical characteristics with regional FA abnormalities. Results Our meta-analysis included 488 OCD patients and 519 controls across 17 datasets. FA reductions were identified in the genu of the corpus callosum and the left orbitofrontal WM in OCD patients relative to controls. Metaregression analyses showed that the FA in the left orbitofrontal WM was negatively and independently correlated with symptom severity and illness duration in patients with OCD. Conclusions The current study provides a quantitative overview of TBSS findings in OCD and demonstrates the most prominent and replicable WM abnormalities in OCD are in the anterior part of the brain including interhemispheric connection and orbitofrontal region. Additionally, our findings suggest that FA reduction in the orbitofrontal WM might be a potential biomarker in predicting disease severity and progression in patients with OCD.

BackgroundMajor depressive disorder (MDD) is a clinically and biologically heterogeneous syndrome. Identifying discrete subtypes of illness with distinguishing neurobiological substrates and clinical features is a promising strategy for guiding personalised therapeutics.AimsThis study aimed to identify depression subtypes with correlated patterns of functional network connectivity and clinical symptoms by clustering patients according to a weighted linear combination of both features in a relatively large, medication-naïve depression sample.MethodWe recruited 115 medication-naïve adults with MDD and 129 matched healthy controls, and evaluated all participants with magnetic resonance imaging. We used regularised canonical correlation analysis to identify component mapping relationships between functional network connectivity and symptom profiles, and K-means clustering was used to define distinct subtypes of patients.ResultsTwo subtypes of MDD were identified: insomnia-dominated subtype 1 and anhedonia-dominated subtype 2. Subtype 1 was characterised by abnormal hyperconnectivity within the ventral attention network and sleep maintenance insomnia. Subtype 2 was characterised by abnormal hypoconnectivity in the subcortical and dorsal attention networks, and prominent anhedonia symptoms.ConclusionsOur study identified two distinct subtypes of patients with specific neurobiological and clinical symptom profiles. These findings advance understanding of the biological and clinical heterogeneity of MDD, offering a pathway for defining categorical subtypes of illness via consideration of both biological and clinical features.

BackgroundFamily environment and life events have long been suggested to be associated with adolescent depression. The hippocampus plays a crucial role in the neural mechanism of major depressive disorder (MDD) through memory during stressful events. However, few studies have explored the exact neural mechanisms underlying these associations. Thus, the current study aimed to explore alterations in hippocampal functional connectivity (FC) in adolescent MDD based on resting-state functional magnetic resonance imaging and further investigate the relationship between hippocampal FC, environmental factors, and clinical symptom severity.MethodsHippocampal FC was calculated using the seed-based approach with the bilateral hippocampus as the seed for 111 adolescents with and without MDD; comparisons were made between participants with MDD and controls. We applied the Chinese version of the Family Environment Scale (FES-CV) and Adolescents Self-Rating Life Events Checklist (ASLEC) to evaluate family environment and life stress. Their relationship with hippocampal FC alterations was also investigated.ResultsWe found that compared to controls, adolescents with MDD showed decreased connectivity between the left hippocampus and bilateral orbital frontal cortex (OFC) and right inferior temporal gyrus. In addition, the hippocampal-OFC connectivity was negatively correlated with conflict scores of the FES-CV in the MDD group and mediated the association between family conflict and depressive and anxiety symptoms.ConclusionOur findings are novel in the field and demonstrate how family conflict contributes to MDD symptomatology through hippocampal-OFC connectivity; these findings may provide potential targets for personalized treatment strategies.

