Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Community composition of phytopathogenic fungi significantly influences ectomycorrhizal fungal communities during subtropical forest succession.

Ectomycorrhizal fungi (EMF) can form symbiotic relationships with plants, aiding in plant growth by providing access to nutrients and defense against phytopathogenic fungi. In this context, factors such as plant assemblages and soil properties can impact the interaction between EMF and phytopathogenic fungi in forest soil. However, there is little understanding of how these fungal interactions evolve as forests move through succession stages. In this study, we used high-throughput sequencing to investigate fungal communities in young, intermediate, and old subtropical forests. At the genus level, EMF communities were dominated by Sebacina, Russula, and Lactarius, while Mycena was the most abundant genus in pathogenic fungal communities. The relative abundances of EMF and phytopathogenic fungi in different stages showed no significant difference with the regulation of different factors. We discovered that interactions between phytopathogenic fungi and EMF maintained a dynamic balance under the influence of the differences in soil quality attributed to each forest successional stage. The community composition of phytopathogenic fungi is one of the strong drivers in shaping EMF communities over successions. In addition, the EMF diversity was significantly related to plant diversity, and these relationships varied among successional stages. Despite the regulation of various factors, the positive relationship between the diversity of phytopathogenic fungi and EMF remained unchanged. However, there is no significant difference in the ratio of the abundance of EMF and phytopathogenic fungi over the course of successions. These results will advance our understanding of the biodiversity-ecosystem functioning during forest succession. KEY POINTS: •Community composition of both EMF and phytopathogenic fungi changed significantly over forest succession. •Phytopathogenic fungi is a key driver in shaping EMF community. •The effect of plant Shannon's diversity on EMF communities changed during the forest aging process.

Indocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial.

Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P < 0.001). Both OS and DFS in the ICG group are significantly better than that in the non-ICG group (log-rank P = 0.015; log-rank P = 0.012, respectively). There is a difference in the overall recurrence rates between the ICG and non-ICG groups (17.8% vs 31.0%). Compared with conventional lymphadenectomy, ICG guided laparoscopic lymphadenectomy is safe and effective in prolonging survival among patients with resectable GC.

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

Association of Adipokines with Alzheimer's Disease in a Chinese Cohort.

BACKGROUND: The correlation between plasma adipose factor levels and Alzheimer's patients is not entirely clear. OBJECTIVE: We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin. METHODS: A single-center, cross-sectional study recruited AD patients (n = 148) and cognitively normal (CN) controls (n = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD. RESULTS: After adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95% CI: 0.272-0.638, p < 0.0001) and adiponectin (OR = 1.249, 95% CI: 1.151-1.354, p < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p < 0.0001) and was positively with CDR scores (p < 0.0001) and age (p < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p < 0.0001) and positively correlated with MMSE scores (p < 0.0001). Both adiponectin (p < 0. 0001) and leptin (p < 0. 0001) featured higher AUC than the random chance. CONCLUSIONS: Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD.

Back acupoint location method based on prior information and deep learning.

Acupuncture points have a positive effect on the auxiliary prevention and treatment of diseases, so medical devices such as acupuncture robots often need to combine acupuncture points to improve the treatment effect when working, however, intelligent acupoint selection technology is not yet mature, the automatic rapid and accurate positioning of acupoints is still challenging. Therefore, this paper proposes a method of back acupoint location and an evaluation index of acupoint location. First, we propose an improved Keypoint RCNN network for the preliminary location of back acupoints and introduce a channel and spatial attention mechanism module (CBAM) to improve the performance of the model. Then, we set up a posterior median line positioning method to improve the accuracy of acupoint positioning. Finally, expand and locate other acupoints according to the prior information of acupoints. According to the experimental results, the accuracy of acupoint positioning was 87.32%. After the correction of acupoint positioning, the accuracy was increased by 2.8%, which was 90.12%. In this paper, the application of depth learning in automatic location of back acupoints is realized for the first time. Only one image can be used to locate the back acupoints, with an accuracy of 90.12%.

HnRNPK is involved in stress-induced depression-like behavior via ERK-BDNF pathway in mice.

