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Clinical response of primary-refractory HL in patients receiving CART-30 cell therapy.

The adverse event after the CART-30 cell infusion.

Case selection criteria;Methods;Figure Legends

Lymphocyte recovery is a probable indictor of response.

Maximum reduction in target lesion size.

Progression-free survival by Kaplan-Meier method.

Purpose: Relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma.Experimental Design: Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR).Results: Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors.Conclusions: CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment. Clin Cancer Res; 23(5); 1156–66. ©2016 AACR.

Supplementary Table S1. Phonotypical characteristics of PBMCs and expanded T Cells as well as transduction efficiency of infused cell products. Supplementary Table S2. Detailed prior chemotherapy regimens for patients before CD30-CART treatment. Supplementary Table S3. Statistics of patient characteristics. Supplementary Table S4. The absolute doses of conditioning regimens for all enrolled patients. Supplementary Table S5. Toxicities possibly related to CD30-CART infusion-containing protocol. Supplementary Table S6. Maximum change from baseline of target measurable lesions. Supplementary Table S7. Clinical response in CD30-CAR T cell- treated patients.

The change of cytokine levels within three months after CART-30 cell infusion.

Zhong Wang,1,* Kai Yuan,1,* Yan-Bin Ji,2,* Su-Xia Li,3 Le Shi,1 Zhe Wang,1 Xin-Yu Zhou,4 Yan-Ping Bao,3 Wen Xie,5 Ying Han,3 Jie Shi,3 Lin Lu,1,3,6 Wei Yan,1 Wen-Hao Chen1 1Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, 100191, People’s Republic of China; 2Department of Neurology, Qilu Hospital of Shandong University, Shandong University, Jinan, 250012, People’s Republic of China; 3National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, People’s Republic of China; 4Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 5Mental Health Center of Anhui Province, Hefei, 230032, People’s Republic of China; 6Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen-Hao Chen; Wei Yan Peking University Sixth Hospital/Peking University Institute of Mental Health, 51 Huayuanbei Road, Haidian District, Beijing, 100191, People’s Republic of ChinaTel +86-10-82801342; Tel +86-10-62723704Email chenwenhao@bjmu.edu.cn; weiyan@bjmu.edu.cnIntroduction: Accumulating evidence suggests that both sleep loss and gut dysbiosis can lead to metabolic disorders. However, less is known about the impact of total sleep deprivation (SD) and sleep recovery on the composition, function, and metabolic dynamics of the gut microbiota.Methods: Specific-pathogen free Sprague–Dawley rats were subjected to 48 h of SD with gentle handling and then allowed to recover for 1 week. Taxonomic profiles of fecal microbiota were obtained at baseline, 24 h of SD, 48 h of SD, and 1 week of recovery. We used 16S rRNA gene sequencing to analyze the gut microbial composition and function and further characterize microbiota-derived metabolites in rats.Results: The microbiota composition analysis revealed that gut microbial composition and metabolites did not change in the rats after 24 h of SD but were significantly altered after 48 h of SD. These changes were reversible after 1 week of sleep recovery. A functional analysis was performed based on Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, indicating that 19 KEGG pathways were significantly altered in the gut microbiota in SD rats. These functional changes occurred within 24 h of SD, were more apparent after 48 h of SD, and did not fully recover after 1 week of sleep recovery.Conclusion: These results indicate that acute total SD leads to significant compositional and functional changes in the gut microbiota, and these changes are reversible.Keywords: gut microbiota, sleep deprivation, short-chain fatty acid, function prediction