Type 2 diabetes mellitus (T2DM) is associated with abnormal communication among large-scale brain networks, revealed by resting-state functional connectivity (rsFC), with inconsistent results between studies. We performed a meta-analysis of seed-based rsFC studies to identify consistent network connectivity alterations. Thirty-three datasets from 30 studies (1014 T2DM patients and 902 healthy controls [HC]) were included. Seed coordinates and between-group effects were extracted, and the seeds were divided into networks based on their location. Compared to HC, T2DM patients showed hyperconnectivity and hypoconnectivity within the DMN, DMN hypoconnectivity with the affective network (AN), ventral attention network (VAN) and frontal parietal network, and DMN hyperconnectivity with the VAN and visual network. T2DM patients also showed AN hypoconnectivity with the somatomotor network and hyperconnectivity with the VAN. T2DM illness durations negatively correlated with within-DMN rsFC. These DMN-centered impairments in large-scale brain networks in T2DM patients may help to explain the cognitive deficits associated with T2DM.

Schizophrenia is a disorder resulting from aberrant brain networks and circuits. In the current study, we aimed to investigate specific network alterations in adolescent-onset schizophrenia (AOS) and to help identify the neurophysiological mechanisms of this adolescent disorder. We recruited forty-one subjects, including 20 AOS patients and 21 matched healthy controls (HCs), and we acquired brain images to examine the specific changes in functional network patterns using degree centrality (DC), which quantifies the strength of the local functional connectivity hubs. Whole-brain correlation analysis was applied to assess the relationships between clinical characteristics and DC measurements. The AOS group exhibited increased DC in the right inferior frontal lobe, right fusiform gyrus and right thalamus (p

Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative treatment for obsessive-compulsive disorder (OCD). However, the most effective rTMS parameters, such as the targets and stimulation frequencies, remain controversial. Therefore, we aimed to compare and rank the efficacy and tolerability of different rTMS strategies for OCD treatment. We searched five electronic databases from the date of their inception to March 25, 2020. Pairwise meta-analyses and network meta-analyses were performed to synthesize data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Twenty-two eligible randomized controlled trials (RCTs) were included. For efficacy, low-frequency (LF) rTMS over the dorsolateral prefrontal cortex (DLPFC; mean difference (MD) 6.34, 95% credible interval (CrI) 2.12–10.42) and supplementary motor area (MD 4.18, 95% CrI 0.83–7.62), and high-frequency rTMS over the DLPFC (MD 3.75, 95% CrI 1.04–6.81) were more effective than sham rTMS. Regarding tolerability, all rTMS treatment strategies were similar to the sham rTMS. The estimated ranking probabilities of treatments showed that LF-rTMS over the DLPFC might be the most effective intervention among all rTMS strategies. However, the quality of evidence regarding efficacy was evaluated as very low. Current evidence suggested a marginal advantage for LF-rTMS over the DLPFC on OCD treatment. High-quality RCTs with low selection and performance bias are needed to further verify the efficacy of specific rTMS strategies for the OCD treatment.

Major depressive disorder (MDD) shows sex differences in terms of incidence and symptoms, but the neurobiological basis underlying these sex differences remains to be clarified. High resolution T1-weighted Magnetic Resonance Imaging (MRI) scans were obtained from 123 non-comorbid treatment-naïve individuals with MDD and 81 age-, sex-, and handedness-matched healthy controls (HCs). MRI data were preprocessed with FreeSurfer software and four cortical measures were extracted: cortical thickness (CT), surface area (SA), cortical volume (CV), and local gyrification index (LGI). We tested for both sex-specific and sex-nonspecific patterns of cortical anatomic alterations. Regardless of sex, individuals with MDD showed significantly higher LGI in posterior cortex relative to HCs. Significant sex-by-group interactions were observed, and subsequent post-hoc analyses revealed that female individuals with MDD showed significantly lower SA in left ventrolateral prefrontal cortex (vlPFC), lower CV in right rostromedial prefrontal cortex (rmPFC), and higher LGI in left visual cortex compared with sex-matched HCs, whereas the opposite patterns of significant effects were seen in male individuals with MDD relative to their sex-matched HCs. Thus, sex-nonspecific and specific morphometric differences from HCs were found in posterior cortex, while in PFC alterations were highly sex-specific early in the illness course. This may involve sex-specific alterations in brain development or processes related to illness onset. These findings highlight the presence and regional distribution of generalized as well as sex-specific alterations of brain neurobiology in MDD.

