Ru-catalyzed asymmetric hydrogenation of α,ß-unsaturated ketones via a hydrogenation/isomerization cascade.

Ru-catalyzed asymmetric hydrogenation of α-substituted α,ß-unsaturated ketones has been developed for the enantioselective synthesis of chiral α-substituted secondary alcohols with high diastereo- and enantioselectivities (up to >99 : 1 dr, 98% ee). Mechanistic experiments suggest that the reaction proceeds via a Ru-catalyzed asymmetric hydrogenation of the CO bond in concert with a base-promoted allylic alcohol isomerization, and the final stereoselectivities were controlled by a DKR process during the asymmetric hydrogenation of the ketone intermediate.

Effect of high-field iMRI guided resection in cerebral glioma surgery: A randomized clinical trial.

BACKGROUND: Extent of resection (EOR) in glioma contributes to longer survival. The purpose of NCT01479686 was to prove whether intraoperative magnetic resonance imaging (iMRI) increases EOR in glioma surgery and benefit survival. METHODS: Patients were randomized (1:1) to receive the iMRI (n = 161) or the conventional neuronavigation (n = 160). The primary endpoint was gross total resection (GTR); secondary outcomes reported were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 188 high-grade gliomas (HGGs) and 133 low-grade gliomas (LGGs) were enrolled. GTR was 83.85% in the iMRI group vs. 50.00% in the control group (P < 0.0001). In 321 patients, the median PFS (mPFS) was 65.12 months in the iMRI group and 61.01 months in the control group (P = 0.0202). For HGGs, mPFS was improved in the iMRI group (19.32 vs. 13.34 months, P = 0.0015), and a trend of superior OS compared with control was observed (29.73 vs. 25.33 months, P = 0.1233). In the predefined eloquent area HGG subgroup, mPFS, and mOS were 20.47 months and 33.58 months in the iMRI vs. 12.21 months and 21.16 months in the control group (P = 0.0098; P = 0.0375, respectively). From the exploratory analyses of HGGs, residual tumor volume (TV) < 1.0 cm3 decreased the risk of survival (mPFS: 18.99 vs. 9.43 months, P = 0.0055; mOS: 29.77 vs. 18.10 months, P = 0.0042). LGGs with preoperative (pre-OP) TV > 43.1 cm3 and postoperative (post-OP) TV > 4.6 cm3 showed worse OS (P= 0.0117) CONCLUSIONS: It showed that iMRI significantly increased EOR and indicated survival benefits for HGGs, particularly eloquent HGGs. Residual TV in either HGGs or LGGs is a prognostic factor for survival.

MRI-derived radiomics assessing tumor-infiltrating macrophages enable prediction of immune-phenotype, immunotherapy response and survival in glioma.