Background Major depressive disorder (MDD) is the most common mental disorder associated with suicide attempts. When a patient first visits the clinic, clinicians are often expected to make concrete diagnose about acute suicidal risk. However, the timeliness of suicide attempts correlates with patients with MDD has not been tested. Methods We divided 1718 first-episode and untreated MDD outpatients into those who did not have suicide attempts (non-attempts), recent suicide attempters (≤14 days before assessment) and long - dated suicide attempters (> 30 days before assessment). Positive Symptom Scale of Positive and Negative Syndrome Scale (PANSS), the 17-item Hamilton Depression Scale, 14 - item Hamilton Anxiety Scale, and clinical global impression of severity scale (CGI-S) was assessed. Body mass index, some glycolipid metabolism and thyroid hormone parameters were measured. A gradient-boosted decision trees statistical model was used to generate equally weighted classification for distinguishing recent and long - dated suicide attempters from non-attempts. Results The classifier identified higher excitement, hostility, anxiety, depression symptoms and higher free thyroxine (FT4) as risk factors for recent suicide attempters with an estimated accuracy of 87% (sensitivity, 59.1%; specificity, 61.2 %). For long - dated suicide attempters’ risk factors, single status, higher anxiety and hostility symptoms, higher LDLC and lower BMI, the estimated accuracy was 88% (sensitivity, 52.8%; specificity, 49.6%). Conclusions Risk factors for suicide attempt among patients with MDD can be identified by integrating demographic, clinical, and biological variables as early as possible during the first time see a doctor.

To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the sleep quality and nocturnal heart rate variability (HRV) in patients with primary insomnia.Twenty-one patients with primary insomnia were included. Using SDZ-ⅡB electric acupuncture apparatus, Xin (COAfter treatment, the score of each item and the total score of PSQI and SL were all reduced as compared with those before treatment (The taVNS improves the sleep quality and objective sleep structure in patients with primary insomnia, which is probably related to the regulation of autonomic nervous functions.

In the post-pandemic era, the emergence of sporadic cases of coronavirus disease 2019 (COVID-19) and the scale of the pandemic are unpredictable. Therefore, the impact of sporadic cases of COVID-19 and isolation measures on mental health and sleep in different groups of people need to be analyzed.To clarify the severity of psychological problems and insomnia of staff and community residents around a hospital with sporadic cases of COVID-19, and their relationship with quarantine location and long-term changes.A cross-sectional survey was conducted on community residents and medical staff. Many of these medical staff had been subjected to different places of quarantine. Community residents did not experience quarantine. Hospital anxiety and depression scale (HADS), acute stress disorder scale (ASDS) and insomnia severity index (ISI) were used to evaluate anxiety and depression, acute stress disorder symptoms, and the severity of insomnia. Additionally, we conducted a 1-year follow-up study on medical staff, with related scales measurement immediately after and one year after the 2-wk quarantine period.We included 406 medical staff and 226 community residents. The total scores of ISI and subscale in HADS of community residents were significantly higher than that of medical staff. Further analysis of medical staff who experienced quarantine showed that 134 were quarantined in hotels, 70 in hospitals and 48 at home. Among all subjects, the proportions of HADS, ASDS and ISI scores above normal cutoff value were 51.94%, 19.17% and 31.11%, respectively. Multivariable logistic regression analysis found that subjects with higher total ASDS scores had a greater risk to develop anxiety and depression. The total ISI score for medical staff in hotel quarantine was significantly higher than those in home quarantine. Total 199 doctors and nurses who completed the 1-year follow-up study. Compared with baseline, HADS and ASDS scores decreased significantly one year after the end of quarantine, while ISI scores did not change significantly.Sporadic COVID-19 cases had a greater psychological impact on residents in surrounding communities, mainly manifested as insomnia and depressive symptoms. Hotel quarantine aggravated the severity of insomnia in medical staff, whose symptoms lasted ≥ 1 year.