Altered resting-state functional connectivity (rsFC) has been noted in large-scale functional networks in attention-deficit/hyperactivity disorder (ADHD). However, identifying consistent abnormalities of functional networks is difficult due to varied methods and results across studies. To integrate rsFC alterations and search for coherent patterns of intrinsic functional network impairments in ADHD, this research conducts a coordinate-based meta-analysis of voxel-wise seed-based rsFC studies comparing rsFC between ADHD patients and healthy controls. A total of 25 datasets from 21 studies including 700 ADHD patients and 580 controls were analyzed. We extracted the coordinates of seeds and between-group effects. Each seed was then categorized into a seed-network by its location within priori 7-network parcellations. Then, pooled meta-analyses were conducted for the default mode network (DMN), frontoparietal network (FPN) and affective network (AN) separately, but not for the ventral attention network (VAN), dorsal attention network (DAN), somatosensory network (SSN) and visual network due to a lack of primary studies. The results showed that ADHD was characterized by hyperconnectivity between the FPN and regions of the DMN and AN as well as hypoconnectivity between the FPN and regions of the VAN and SSN. These findings not only support the triple-network model of pathophysiology associated with ADHD but also extend this model by highlighting the involvement of the SSN and AN in the mechanisms of network interactions that may account for motor hyperactivity and impulsive symptoms.

Objective Amygdala-based network dysfunction has been found to be centrally implicated in major depressive disorder (MDD). However, relatively little is known about how different forms of effective or cognitive dysfunction are modulated in MDD. Therefore, in the current study, we aimed to examine the alteration of amygdala subregional networks in adult patients with MDD to explore whether different parts of the amygdala that are functionally connected to different regions contribute differently to the cerebral network mechanism of depression. Methods Resting-state fMRI scans were obtained from 70 medication-free adults with MDD and 70 age- and sex-matched healthy controls (HC). Functional connectivity maps of four distinct regions of the amygdala, including the amygdalostriatal transition area (AStr) and the basolateral (BLA), centromedial (CM) and superficial (SF) amygdala, were generated and compared between the two groups. Results Compared with HC, patients with MDD showed hypoconnectivity between the AStr/BLA and the orbitofrontal cortex (OFC), between the CM/SF and the brainstem/cerebellum, and within AStr/CM/SF-thalamic/striatal networks. Hyperconnectivity was observed between the left AStr/BLA and the fusiform gyrus. There was no difference in the gray matter volume of the amygdala or any of its subregions between the two groups. Conclusions These findings suggest that amygdala subregional-network dysfunction in MDD is independent of structural changes and, more important, that hypoconnectivity and hyperconnectivity in different subregional networks may reflect imbalanced network function, which may modulate different forms of emotional and cognitive dysfunction in MDD.

Introduction: Epigenetic modification without DNA sequence mutation plays an important role in cancer development. Some small molecular inhibitors targeting key epigenetic molecules have been approved by the Food and Drug Administration to treat hematological malignancies. However, the anticancer effects of these drugs on solid tumors are not satisfactory, and the mechanisms of action remain largely unknown. Areas covered: The review summarizes the latest research on cancer epigenetics and discusses the potentials and limitations of using epigenetic drugs to treat solid tumors. An analysis of possible reasons for epigenetic drug treatment failure in solid tumors in some clinical trials is discussed along with prospects for future development. Expert commentary: Next-generation small molecule inhibitors will target novel epigenetic regulators with high cancer specificity. Combined modalities exploiting epigenetic drugs with chemo-/radiotherapy, molecular-targeting drugs, and immunotherapy will be able to effectively treat solid tumors in the near future.

The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR-regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer.

