Myeloid Derived Suppressor Cells (MDSCs) play important roles in constituting the immune suppressive environment promoting cancer development and progression. They are consisted of a heterogeneous population of immature myeloid cells including polymorphonuclear MDSC (PMN-MDSC) and monocytes MDSC (M-MDSC) that are found in both the systemic circulation and in the tumor microenvironment (TME). While previous studies had shown that all-trans retinoic acid (ATRA) could induce MDSC differentiation and maturation, the very poor solubility and fast metabolism of the drug limited its applications as an immune-modulator for cancer immunotherapy. We aimed in this study to develop a drug encapsulated liposome formulation L-ATRA with sustained release properties and examined the immuno-modulation effects. We showed that the actively loaded L-ATRA achieved stable encapsulation and enabled controlled drug release and accumulation in the tumor tissues. In vivo administration of L-ATRA promoted the remodeling of the systemic immune homeostasis as well as the tumor microenvironment. They were found to promote MDSCs maturation into DCs and facilitate immune responses against cancer cells. When used as a single agent treatment, L-ATRA deterred tumor growth, but only in immune-competent mice. In mice with impaired immune functions, L-ATRA at the same dose was not effective. When combined with checkpoint inhibitory agents, L-ATRA resulted in greater anti-cancer activities. Thus, L-ATRA may present a new IO strategy targeting the MDSCs that needs be further explored for improving the immunotherapy efficacy in cancer.
Previous studies have revealed changed functional connectivity patterns between brain areas in chess players using resting-state functional magnetic resonance imaging (rs-fMRI). However, how to exactly characterize the voxel-wise whole brain functional connectivity pattern changes in chess players remains unclear, which could provide more convincing evidence for establishing the relationship between longterm chess practice and brain function changes. In this study, we employed newly developed whole brain functional connectivity pattern homogeneity (FcHo) method to identify the voxel-wise changes of functional connectivity patterns in 28 chess master players and 27 healthy novices. Seed-based functional connectivity analysis was used to identify the alteration of corresponding functional couplings. FcHo analysis revealed signi cantly increased whole brain functional connectivity pattern similarity in anterior cingulate cortex (ACC), anterior middle temporal gyrus (aMTG), primary visual cortex (V1), and decreased FcHo in thalamus and precentral gyrus in chess players. Resting-state functional connectivity analyses identi ed chess players showed decreased functional connections between V1 and precentral gyrus. Besides, a linear support vector machine (SVM) based classi cation achieved an accuracy of 85.45%, a sensitivity of 85.71% and a speci city of 85.19% to differentiate chess players from novices by leave-one-out cross-validation. Finally, correlation analyses revealed that the mean FcHo values of thalamus were signi cantly negatively correlated with the training time. Our ndings provide new evidences for the important roles of ACC, aMTG, V1, thalamus and precentral gyrus in chess players and indicate that long-term professional chess training may enhance the semantic and episodic processing, e ciency of visual-motor transformation, and cognitive ability.
ObjectiveTo investigate the effects of sport stacking on the overall cognition and brain function in patients with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI).MethodsA single-blind randomized controlled design was performed using sport stacking for 30 min, 5 days/week for 12 weeks. Forty-eight subjects with mild AD or MCI were randomly divided into the sport stacking group (T-mAD = 12, T-MCI = 12) and the active control group (C-mAD = 11, C-MCI = 13). Auditory Verbal Learning Test (AVLT), Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL), Geriatric Depression Scale (GDS-30), and Pittsburgh Sleep Quality Index (PSQI) were performed, the level of amyloid β-protein-40 (Aβ-40), Aβ-42, brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1(IGF-1), tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and soluble trigger receptor expressed on myeloid cells 2 (sTREM2) in plasma were tested, and brain functional connectivity in resting state and activation under finger movement task were analyzed by functional near-infrared spectroscopy (fNIRS).ResultsThirty-nine patients completed the trial. After 4 weeks, we found a significant increase in AVLT score in T-MCI (6.36 ± 5.08 vs. −1.11 ± 4.23, p = 0.004), and T-mAD group (4.60 ± 4.77 vs. −0.11 ± 2.89, p = 0.039). After 12 weeks, there was a significantly improved in AVLT (9.64 ± 4.90 vs. −0.33 ± 6.10, p = 0.002) and ADCS-ADL (3.36 ± 3.59 vs. −1.89 ± 2.71, p = 0.003) in T-MCI. There was a significant improvement in AVLT (5.30 ± 5.42 vs. 0.44 ± 2.40) in T-mAD (p < 0.05). Plasma levels of BDNF were upregulated in both T-MCI and T-mAD, and IGF-1 increased in T-MCI (P < 0.05) compared to the control groups. The functional connectivity in MCI patients between DLPFC.R and SCA.R, SMA.L, and SCA.R was decreased. In contrast, in mAD patients, the brain regional function connection was increased between DLPFC.R and Broca's.L. The activation of channel 36 located in the left primary somatosensory cortex was significantly increased after 12-week training, which was correlated with the improved AVLT and the increase of BDNF.ConclusionOur findings suggested that sport stacking is effective for patients with MCI and mild AD, possibly through increasing the expression of neuroprotective growth factors and enhancing neural plasticity to improve neurocognitive performance.Clinical Trial Registrationhttps://www.ClinicalTrials.gov, ChiCTR.org.cn, identifier: ChiCTR-2100045980.
An outstanding chess player needs to accumulate massive visual and spatial information for chess configurations. Visual motion area (MT) is considered as a brain region specialized for visual motion perception and visuospatial attention processing. However, how long-term chess training shapes the functional connectivity patterns of MT, especially its functional subregions, has rarely been investigated. In our study, using resting-state functional connectivity (RSFC) and Granger causality analysis (GCA), we studied the changed functional couplings of MT subregions between 28 chess master players and 27 gender- and age-matched healthy novices to reveal the neural basis of long-term professional chess training. RSFC analysis identified decreased functional connections between right dorsal-anterior subregion (CI1.R) and left angular gyrus, and increased functional connections between right ventral-anterior MT subregion (CI2.R) and right superior temporal gyrus in chess experts. Moreover, GCA analyses further found increased mutual interactions of left angular gyrus and CI1.R in chess experts compared to novice players. These findings demonstrate that long-term professional chess training could enhance spatial perception and reconfiguration and semantic processing efficiency for superior performance.
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