Accumulated reports have indicated that circadian rhythm is closely related to the pathogenesis of major depressive disorder (MDD). Recently, adenosine has been identified to modulate circadian clock via adenosine A1 and A2A receptor signaling pathways. Cyclic AMP-response element binding protein (CREB) is a convergent point that plays a critical role in the pathogenesis of depression and is a downstream molecule of adenosine A1 receptor signaling pathway as an endpoint that can regulate the expression of circadian genes Period1 (Per1) and Period2 (Per2). However, whether Per mediates the development of MDD via CREB has not been elucidated. We used chronic unpredictable stress (CUS) to induce depression-like behaviors and found that it could induce decrease in p-CREB and PER1 levels in the hippocampal CA1 region in rats. Both depression-like behaviors and the decreased protein levels could be rapidly rescued by the administration of adenosine A1 receptor agonist 2-Choro-N6-cyclopentyladenosine (CCPA). Furthermore, knockdown of Per1 in hippocampal CA1 region could also induce depression-like behaviors, which could also be rescued by CCPA. Interestingly, Per2 knockdown in hippocampal CA1 region resulted in potential antidepressant-like effect. In addition, knockout of CRE sequence in the promoter regions of either Per1 or Per2 led to depression-like behaviors, which could not be rescued by CCPA. These results indicated that clock genes Per1 and Per2 play critical roles in the pathophysiology of depression and CRE sequences in the promoter regions of Per1 and Per2 may be a critical antidepressant target.HighlightsCUS induces both depression-like behaviors and decreases in the expression of p-CREB and PER1 levels in the hippocampal CA1 region in rats, which can be rapidly rescued by 2-Choro-N6-cyclopentyladenosine (CCPA).Knockdown of clock gene Per1 in the hippocampal CA1 brain region leads to depression-like behaviors in rats, which can be also rescued by CCPA.Knockdown of clock gene Per2 in the hippocampal CA1 brain region may have potential antidepressant-like effect.Knockout of the CRE sequence on the promoter region of the clock genes Per1 and Per2 produces depression-like behaviors, which cannot be rescued by CCPA.

To evaluate the efficacy and safety of CHOP regimen based on doxorubicin hydrochloride liposome in the initial treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL).Thirty-one patients with DLBCL treated from January 1, 2012 to December 31, 2019 were analyzed retrospectively, their median age was 83 (71-95) years old, and all of them were in Ⅲ-Ⅳ stage, including 17 cases who had international prognostic index (IPI) ≥ 3. The patients were treated with R-CHOP and CHOP regimens based on doxorubicin hydrochloride liposome. The efficacy and safety were evaluated during and after treatment.A total of 219 chemotherapy cycles and 7 median cycles were performed in 31 patients. The overall response (OR) rate and complete remission (CR) rate was 80.7% (25/31) and 61.3% (19/31), respectively, as well as 2 cases (6.5%) stable, 4 cases (12.9%) progressive. The main toxicities were as follows: the incidence of grade Ⅲ -Ⅳ neutropenia was 29% (9/31); two patients (6.5%) developed degree Ⅰ-Ⅱ cardiac events, which were characterized by new degree Ⅰ atrioventricular block; there were no cardiac events requiring emergency treatment and discontinuation of chemotherapy. The 1-year, 2-year and 3-year overall survival rate was 83.9%, 77.4% and 61.3%, respectively. The 1-year, 2-year and 3-year progression-free survival rate was 77.4%, 64.5% and 61.3%, respectively.The chemotherapy regimen based on doxorubicin hydrochloride liposome has better efficacy and higher cardiac safety for elderly patients with DLBCL.以盐酸多柔比星脂质体为基础的CHOP联合方案治疗初治高龄弥漫大B细胞淋巴瘤患者的回顾性研究.评价以盐酸多柔比星脂质体为基础的CHOP联合方案治疗初治高龄弥漫大B细胞淋巴瘤（DLBCL）患者的有效性和安全性.回顾性分析2012年1月1日至2019年12月31日本中心血液科收治的初治DLBCL患者31例，中位年龄为83（71-95）岁，均为Ⅲ-Ⅳ期患者，国际预后指数≥3分患者为17例。治疗方案采用以盐酸多柔比星脂质体为主的R-CHOP及CHOP方案。在治疗过程中和治疗后对其疗效和安全性进行评价.31例患者共进行219个化疗周期，中位周期7个，总缓解率和完全缓解率分别为80.7%（25/31）和61.3%（19/31），疾病稳定2例（6.5%），疾病进展4例（12.9%）。主要毒副反应为：Ⅲ-Ⅳ级中性粒细胞减少症发生率为29%（9/31）；2例（6.5%）患者出现Ⅰ-Ⅱ度心脏事件，表现为新发的Ⅰ度房室传导阻滞；未出现需要紧急治疗和中止化疗的心脏事件。1、2、3年的总生存率分别为83.9%、77.4%和61.3%，无进展生存率分别为77.4%、64.5%和61.3.对于高龄DLBCL患者，以盐酸多柔比星脂质体为主的化疗方案疗效较好，患者心脏安全性较高.