In order to solve the problem that the existing routing ant colony algorithm for micro-nano satellite network is easy to fall into local optimal solution and slow convergence speed, an improved quantum ant colony QoS (Quality of Service) routing algorithm using Q-learning is proposed in this paper. First, a qubit heuristic factor is added to the transfer probability of the ant colony algorithm to avoid falling into the local optimal solution. Then, the thought of Q-learning is introduced into the algorithm, and the pheromones of ant colony algorithm are mapped to the Q value of Q-learning, which accelerates the convergence speed of the algorithm. Simulation results show that the proposed routing algorithm can improve the packet delivery rate, reduce the average end-to-end delay and the average node energy consumption. The proposed Q-learning quantum ant colony routing algorithm is suitable for micro-nano satellite network with high speed mobile nodes.

Obsessive–compulsive disorder (OCD) displays alterations in regional brain activity represented by the amplitude of low‐frequency fluctuation (ALFF), but the time‐varying characteristics of this local neural activity remain to be clarified. We aimed to investigate the dynamic changes of intrinsic brain activity in a relatively large sample of drug‐naïve OCD patients using univariate and multivariate analyses. We applied a sliding‐window approach to calculate the dynamic ALFF (dALFF) and compared the difference between 73 OCD patients and age‐ and sex‐matched healthy controls (HCs). We also utilized multivariate pattern analysis to determine whether dALFF could differentiate OCD patients from HCs at the individual level. Compared with HCs, OCD patients exhibited increased dALFF mainly within regions of the cortical–striatal–thalamic–cortical (CSTC) circuit, including the bilateral dorsal anterior cingulate cortex, medial prefrontal cortex and striatum, and right dorsolateral prefrontal cortex (dlPFC). Decreased dALFF was identified in the bilateral inferior parietal lobule (IPL), posterior cingulate cortex, insula, fusiform gyrus, and cerebellum. Moreover, we found negative correlations between illness duration and dALFF values in the right IPL and between dALFF values in the left cerebellum and Hamilton Depression Scale scores. Furthermore, dALFF can distinguish OCD patients from HCs with the most discriminative regions located in the IPL, dlPFC, middle occipital gyrus, and cuneus. Taken together, in the current study, we demonstrated a characteristic pattern of higher variability of regional brain activity within the CSTC circuits and lower variability in regions outside the CSTC circuits in drug‐naïve OCD patients., We used the dynamic amplitude of low‐frequency fluctuation to determine the temporal variability properties of regional brain activity. We demonstrated a characteristic pattern of higher time‐varying intrinsic activity within the cortical–striatal–thalamic–cortical circuits and lower variability in regions outside the circuits in drug‐naïve obsessive–compulsive disorder (OCD) patients. We emphasize that the dysfunction of regions outside the cortical–striatal–thalamic–cortical circuits, particularly the parietal cortex and cerebellum, plays an important role in the pathophysiology of OCD. ​

Posttraumatic stress disorder (PTSD) is associated with dysfunction in large-scale brain functional networks, as revealed by resting-state functional connectivity studies. However, it remains unclear which networks have been most consistently affected and, more importantly, what role disease and trauma may play in the disrupted functional networks. We performed a systematic review of studies exploring network alterations using seed-based functional connectivity analysis, comparing individuals with PTSD to controls in general as well as trauma-exposed or nonexposed controls specifically, and quantitative meta-analysis was conducted when the number of studies was appropriately high. We found that hypoconnectivity within the default-mode network (DMN) as well as between the affective network (AN) and DMN were specifically associated with traumatic experience. Additionally, hyperconnectivity between the AN and somatomotor network (SMN) and between the DMN and SMN were specifically related to PTSD. Our results emphasize the effect of trauma itself on alterations in intrinsic brain networks and highlight disease-associated network alterations, which may help us better understand the neural mechanisms of trauma and PTSD.

Speech emotion recognition (SER) plays a vital role in natural interaction between humans and machines. However, due to the complexity of human emotions, the features learned in existing researches contain a large amount of redundant information that has nothing to do with emotions, which reduces the performance of SER. To alleviate the problem, in this paper we propose a novel model, named as Upgraded Attention-based Local Feature Learning Block (UA-LFLB). Concretely, the LFLB is used to extract deep local sequence features and as input to the UA mechanism to capture the salient features of the discourse level with contextual information. In doing this, more accurate and discriminative features can be learned, which greatly reduces redundant information in the features. To evaluate the feasibility of the proposed model, We conduct experiments on a widely used emotional database. Experimental results show that the proposed model outperforms the state-of-the-art methods on the IEMOCAP database and achieving 9% improvement in terms of average accuracy.