As a ubiquitous RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) interacts with numerous nucleic acids and proteins and is involved in various cellular functions. Available literature indicates that it can regulate dendritic spine density through the extracellular signal-regulating kinase (ERK) - brain-derived neurotrophic factor (BDNF) pathway, which is crucial to retain the synaptic plasticity in patients with major depressive disorder (MDD) and mouse depression models. However, ERK upstream regulatory kinase has not been fully elucidated. Furthermore, it remains unexplored whether hnRNPK may impact the depressive condition via the ERK pathway. The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing. We found that hnRNPK in the brain was mainly distributed in the hippocampal neurons; that it was significantly downregulated in mice that displayed stress-induced depression-like behaviors; and that the level of hnRNPK markedly decreased in MDD patients from the GEO database. Further in vivo and in vitro analyses revealed that the changes in the expressions of BDNF and PSD95 and in the phosphorylation of ERK (Thr202/Tyr204) paralleled the variation of hnRNPK levels in the ventral hippocampal neurons in mice with depression-like behaviors. Finally, esketamine treatment significantly increased the level of hnRNPK in mice. These findings evidence that hnRNPK involved in the pathogenesis of depression via the ERK-BDNF pathway, pinpointing hnRNPK as a potential therapeutic target in treating MDD patients.

The Diagnostic Potential of Circulating Autoantibodies to Amyloid-ß in Alzheimer's Disease.

BACKGROUND: The profile of naturally occurring antibodies to amyloid-ß (NAbs-Aß) is altered in patients with Alzheimer's disease (AD). However, the diagnostic potential of NAbs-Aß for AD is not clear yet. OBJECTIVE: This study aims to investigate the diagnostic capacities of NAbs-Aß for AD. METHODS: A total of 40 AD patients and 40 cognitively normal (CN) controls were enrolled in this study. Levels of NAbs-Aß were detected by ELISA. The correlations of NAbs-Aß levels with cognitive function and AD-associated biomarkers were examined by Spearman correlation analysis. Diagnostic abilities of NAbs-Aß were evaluated by the receiver operating characteristic (ROC) curve analyses. The integrative diagnostic models were established by logistic regression models. RESULTS: We found that NAbs-Aß7-18 had the highest diagnostic capability (AUC = 0.72) among all single NAbs-Aß. The combined model (NAbs-Aß7-18, NAbs-Aß19-30, and NAbs-Aß25-36) had a noticeable improvement (AUC = 0.84) in the diagnostic capacity compared with each single NAbs-Aß. CONCLUSION: NAbs-Aßs are promising in the diagnosis of AD. Further investigations are needed to confirm the translational potential of this diagnostic strategy.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-ß and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits.

Deficiencies in the clearance of peripheral amyloid ß (Aß) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aß is decreased in AD. However, the exact mechanism of Aß clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aß. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aß in vivo and in vitro. Moreover, enhancing blood monocyte Aß phagocytosis by improving energy metabolism alleviated brain Aß deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aß phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Associations of Blood and Cerebrospinal Fluid Aß and tau Levels with Renal Function.

Amyloid ß (Aß) and tau play pivotal roles in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that brain-derived Aß and tau can be cleared through transport into the periphery, and the kidneys may be vital organs involved in the clearance of Aß and tau. However, the effects of deficiency in the clearance of Aß and tau by the kidneys on brain AD-type pathologies in humans remain largely unknown. In this study, we first recruited 41 patients with chronic kidney disease (CKD) and 40 age- and sex-matched controls with normal renal function to analyze the associations of the estimated glomerular filtration rate (eGFR) with plasma Aß and tau levels. To analyze the associations of eGFR with cerebrospinal fluid (CSF) AD biomarkers, we recruited 42 cognitively normal CKD patients and 150 cognitively normal controls with CSF samples. Compared with controls with normal renal function, CKD patients had higher plasma levels of Aß40, Aß42 and total tau (T-tau), lower CSF levels of Aß40 and Aß42 and higher levels of CSF T-tau/Aß42 and phosphorylated tau (P-tau)/Aß42. Plasma Aß40, Aß42, and T-tau levels were negatively correlated with eGFR. In addition, eGFR was negatively correlated with CSF levels of T-tau, T-tau/Aß42, and P-tau/Aß42 but positively correlated with Mini-Mental State Examination (MMSE) scores. Thus, this study showed that the decline in renal function was correlated with abnormal AD biomarkers and cognitive decline, which provides human evidence that renal function may be involved in the pathogenesis of AD.

Comparison of the efficacy between immunochemotherapy and chemotherapy in gastric cancer accompanied with synchronous liver metastases: A real-world retrospective study.