To perform challenging visual search tasks, attention should be selectively allocated to promote targets and inhibit distractors. Rejection templates based on the distractor9s feature can be built to constrain the search process by filtering-out matched stimuli. We measured electroencephalography (EEG) of human participants when they performed a visual search task under conditions in which the distractor cues were constant within a block (fixed-cueing) or changed on a trial-by-trial basis (varied-cueing). Sustained representation of the cued colors could be decoded from the whole-brain EEG signal during the retention interval in the fixed-cueing condition, implying a formed rejection template. By contrast, transient representation of the cued colors was observed in the varied-cueing condition only after cue onset with significant but lower decoding accuracy than the fixed-cueing condition. The differential neural representations of the to-be-ignored color in the two cueing conditions agreed with the visual search performance that the fixed-cueing condition demonstrated a larger inhibition benefit of the distractor cueing than the varied-cueing condition. During the retention interval, we also observed stronger posterior alpha lateralization and mid-frontal theta/beta power in the varied-cueing condition, indicating the cognitive costs in template formation caused by the trialwisely change of distractor colors. The stable template formed in the fixed-cueing condition was utilized to inhibit the matched distractors in the search array and this was accompanied by larger mid-frontal theta activity. Taken together, our findings highlighted the critical roles of distractor consistency in linking template formation to successful distractor inhibition and the functional relevance of frontal theta activity in support of template formation and implementation.

SummaryRegulation of chromatin accessibility determines the transcription activities of genes, which endow the host with function-specific gene expression patterns. It remains unclear how chromatin accessibility is specifically directed, particularly, during host defense against viral infection. We previously reported that the nuclear matrix protein SAFA surveils viral RNA and regulates antiviral immune genes expression. However, how SAFA regulates the expression and what determines the specificity of antiviral immune genes remains unknown. Here, we identified that the depletion of SAFA specifically decreased the chromatin accessibility, activation and expression of virus induced genes in a genome-wide scale after VSV infection. SAFA exclusively bound with antiviral related RNAs, which mediated the specific opening of the according chromatin and robust transcription of these genes. Knockdown of these associated RNAs dampened the accessibility of corresponding genes in an extranuclear signaling pathway dependent manner. Moreover, VSV infection cleaved SAFA protein at the C-terminus which deprived its RNA binding ability for immune evasion. Thus, our results demonstrated that SAFA and the interacting RNA products during viral infection collaborate and remodel chromatin accessibility to facilitate antiviral innate immune response.

Ketamine is a popular recreational substance of abuse that induces persistent behavioral deficits. Although disrupted oxytocinergic systems have been considered to modulate vulnerability to developing drugs of abuse, the involvement of central oxytocin in behavioral abnormalities caused by chronic ketamine has remained largely unknown. Herein, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex (mPFC) in social avoidance and cognitive impairment resulting from repeated ketamine administration in mice. We found that ketamine injection (5 mg/kg, i.p.) for 10 days followed by a 6-day withdrawal period induced behavioral disturbances in social interaction and cognitive performance, as well as reduced oxytocin levels both at the periphery and in the mPFC. Repeated ketamine exposure also inhibited mPFC neuronal activity as measured by a decrease in c-fos-positive cells. Furthermore, direct microinjection of oxytocin into the mPFC reversed the social avoidance and cognitive impairment following chronic ketamine exposure. In addition, oxytocin administration normalized ketamine-induced inflammatory cytokines including TNF-α, IL-6, and IL-1β levels. Moreover, the activation of immune markers such as neutrophils and monocytes, by ketamine was restored in oxytocin-treated mice. Finally, the reversal effects of oxytocin on behavioral performance were blocked by pre-infusion of the oxytocin receptor antagonist atosiban into the mPFC. These results demonstrate that enhancing oxytocin signaling in the mPFC is a potential pathway to reverse social avoidance and cognitive impairment caused by ketamine, partly through inhibition of inflammatory stimulation.