Obsessive-compulsive disorder (OCD) displays widespread disruption across brain regions revealed by resting-state functional connectivity (rsFC) with inconsistent results between studies. We performed a systematic review of 47 seed-based rsFC studies (1863 patients; 1795 healthy controls) to explore brain intrinsic connectivity alterations. Quantitative coordinate-based meta-analysis was conducted for seed regions in the striatum (putamen, caudate, nucleus accumbens [Nac]), thalamus, and anterior cingulate cortex (ACC) because there were an adequate number of studies. We found that OCD patients demonstrated (1) characteristic dysconnectivity between striatum and cortical networks (i.e., caudate hyperconnectivity with the fronto-limbic network and hypoconnectivity with frontoparietal network regions; Nac hypoconnectivity with fronto-limbic network regions), (2) hypoconnectivity between thalamus and striatum (putamen and caudate), and (3) dysconnectivity between the ACC and fronto-limbic network regions. Furthermore, there were negative correlations between particular connectivities and symptom severity and onset age. Our results characterize the traditional cortico-striato-thalamo-cortical circuit model of OCD pathophysiology through the cerebral intrinsic connectivity, and unified neurocircuitry and brain network models into one integrity to elaborate the neural mechanism of OCD.

BACKGROUND: The amygdala has been implicated in obsessive–compulsive disorder (OCD), a common, disabling illness. However, the regional distribution of anatomic alterations in this structure and their association with the symptoms of OCD remains to be established. METHODS: We collected high-resolution 3D T(1)-weighted images from 81 untreated patients with OCD and no lifetime history of comorbid psychotic, affective or anxiety disorders, and from 95 age- and sex-matched healthy controls. We extracted the volume of the central nucleus of the amygdala (CeA) and the basolateral complex of the amygdala (BLA) and compared them across groups using FreeSurfer 6.0. In exploratory analyses, we evaluated other subnuclei, including the cortical medial nuclei, the anterior amygdaloid area, and the corticoamygdaloid transition area. RESULTS: Patients with OCD had reduced amygdala volume bilaterally compared with healthy controls (left, p = 0.034; right, p = 0.002). Volume reductions were greater in the CeA (left: −11.9%, p = 0.002; right: −13.3%, p < 0.001) than in the BLA (left lateral nucleus: −3.3%, p = 0.029; right lateral nucleus: −3.9%, p = 0.018; right basal nucleus: −4.1%, p = 0.017; left accessory basal nucleus: −6.5%, p = 0.001; right accessory basal nucleus: −9.3%, p < 0.001). Volume reductions in the CeA were associated with illness duration. Exploratory analysis revealed smaller medial (left: −15.4%, p < 0.001, η(2) = 0.101) and cortical (left: −9.1%, p = 0.001, η(2) = 0.058; right: −15.4%, p < 0.001, η(2) = 0.175) nuclei in patients with OCD compared with healthy controls. LIMITATIONS: Although the strict exclusion criteria used in the study helped us to identify OCD-specific alterations, they may have limited generalizability to the broader OCD population. CONCLUSION: Our results provide a comprehensive anatomic profile of alterations in the amygdala sub-nuclei in untreated patients with OCD and highlight a distinctive pattern of volume reductions across subnuclei in OCD. Based on the functional properties of the amygdala subnuclei established from preclinical research, CeA impairment may contribute to behavioural inflexibility, and BLA disruption may be responsible for altered fear conditioning and the affective components of OCD.