BACKGROUND: The tumor immune microenvironment can influence the prognosis and treatment response to immunotherapy. We aimed to develop a non-invasive radiomic signature in high-grade glioma (HGG) to predict the absolute density of tumor-associated macrophages (TAMs), the preponderant immune cells in the microenvironment of HGG. We also aimed to evaluate the association between the signature, and tumor immune phenotype as well as response to immunotherapy. METHODS: In this retrospective setting, total of 379 patients with HGG from three independent cohorts were included to construct a radiomic model named Radiomics Immunological Biomarker (RIB) for predicting the absolute density of M2-like TAM using the mRMR feature ranking method and LASSO classifier. Among them, 145 patients from the TCGA microarray cohort were randomly allocated into a training set (N=101) and an internal validation set (N=44), while the immune-phenotype cohort (N=203) and the immunotherapy-treated cohort (N=31, patients from a prospective clinical trial treated with DC vaccine) recruited from Huashan Hospital were used as two external validation sets. The immunotherapy-treated cohort was also used to evaluate the relationship between RIB and immunotherapy response. Radiogenomic analysis was performed to find functional annotations using RNA sequencing data from TAM cells. RESULTS: An 11-feature radiomic model for M2-like TAM was developed and validated in four datasets of HGG patients (area under the curve = 0.849, 0.719, 0.674, and 0.671) using MRI images of post contrast enhanced T1-weighted (T1CE). Patients with high RIB scores had a strong inflammatory response. Four hub-genes (SLC7A7, RNASE6, HLA-DRB1 and CD300A) expressed by TAM were identified to be closely related to the RIB, providing important evidence for biological interpretation. Only individuals with a high RIB score were shown to have survival benefits from DC vaccine [DC vaccine vs. Placebo: median progression-free survival (mPFS), 10.0 mos vs. 4.5 mos, HR=0.17, P=0.0056, 95%CI=0.041-0.68; median overall survival (mOS), 15.0 mos vs. 7.0 mos, HR=0.17, P =0.0076, 95%CI=0.04-0.68]. Multivariate analyses also confirmed that treatment by DC vaccine was an independent factor for improved survival in the high RIB score group. However, in the low RIB score group, DC vaccine was not associated with improved survival. Furthermore, a radiomic nomogram based on the RIB score and clinical factors could efficiently predict the 1-, 2-, and 3-year survival rates, as confirmed by ROC curve analysis (AUC for 1-, 2- and 3-year survival: 0.705, 0.729 and 0.684, respectively). CONCLUSIONS: The radiomic model could allow for non-invasive assessment of the absolute density of TAM from MRI images in HGG patients. Of note, our RIB model is the first immunological radiomic model confirmed to have the ability to predict survival benefits from DC vaccine in gliomas, thereby providing a novel tool to inform treatment decisions and monitor patient treatment course by radiomics.

In Vivo Characterization of Cerebellar Peduncles in Chronic Ankle Instability: A Single and Multishell Diffusion-Weighted Imaging Study.

BACKGROUND: Ankle sprain causes proprioceptor injuries and prolonged joint deafferentation, which might lead to maladaptive neuroplasticity in patients with chronic ankle instability (CAI), especially in the cerebellum. Previous studies have indicated the impairment of superior cerebellar peduncle (SCP), but the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) have not been fully analyzed. HYPOTHESIS: The cerebellar peduncles of participants with CAI would have altered fractional anisotropy (FA) and orientation dispersion index (ODI) in comparison with healthy controls without ankle injury history. In addition, FA and ODI would be correlated with the duration or severity of the sensorimotor deficits in CAI. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A group of 27 participants with CAI and 26 healthy controls underwent diffusion-weighted imaging scanning, with the cerebellar peduncles as the regions of interest. The measures obtained by single-shell diffusion tensor imaging and the multishell neurite orientation dispersion and density imaging were used. Correlation analyses were performed to examine the potential relationship between the FA/ODI and both the normalized Y-balance scores and the durations of ankle instability. RESULTS: The ipsilateral ICP of the injured ankle in participants with CAI showed significantly lower FA (Cohen d 95% CI, -1.33 to -0.21; P = 0.04) and marginally significant higher ODI (Cohen d 95% CI, 0.10 to 1.20, P = 0.08) when compared with the same measures in the control group, with the ODI being positively correlated with the duration of ankle instability (r = 0.42, P = 0.03). CONCLUSION: The ICP in participants with CAI exhibited impaired integrity and a trend of abnormally organized neurites in comparison with a healthy control group. CLINICAL RELEVANCE: The impairments of ICP might be an ongoing part of the pathological process of CAI, having the potential to become a target for the diagnostic evaluation of this clinical entity.

Prospective prescription review system correlated with more rational PPI medication use, better clinical outcomes and reduced PPI costs: experience from a retrospective cohort study.