Sleep deprivation (SD) is increasingly common in modern society, which can lead to the dysregulation of inflammatory responses and cognitive impairment, but the mechanisms remain unclear. Emerging evidence suggests that gut microbiota plays a critical role in the pathogenesis and development of inflammatory and psychiatric diseases, possibly via gut microbiota-brain interactions and neuroinflammation. The present study investigated the impact of SD on gut microbiota composition and explored whether alterations of the gut microbiota play a causal role in chronic inflammatory states and cognitive impairment that are induced by SD. We found that SD-induced gut dysbiosis, inflammatory responses, and cognitive impairment in humans. Moreover, the absence of the gut microbiota suppressed inflammatory response and cognitive impairment induced by SD in germ-free (GF) mice. Transplantation of the "SD microbiota" into GF mice activated the Toll-like receptor 4/nuclear factor-κB signaling pathway and impaired cognitive function in the recipient mice. Mice that harbored "SD microbiota" also exhibited increases in neuroinflammation and microglial activity in the hippocampus and medial prefrontal cortex. These findings indicate that gut dysbiosis contributes to both peripheral and central inflammatory processes and cognitive deficits that are induced by SD, which may open avenues for potential interventions that can relieve the detrimental consequences of sleep loss.

Patients with depression often suffer from sleep disorders and non-sleep circadian disorders. However, whether they precede and predict subsequent depression is unclear. We conducted a meta-analysis of studies on sleep disorders and non-sleep circadian disorders. We found insomnia, hypersomnia, short and long sleep duration, obstructive sleep apnea, restless legs syndrome and eveningness orientation at baseline all led to subsequent depression. Those with propensity to late meal patterns, heightened levels of cortisol in awakening response and low robustness of rest-activity rhythm at baseline had higher risks for later depression. Among insomnia subtypes, difficulty initiating sleep and difficulty maintaining sleep predicted future depression. Notably, persistent insomnia at baseline contributed to more than two-fold risk of incident depression compared to insomnia. Moreover, insomnia symptom numbers showed dose-dependent relationship with the incident depression. In conclusion, different types of sleep disorders and non-sleep circadian disorders were proven to be risk factors of subsequent depression, and mechanisms underlying the relationship between sleep disorders, non-sleep circadian disorders and subsequent depression should be further elucidated in the future.

Omega-3 fatty acids (FA), as a nutrient, has been proven effective in major depressive disorder (MDD), however, the results of monotherapy in perinatal depression (PND) remain unclear. To examine the efficacy and safety of omega-3 fatty acids (FA) monotherapy for perinatal depression (PND) compared with placebo. PubMed, Embase, PsycINFO, MEDLINE, Cochrane Library, and CINAHL were searched from inception up to November 2019. The reference lists of relevant review articles and included studies were also reviewed. Randomized placebo-controlled trials examining the efficacy and safety of omega-3 FA monotherapy in perinatal women with depressive symptoms were included. Pooled standard mean differences (SMD) were calculated and random-effects models were adopted for all analyses. Subgroups analyses and meta-regression were performed to quantify characteristics of the subjects and trials influencing the omega-3 response. In addition, meta-regression was conducted to identify the source of heterogeneity. The study protocol was registered at PROSPERO, CRD42020159542. Eight eligible randomized placebo-controlled trials were included involving 638 participants. There was a significant effect of omega-3 FA on perinatal depression. Omega-3 with higher ratio of EPA/DHA (≥1.5) had significant efficacy both in mild-to-moderate pregnant and postpartum depression with low incidence of side effects. Among the included trials reporting adverse effects, there was no significant difference in incidence of gastrointestinal and neurologic events between the omega-3 and placebo groups. There was no evidence of publication bias. Our findings suggested that omega-3 FA significantly improved depressive symptoms in perinatal women regardless of pregnant or postpartum and well-tolerated. Furthermore, the omega-3 response was linked to higher EPA proportion in omega-3 formula and mild- to-moderate depression.