Attention-deficit/hyperactivity disorder has been identified to involve the impairment of large-scale functional networks within grey matter, and recent studies have suggested that white matter, which also encodes neural activity, can manifest intrinsic functional organization similar to that of grey matter. However, the alterations in white matter functional networks in attention-deficit/hyperactivity disorder remain unknown. We recruited a total of 99 children, including 66 drug-naive patients and 33 typically developing controls aged from 6 to 14, to characterize the alterations in functional networks within white matter in drug-naive children with attention-deficit/hyperactivity disorder. Using clustering analysis, resting-state functional MRI data in the white matter were parsed into different networks. Intrinsic activity within each network and connectivity between networks and the associations between network activity strength and clinical symptoms were assessed. We identified eight distinct white matter functional networks: the default mode network, the somatomotor network, the dorsal attention network, the ventral attention network, the visual network, the deep frontoparietal network, the deep frontal network and the inferior corticospinal-posterior cerebellum network. The default mode, somatomotor, dorsal attention and ventral attention networks showed lower spontaneous neural activity in patients. In particular, the default mode network and the somatomotor network largely showed higher connectivity with other networks, which correlated with more severe hyperactive behaviour, while the dorsal and ventral attention networks mainly had lower connectivity with other networks, which correlated with poor attention performance. In conclusion, there are two distinct patterns of white matter functional networks in children with attention-deficit/hyperactivity disorder, with one being the hyperactivity-related hot networks including default mode network and somatomotor network and the other being inattention-related cold networks including dorsal attention and ventral attention network. These results extended upon our understanding of brain functional networks in attention-deficit/hyperactivity disorder from the perspective of white matter dysfunction., There are two distinct patterns of white matter functional networks in children with attention-deficit/hyperactivity disorder. One is the hyperactive behaviour-related hot networks including default mode network and somatomotor network, and the other is inattention-related cold networks including dorsal attention and ventral attention network., Graphical Abstract Graphical Abstract

Background The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. Methods Cell viability or clonogenicity was tested by violet crystal assay. Cell apoptosis or cell cycle was analyzed by flow cytometry, and chromosome misalignment was observed by a fluorescent microscopy. The protein interaction of PLK1 and USP7 was detected by tandem affinity purification and high throughput proteomics, and further confirmed by co-immunoprecipitation, GST pull-down and protein co-localization. The correlation between USP7 level of tumor tissues and taxane-resistance was evaluated. Results Pharmacological USP7 inhibition by P5091 retarded cell proliferation and induced cell apoptosis. Further studies showed that P5091 induced cell cycle arrest at G2/M phase, and particularly induced chromosome misalignment, indicating the key roles of USP7 in mitosis. USP7 protein was detected in the PLK1-interacted protein complex. USP7 interacts with PLK1 protein through its PBD domain by catalytic activity. USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway. By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival. Both USP7 and PLK1 were overexpressed in taxane-resistant cancer cells, and negatively correlated with the MP scores in tumor tissues. Either USP7 or PLK1 knockdown by RNAi significantly sensitized taxane-resistant cells to taxane cell killing. Conclusion This is the first report that PLK1 is a novel substrate of USP7 deubiquitinase, and that USP7 sustained the protein stability of PLK1. USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.

Background: Previous studies mapping intrinsic brain connectivity have facilitated the neuropathological model of attention-deficit/hyperactivity disorder (ADHD) which encompasses a number of different large-scale networks. However, these studies have traditionally focused on the functional connectivity within grey matter regions, ignoring the critical role played by white matter in supporting brain functions. This study aimed to investigate the characteristic alterations of activity and connectivity within white matter functional networks in children with ADHD. Methods: K-means clustering was performed on the white matter resting-state fMRI data to identify white matter functional networks for a total of ninety-nine drug-naive children with ADHD and typically developing controls. Intrinsic activity in each network and functional connectivity between each network were assessed as well as the associations between network activity and ADHD clinical symptoms. Outcomes: Eight distinct white matter functional networks were identified. DMN, SMN, DAN and VAN showed lower spontaneous neural activity in children with ADHD. In particular, the DMN and SMN mainly showed increased connectivity with other networks while the DAN and VAN had more decreased connectivity. Interpretation: This study for the first time uncovered the feature of intrinsic functional organization of white matter networks in children with ADHD. Our findings demonstrated that the abnormal white matter network activity and connectivity in DMN, SMN, DAN and VAN share similar characteristic changes with those of grey matter, which suggests abnormal white matter network interactions that encode neural activity may underlie ADHD neuropathology. Funding Statement: This study was supported by the National Natural Science Foundation (Grant No. 81671669) and Science and Technology Project of Sichuan Province (Grant No. 2017JQ0001). Declaration of Interests: The authors stated: "None declared." Ethics Approval Statement: The Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University approved the study. All participants and their parents were fully informed about the purpose and procedures of this study, and written informed consent was obtained from the parents.