BACKGROUND: Few studies have investigated the efficacy of comprehensive therapies, including immunotherapy, for gastric cancer with synchronous liver metastases (GCLM). We retrospectively compared the effect of immunochemotherapy and chemotherapy alone as conversion therapies on the oncological outcomes of patients with GCLM. METHODS: The clinicopathological data of 100 patients with GCLM from February 2017 to October 2021 at our institution were retrospectively analyzed. Patients were divided into immunochemotherapy (n = 33) and chemotherapy-alone (n = 67) groups. RESULTS: Baseline clinicopathological data did not differ significantly between the two groups. The immunochemotherapy group had a higher overall response rate (59.4% vs. 44.0%, p = 0.029) and disease control rate (71.9% vs. 49.2%, p = 0.036) than the chemotherapy group. The immunochemotherapy group showed better tumor regression in the gastric mass, metastatic lymph nodes, and liver lesions than the chemotherapy group. Ten (30.3%) patients in the immunochemotherapy group and 13 (19.4%) patients in the chemotherapy group underwent surgery after conversion therapy. However, the difference was not statistically significant. The overall survival (OS) and progression-free survival (PFS) rates were better in the immunochemotherapy group than in the chemotherapy group. Treatment-related adverse events occurred in 24 (72.7%) and 47 (70.1%) patients in the immunochemotherapy and chemotherapy groups, respectively. CONCLUSIONS: As a conversion therapy for GCLM, immunotherapy yielded better primary and metastatic tumor regression and survival benefits, with no increase in adverse events compared to chemotherapy.

Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-ß Levels in Alzheimer's Disease: The Chongqing Ageing & Dementia Study.

BACKGROUND: The kidney-brain crosstalk has been involved in Alzheimer's disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. OBJECTIVE: To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. METHODS: We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-ß (Aß)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aß, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. RESULTS: We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aß42, Aß40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aß42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aß42. CONCLUSION: Renal function impacts brain Aß metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

Analysis on the Effect of Radiofrequency Ablation and Electrocautery in the Treatment of Vaginal Intraepithelial Neoplasia.

Objective: This research intends to investigate the clinical efficacy of radiofrequency ablation and electrocautery in treating grade I or II vaginal intraepithelial neoplasia (VaIN). Methods: This is a single-center retrospective study, which collected the clinical data of 100 patients with VaIN diagnosed by colposcopy and pathological biopsy in the Gynecology and Cervical Center of Xiangzhu Branch of the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region between January 2020 and June 2021. Patients were divided into the study group (radiofrequency ablation treatment) and the control group (electrocautery) according to differences in treatment approaches. 6- and 12-month follow-ups were performed on all patients. Gynecological examination results, liquid-based thin-layer cytology (TCT), negative conversion of human papillomavirus (HPV), curative effects, and prognosis were recorded. Results: All patients completed regular follow-ups that lasted for 6 and 12 months. The 6- and 12-month cure rates of the study group were 76.0% and 92.0%, respectively, and the data in the control group were 70.0% and 82.0%, respectively. In terms of the 6- and 12-month negative conversion rates of HPV, the data in the study group were 68.0% and 78.0%, versus 60% and 68% in the control group, respectively. The lesion duration rate showed no statistical significance between the study group (8.0%) and the control group (P > 0.05). The analysis of postoperative follow-up complications revealed that the study group had a statistically lower overall incidence of vaginal bleeding, excessive vaginal discharge, vaginal burning sensation, and decreased vaginal elasticity than the control group (8.0% vs. 24.0% P < 0.05). Conclusion: Both radiofrequency ablation and electrocautery have obvious clinical effects in patients with grade I or II VaIN, but the former contributed to fewer operative complications and a good prognosis, which deserves clinical promotion.

Diverse mating consequences of the evolutionary breakdown of the sexual polymorphism heterostyly.