To investigate effects of agomelatine and mirtazapine on sleep disturbances in patients with major depressive disorder. A total of 30 depressed patients with sleep disturbances, 27 of which completed the study, took agomelatine or mirtazapine for 8 weeks. Subjective scales were administered, and polysomnography was performed at baseline and at the end of week 1 and 8. Functional magnetic resonance imaging was performed at baseline and at the end of week 8. Compared with baseline, scores on the Hamilton Depression Scale, Hamilton Anxiety Scale, Pittsburgh Sleep Quality Index, Sleep Dysfunction Rating Scale, and Insomnia Severity Index after 8 weeks of treatment significantly decreased in both groups, with no significant differences between groups, accompanied by significant increases in total sleep time, sleep efficiency, and rapid eye movement (REM) sleep and significant decrease in wake after sleep onset. Mirtazapine treatment increased N3 sleep at week 1 compared with agomelatine treatment, but this difference disappeared at week 8. The increases in the percentage and duration of N3 sleep were positively correlated with increases in connectivity between right dorsal lateral prefrontal cortex (dlPFC) and right precuneus and between left posterior cingulate cortex and right precuneus in both groups, respectively. Functional connectivity (FC) between right dlPFC and left precuneus in mirtazapine group was higher compared with agomelatine group after 8 weeks of treatment. These findings indicated that both agomelatine and mirtazapine improved sleep in depressed patients, and the effect of mirtazapine was greater than agomelatine with regard to rapidly increasing N3 sleep and gradually improving FC in the brain.

Background Previous studies have shown escitalopram is related to sleep quality. However, effects of escitalopram on dynamics of electroencephalogram (EEG) features especially during different sleep stages have not been reported. This study may help to reveal pharmacological mechanism underlying escitalopram treatment. Methods The spatial and temporal responses of patients with major depressive disorder (MDD) to escitalopram treatment were analyzed in this study. Eleven MDD patients and eleven healthy control subjects who completed eight weeks’ treatment of escitalopram were included in the final statistics. Six-channel sleep EEG signals were acquired during sleep. Power spectrum and nonlinear dynamics were used to analyze the spatio-temporal dynamics features of the sleep EEG after escitalopram treatment. Results For temporal dynamics: after treatment, there was a significant increase in the relative energy (RE) of δ1 band (0.5 - 2 Hz), accompanied by a significant decrease in the RE of β2 band (20 - 30 Hz). Lempel-Ziv complexity and Co - complexity values were significantly lower. EEG changes at different sleep stages also showed the same regulation as throughout the night sleep. For spatio dynamics: after treatment, the EEG response of the left and right hemisphere showed asymmetry. Regarding band-specific EEG complexity estimations, δ1 and β2 in stage-1 and δ1 in stage-2 sleep stage in frontal cortex is found to be much more sensitive to escitalopram treatment in comparison to central and occipital cortices. Conclusions The sleep quality of MDD patients improved, EEG response occurred asymmetry in left and right hemispheres due to escitalopram treatment, and frontal cortex is found to be much more sensitive to escitalopram treatment. These findings may contribute to a comprehensive understanding of the pharmacological mechanism of escitalopram in the treatment of depression.

Schizophrenia is characterized by the dysfunction of various brain networks. Previous studies suggested that pharmacological treatments for schizophrenia induce functional changes in localized brain regions. However, the effects of antipsychotic treatments on brain networks associated with symptom improvement are still elusive. The elucidation of antipsychotic-induced functional brain changes is essential for the development of biologically informed treatment strategies. Forty-five healthy controls and 44 patients with schizophrenia underwent resting-state fMRI scans at baseline. The patients underwent a second scan after 6 weeks of antipsychotic treatment. At baseline, patients exhibited a significant decrease in functional connectivity of the cingulate gyrus in the default mode network compared to healthy controls, and this decrease was negatively correlated with symptom severity. Clinical improvements were observed after 6 weeks treatment, accompanied by an increase in functional connectivity of the cingulate gyrus in the default mode network and the inferior parietal lobule in the executive control network. The changes in functional connectivity of the inferior parietal lobule were significantly correlated with symptom improvement. These longitudinal neuroimaging findings suggest that schizophrenia might be an outcome of the disruption of the optimal balance of brain networks, and reestablishing this balance through antipsychotic treatment may result in clinical symptom improvement.