The dorsolateral prefrontal cortex (DLPFC), a key structure in the executive system, has consistently emerged as a crucial element in the pathophysiology of obsessive–compulsive disorder (OCD). However, the neural primacy of the DLPFC remains elusive in this disorder. We investigated the causal interaction (measured by effective connectivity) between the DLPFC and the remaining brain areas using bivariate Granger causality analysis of resting-state fMRI collected from 88 medication-free OCD patients and 88 matched healthy controls. Additionally, we conducted seed-based functional connectivity (FC) analyses to identify network-level neural functional alterations using the bilateral DLPFC as seeds. OCD patients demonstrated reduced FC between the right DLPFC and right orbitofrontal cortex (OFC), and activity in the right OFC had an inhibitory effect on the right DLPFC. Additionally, we observed alterations in both feedforward and reciprocal influences between the inferior temporal gyrus (ITG) and the DLPFC in patients. Furthermore, activity in the cerebellum had an excitatory influence on the right DLPFC in OCD patients. These findings may help to elucidate the psychopathology of OCD by detailing the directional connectivity between the DLPFC and the rest of the brain, ultimately helping to identify regions that could serve as treatment targets in OCD.

A great number of studies have demonstrated functional abnormalities in children with attention-deficit/hyperactivity disorder (ADHD), although conflicting results have also been reported. And few studies analyzed homotopic functional connectivity between hemispheres. In this study, resting-state functional magnetic resonance imaging (MRI) data were recorded from 45 medication-naïve ADHD children and 26 healthy controls. The regional homogeneity (ReHo), degree centrality (DC) and voxel-mirrored homotopic connectivity (VMHC) values were compared between the two groups to depict the intrinsic brain activities. We found that ADHD children exhibited significantly lower ReHo and DC values in the right middle frontal gyrus and the two values correlated with each other; moreover, lower VMHC values were found in the bilateral occipital lobes of ADHD children, which was negatively related with anxiety scores of Conners' Parent Rating Scale (CPRS-R) and positively related with completed categories of Wisconsin Card Sorting Test (WCST). Our results might suggest that less spontaneous neuronal activities of the right middle frontal gyrus and the bilateral occipital lobes in ADHD children.注意缺陷多动障碍（ADHD）儿童的大脑功能异常已经被广泛报道，但是其结果存在不一致性，且半球间功能连接相关研究较少。本研究纳入了 45 名首发未用药 ADHD 儿童和 26 名正常对照儿童，进行静息态功能磁共振扫描。采用局部一致性（ReHo）、度中心性（DC）和镜像同伦功能连接（VMHC）三种测量指标对两组受试的静息态脑活动进行比较分析。发现与正常儿童相比，ADHD 儿童 ReHo 值和 DC 值在右侧额中回区域降低，且两者呈正相关；VMHC 值在双侧枕叶降低，且该改变与 Conners 父母用量表焦虑得分呈负相关，与威斯康星卡片测验正确分类数呈正相关。本研究结果提示了 ADHD 儿童右侧额中回及双侧枕叶自发神经活动的异常。.

Background The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. Methods Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. Results PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. Conclusions Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials.

Table S1. Genes Confirmed to Induce BRCAness in Prostate Non- and Cancerous Cell Lines. (DOC 51 kb)