INTRODUCTION: Proton pump inhibitor (PPI) abuse poses an overwhelming threat to the allocation of medical resources and places a heavy burden on global medical expenses. In this study, we put forward our prospective prescription review system and evaluated the effects of this system on clinical outcomes, rational medication use and costs related to PPIs. METHODS: A retrospective cohort study was conducted in which the included patients were divided into a preintervention group (2019.10-2020.09) and a postintervention group (2020.10-2021.09). To reduce the bias of patients' baseline characteristics, the propensity score matching (PSM) method was employed. The primary endpoints were the incidence of stress ulcers (SUs), the improvement and cure rates of gastrointestinal haemorrhage, the defined daily dose (DDD), the drug utilization index (DUI) and the DDD/100 patient-days. The secondary endpoints included the types of unreasonable medication orders for PPIs, the PPI utilization rate and PPI costs. RESULTS: A total of 53,870 patients were included to evaluate the secondary endpoints, and 46,922 patients were paired by PSM and assessed to evaluate the primary endpoints. The number of PPIs used and PPI costs were significantly lower in the postintervention group than in the preintervention group (P < 0.001). The rationality evaluation results showed that the frequency of PPI use and the number of drug interactions were significantly higher in the preintervention group than in the postintervention group (P < 0.01). The proportion of patients taking oral PPIs was significantly increased in the postintervention group (29.30% vs. 34.56%, p < 0.01). For the utilization of PPIs both for prevention and treatment, the DUI and DDD/100 patient-days were substantially decreased in the postintervention group (P < 0.001 and P < 0.05, respectively). The incidence of SUs in the postintervention group was 44.95%, and that in the preintervention group was 51.93% (p < 0.05). CONCLUSION: The implementation of the prospective prescription review system on rational PPI use correlated with reduced PPI costs, more rational PPI medication use and better clinical outcomes, and this system is worthy of long-term implementation for further improvement of rational drug use.

Circular RNA METTL15/miR-374a-5p/ESCO2 axis induces colorectal cancer development.

This study investigated the biological role and mechanism of circMETTL15 in colorectal cancer (CRC). Cancer tissues and matched adjacent normal tissues were collected. CircMETTL15, miR-374a-5p, and ESCO2 levels were detected by RT-qPCR and Western Blot. LoVo cells were selected for loss- and gain-of-function assays and rescue assays. Cell proliferation was detected by CCK-8 and colony formation tests, cell apoptosis and cell cycle were detected by flow cytometry, cell migration and invasion were detected by Transwell assay, and protein expression of ki-67, E-cadherin, N-cadherin, and cleaved caspase-3 was detected by Western blot. Through bioinformatics analysis and verification assays, the targeting relationship between circMETTL15, miR-374a-5p, and ESCO2 was studied. The results suggest that circMETTL15 was a stable circRNA that was highly expressed in CRC tissues and cells and was associated with tumor size, higher TNM staging, and lymph node metastasis in CRC patients. Functionally, knocking down circMETTL15 inhibited the proliferation, migration, invasion, and EMT of LoVo cells, and induced apoptosis. Overexpression of circMETTL15 showed the opposite effect. The effects of knockdown or overexpression of circMETTL15 on the biological behavior of LoVo cells were reversed by knockdown of miR-374a-5p or knockdown of ESCO2, respectively. Mechanistically, circMETTL15 acts as a ceRNA for miR-374a-5p to regulate ESCO2 expression, thereby promoting the biological behavior of LoVo cells. In conclusion, the results of this study reveal the role of circMETTL15 in CRC and the underlying molecular mechanism, which provides potential data support for the development of future CRC drugs.

Effect of corticosubcortical iron deposition on dysfunction in CADASIL is mediated by white matter microstructural damage.

Iron dysregulation may attenuate cognitive performance in patients with CADASIL. However, the underlying pathophysiological mechanisms remain incompletely understood. Whether white matter microstructural changes mediate these processes is largely unclear. In the present study, 30 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients were confirmed via genetic analysis and 30 sex- and age-matched healthy controls underwent multimodal MRI examinations and neuropsychological assessments. Quantitative susceptibility mapping and peak width of skeletonized mean diffusivity (PSMD) were analyzed. Mediation effect analysis was performed to explore the interrelationship between iron deposition, white matter microstructural changes and cognitive deficits in CADASIL. Cognitive deterioration was most affected in memory and executive function, followed by attention and working memory in CADASIL. Excessive iron in the temporal-precuneus pathway and deep gray matter specific to CADASIL were identified. Mediation analysis further revealed that PSMD mediated the relationship between iron concentration and cognitive profile in CADASIL. The present findings provide a new perspective on iron deposition in the corticosubcortical circuit and its contribution to disease-related selective cognitive decline, in which iron concentration may affect cognition by white matter microstructural changes in CADASIL.