Background: Patients with depression often suffer from circadian rhythm disruptions, such as insomnia and a lower amplitude of daily rhythms of locomotor activity. However, whether circadian disorders precede depression and act as a predictor for subsequent depression have not been unanimously approved. In light of increasing evidence of an association between disrupted circadian rhythms and affective symptoms, a meta-analysis was conducted to examine the effect of circadian disruptions on incident depression. Methods: A systematic search was performed in PubMed, Embase, Web of Science, PsycINFO, PsycArticles, CINAHL database. The search results were restricted to be published in English up to April 10, 2020.Reference lists from included studies and relevant reviews were also screened. We included longitudinal cohort studies that examined the predictive role of all various types of circadian disruption in incident depression. Two reviewers independently extracted information on study design, participants’ characteristics and diagnostic criteria for circadian disruption and depression. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effect models were applied to all meta-analyses given potential heterogeneity. For insomnia, subgroup analyses were performed based on subject’s characteristics, insomnia symptom domains and numbers and the investigated methods. Pool-effect estimates of relative risks to develop incident depression in groups with circadian disruption compared to groups without. This study is registered with PROSPERO, CRD42020179135. Findings: A total of 49 studies were eligible for this meta-analysis. Of 49 eligible studies, included types of circadian disruption were sleep disturbances (n = 45), chronotype (n = 2), cortisol awakening response (n = 1) and rest - activity rhythm (n = 1). Insomnia, hypersomnia, excessive daytime sleepiness (EDS), short sleep duration, obstructive sleep apnea (OSA), restless legs syndrome (RLS), an evening preference, heightened levels of cortisol in awakening response and low robustness of rest - activity rhythm all acted as significant predictors of occurrence of depression. Among insomnia subtypes, difficulty initiating sleep (DIS) and difficulty maintaining sleep (DMS) predicted future depression. Of note, persistent insomnia (OR: 5.02) contributed to more than two - fold risk of incident depression compared to insomnia (OR: 2.34). Moreover, insomnia symptom numbers were associated with incident depression in a gradient trend. Interpretation: Different types of circadian disorders act as risk factors of onset of depression, which clinicians should be informed of. Future research should be aimed to determine the casual relationship between other types of circadian disorders and onset of depression, and moreover to further elucidate the underlying mechanisms. Funding Statement: This work was supported in part by the National Natural Science Foundation of China (no. 81871071 and 81171251) and Beijing Municipal Natural Science Foundation (no. 7162101). Declaration of Interests: All of the authors declare no conflict of interest.

The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease., What's new? Chemotherapy is the main therapeutic option for alimentary tract (AT) cancer patients, but intrinsic or acquired drug resistance remains an issue. Preclinical and phase I trials have shown the potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine. In this phase Ib/II trial, low‐dose decitabine‐primed chemotherapy with/without cytokine‐induced killer cells treatment was assessed in patients with drug‐resistant relapsed/refractory AT cancers. The epi‐ chemoimmunotherapy exhibited high response rates and prolonged the progression‐free survival (PFS), compared to the pre‐resistant unprimed PFS. The regimen was generally well tolerated. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy make it a promising treatment strategy.

Purpose: Relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma. Experimental Design: Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR). Results: Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors. Conclusions: CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment. Clin Cancer Res; 23(5); 1156–66. ©2016 AACR.

Vibrio vulnificus (V. vulnificus) is an aquatic pathogen that can cause primary sepsis and soft tissue infection. CpG oligodeoxynucleotides (CpG-ODN) are a type of essential immunomodulators, which can trigger or enhance immune responses in mammals, fish, and humans. In this study, we evaluated the effect of CpG-ODN 2007 as a potential immunostimulant for zebrafish infected with V. vulnificus (FJ03-X2). Fish injected with the CpG-ODN 2007 showed lower mortality rate compared with the fish that did not receive treatment. The survival rates of CpG-ODN 2007-treated group and PBS-treated group were 85% and 57.9%, respectively. In addition, our in vitro results demonstrated that CpG-ODN 2007 can effectively reduce the toxicity of V. vulnificus (FJ03-X2) to zebrafish embryonic fibroblast (ZF4) cells. Furthermore, we assessed immune-related genes expression patterns in FJ03-X2 infected zebrafish or ZF4 cells with and without CpG-ODN 2007 treatment, such as TLRs and IL-1β. To sum up, our data indicated that CpG-ODN 2007 protects zebrafish against Vibrio vulnificus induced infection.