Reproductive systems of flowering plants are evolutionarily fluid, with mating patterns changing in response to shifts in abiotic conditions, pollination systems, and population characteristics. Changes in mating should be particularly evident in species with sexual polymorphisms that become ecologically destabilized, promoting transitions to alternative reproductive systems. Here, we decompose female mating portfolios (incidence of selfing, outcross mate number, and intermorph mating) in eight populations of Primula oreodoxa, a self-compatible insect-pollinated herb. This species is ancestrally distylous, with populations subdivided into two floral morphs that usually mate with each other (disassortative mating). Stages in the breakdown of polymorphism also occur, including "mixed" populations of distylous and homostylous (self-pollinating) morphs and purely homostylous populations. Population morph ratios vary with elevation in association with differences in pollinator availability, providing an unusual opportunity to investigate changes in mating patterns accompanying transitions in reproductive systems. Unexpectedly, individuals mostly outcrossed randomly, with substantial disassortative mating in at most two distylous populations. As predicted, mixed populations had higher selfing rates than distylous populations, within mixed populations, homostyles selfed almost twice as much as the distylous morphs, and homostylous populations exhibited the highest selfing rates. Populations with homostyles outcrossed with fewer mates and mate number varied negatively with population selfing rates. These differences indicate maintenance of distyly at low elevation, transition to monomorphic selfing at high elevation, and uncertain, possibly variable fates at intermediate elevation. By quantifying the earliest changes in mating that initiate reproductive transitions, our study highlights the key role of mating in promoting evolutionary divergence.

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aß neurotoxicity and promotes Aß clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

[Effect of Special Structure Bi-Specific Chimeric Antigen Receptor T Cell on Tumor Cells].

OBJECTIVE: To explore and design a novel bi-specific chimeric antigen receptor (CAR) structure. To obtain the corresponding CAR-T cells and verify killing effects on tumor cells in vitro and in vivo. METHODS: Five kinds of bi-specific CAR structures including humanized CD19 scFv and CD79b scFv, CD8 hinge & TM-4-1BB-CD3ζ and/or CD3ε chain intracellular regions were constructed and prepared. CAR-19-79b cells were obtained. Five kinds of CAR-T cells were co-incubated with the 3M-CD19-CD79b-Luc target cells. Luciferase assay and ELISA were used to detecte the killing ability of these five groups of CAR-T cells and the secretion of cytokines and compared. The optimal structure of CAR-T cells was used to treat the leukemia mouse model constructed by Daudi-Luc cells. And the treatment efficacy was evaluated. At the same time, other targets were used in this structure. With the same methods, the stability and effectiveness of the structure were verified. RESULTS: CAR-19-79b-T cells were cultured for 7 days, the expression rates of CAR-19 and CAR-79b were 21.6%-36.3% and 21.7%-37.8%, respectively. The killing rates of 5 kinds of CAR-19-79b-T cells prepared by T cells from 3 healthy donors on 3M-CD19-CD79b-Luc cells were significantly higher than those of the T cell control group at the effect-target ratio of 10∶1. Among them, the killing rates of CAR-19-79b-T cells with No. III and No. IV structures were the strongest. After co-incubation with 3M-CD19-CD79b-Luc target cells, the amount of IFN-γ and TNF-α secreted by CAR-T cells with CAR IV and CARV structures was the lowest. And there was no significance between the two groups (P>0.05). CAR IV cells with remarkable killing effect and low secretion factor had obvious therapeutic effect on Daudi-Luc leukemia mice, extending the survival period of mice to 64 days. And all mice in the T cell control group died at 41.0±2.4 days. The CAR-19-BCMA-T and CAR-19-22-T with the same structure showed significant killing ability and low cytokine expression levels. CONCLUSION: A novel bi-specific CAR structures was successfully designed, which could efficiently kill the corresponding tumor cells and secrete less cytokines (such as TNF-α, IFN-γ). Moreover, it shows obvious therapeutic effect on Daudi lymphoma mouse model. The bi-specific CAR structure shows good killing specificity and safety.

Association of rs2072446 in the NGFR gene with the risk of Alzheimer's disease and amyloid-ß deposition in the brain.

INTRODUCTION AND AIMS: Alzheimer's disease (AD) is the most common form of dementia with a complex genetic background. The cause of sporadic AD (sAD) remains largely unknown. Increasing evidence shows that genetic variations play a crucial role in sAD. P75 neurotrophin receptor (p75NTR, encoded by NGFR) plays a critical role in the pathogenesis of AD. Yet, the relationship between NGFR gene polymorphisms and AD was less studied. This study aims to analyze the relationship of NGFR gene polymorphism with the risk of AD in the Chinese Han population and amyloid-ß deposition in the ADNI cohort. METHODS: This case-control association study was conducted in a Chinese Han cohort consisting of 366 sporadic AD (sAD) patients and 390 age- and sex-matched controls. Twelve tag-SNPs were selected and genotyped with a multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The associations between tag-SNPs and the risk of AD were analyzed by logistic regression. Moreover, another cohort from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database was included to examine the association of one tag-SNP (rs2072446) with indicators of amyloid deposition. Kaplan-Meier survival analysis and Cox proportional hazards models were used to test the predictive abilities of rs2072446 genotypes for AD progression. The mediation effects of Aß deposition on this association were subsequently tested by mediation analyses. RESULTS: After multiple testing corrections, one tag-SNP, rs2072446, was associated with an increased risk of sAD (additive model, OR = 1.79, Padjustment  = 0.0144). Analyses of the ADNI cohort showed that the minor allele (T) of rs2072446 was significantly associated with the heavier Aß burden, which further contributed to an increased risk of AD progression in APOE ε4 non-carrier. CONCLUSION: Our study found that rs2072446 in NGFR is associated with both the risk of sAD in the Chinese Han population and the amyloid burden in the ADNI cohort, which reveals the role of p75NTR in AD from a genetic perspective.

The utility of sentinel Lymph node biopsy in the lateral neck in papillary thyroid carcinoma.

Background: Regional lymph node metastases (LNMs) are very common in papillary thyroid carcinoma (PTC) and associate with locoregional recurrence. The appropriate management of cervical lymph nodes is very important. Therefore, this study evaluated the application of sentinel lymph node biopsy (SLNB) in the lateral neck in PTC patients. Methods: This prospective study was conducted from 1 November 2015 to 31 December 2017 and recruited 78 PTC patients treated with SLNB in the lateral neck and prophylactic lateral neck dissection (compartments II-IV) followed by thyroidectomy or lobectomy and central neck dissection. Results: There were 78 PTC patients enrolled and sentinel lymph nodes (SLNs) were detected among 77 patients. A total of 30 patients were diagnosed with SLN metastases (SLNMs). The remaining 47 patients were pathologically negative of SLN, whereas 4 patients were found with metastases in the non-SLN samples. The detection rate, sensitivity, specificity, and accuracy rate of SLNB in the lateral neck were 98.7%, 87.1%, 98.7%, and 93.6%, respectively. However, the values varied greatly in each specific compartment of the lateral neck, and all of them were no more than 80%. These 34 PTC patients diagnosed with lateral compartment LNM (LLNM) were more likely to be younger (41.38 vs. 48.95 years old, p = 0.002) and exhibit extrathyroidal extension (56.8% vs. 31.7%, p = 0.026) and central compartment LNM (66.7% vs. 12.1%, p < 0.001). Tumors located in the upper third of the thyroid lobe also had a significantly higher probability of LLNM compared with those in middle or inferior location (66.7% vs. 35.3% vs. 34.8%, p = 0.044). At last, age (OR=0.912, p = 0.026), tumor location (upper vs inferior, OR=17.478, p = 0.011), and central compartment LNM (OR=25.364, p < 0.001) were independently predictive of LLNM. Conclusions: SLNB can help surgeons to identify some PTC patients who may benefit from therapeutic lateral neck dissection and protect some patients from prophylactic lateral neck dissection. However, it cannot accurately indicate specific lateral compartment-oriented neck dissection. Meanwhile, LLNM is more likely to occur in PTC patients with younger age or upper pole tumors or central compartment LNM.

The association of serum uric acid with cognitive impairment and ATN biomarkers.

Background: Cognitive impairment (CI) has become a worldwide health problem. The relationship between CI and uric acid (UA) is contradictory. Objective: We included participants with a full spectrum of CI, from cognitively unimpaired (CU) to dementia, from the Chongqing Ageing & Dementia Study (CADS). Methods: First, we identified the relationships between serum UA (sUA) and cognitive function in different stages of CI. Second, we analyzed these relationships among different stages and types of CI. Finally, we explored the association between sUA and amyloid/tangle/neurodegeneration (ATN) biomarkers. Results: We recruited 427 participants from the CADS, including 382 participants with mini-mental state examination (MMSE) evaluation. The levels of sUA were positively correlated with MMSE scores (p < 0.001), and the correlation was prominent in the course of dementia and in the type of Alzheimer's disease (AD). The levels of UA had a positive correlation with plasma amyloid-ß 42 (Aß42) (p = 0.004). Higher levels of sUA weakened the correlation of MMSE scores with CSF ATN biomarkers and the correlation of CSF Aß42 with tau. Conclusion: UA is positively correlated with cognitive function, especially in the advanced stage of AD. The probable neuroprotective effects of sUA mainly act on Aß42 and the downstream pathological cascade.