Evaluation of glymphatic-meningeal lymphatic system with intravenous gadolinium-based contrast-enhancement in cerebral small-vessel disease.

OBJECTIVE: To investigate the feasibility of using noninvasive neuroimaging methods in visualizing and evaluating the clearance of the glymphatic-meningeal lymphatic system (GMLS) in patients with arteriosclerotic cerebral small-vessel disease (CSVD) and controls. METHODS: This observational study recruited patients with high-burden CSVD and controls (age 50-80 years). At multiple time points before and after intravenous administration of a contrast agent, three-dimensional (3D) brain volume T1-weighted imaging and 3D Cube T2-fluid attenuated inversion recovery imaging were performed to visualize and assess the clearance of the glymphatics and meningeal lymphatic vessels (mLVs). We measured the signal intensity ratio (SIR) of four regions of interest representing the glymphatics and mLVs at each time point. The clearance rate at 24 h (CR24h) and changes in the SIR from baseline to 24 h (∆SIR) were defined as the clearance function. The analysis of variance was used to evaluate the group differences after adjusting for hypertension. RESULTS: A total of 20 CSVD patients and 15 controls were included. Cortical periarterial enhancement and the enhancement of enlarged perivascular spaces in the basal ganglia were respectively observed in 11 (55.00%) and 16 (80.00%) CSVD patients, but in none of controls. All CSVD patients and most of controls (80.00%) showed cortical perivenous enhancement. Para-sinus enhancement was observed in all participants. CSVD patients showed lower CR24h and higher ∆SIR of the glymphatics and mLVs (all p < 0.05). CONCLUSION: The impaired drainage of the GMLS in patients with high-burden CSVD could be visually evaluated using noninvasive neuroimaging methods with intravenous gadolinium-based contrast-enhancement. CLINICAL RELEVANCE STATEMENT: Dynamic intravenous contrast-enhanced MRI could visually evaluate the impaired drainage of the glymphatic-meningeal lymphatic system in patients with high-burden cerebral small-vessel disease and could help to explore a new therapeutic target. KEY POINTS: • Signal intensity changes in regions representing the glymphatic-meningeal lymphatic system (GMLS) can reflect the drainage function based on contrast-enhanced 3D-FLAIR and 3D T1-weighted MRI. • Impaired drainage of the GMLS in patients with high-burden CSVD can be visually evaluated using dynamic intravenous contrast-enhanced MRI. • This direct, noninvasive technique could serve as a basis for further GMLS studies and could help to explore a new therapeutic target in CSVD patients.

ß-Arylation of Racemic Secondary Benzylic Alcohols to Access Enantioenriched ß-Arylated Alcohols.

The transformation of alcohols into value-added products is of great importance, as simple alcohols are widespread and can be easily derived from both fossil fuels and biomass. The selective functionalization of a sp3 C-H bond on the alkyl side chain of an alcohol over its hydroxyl group would offer an expedient route to expand the chemical space of alcohols but it remains a challenging task. Harnessing the borrowing hydrogen strategy, the ß-arylation of secondary alcohols with aryl bromides has been achieved in this study, which allows for the selective functionalization of a ß-Csp3 -H bond in an alcohol substrate. Under the catalysis of a Pd complex, secondary alcohols reacted with aryl bromides to afford 1,2-diaryl alcohols with broad substrate scope in the presence of a ketone additive. Furthermore, the enantioconvergent version of the reaction has also been realized, transforming racemic secondary alcohols into enantioenriched chiral 1,2-diaryl alcohols under the cooperative Pd and Ru catalysis. Mechanism studies indicate that the reactions are enabled by borrowing hydrogen catalysis.

Reduced left hippocampal perfusion is associated with insomnia in patients with cerebral small vessel disease.

OBJECTIVES: Insomnia was associated with cerebral structural changes and Alzheimer's disease. However, associations among cerebral perfusion, insomnia with cerebral small vessel disease (CSVD), and cognitive performance were little investigated. METHODS: This cross-sectional study included 89 patients with CSVDs and white matter hyperintensities (WMHs). They were dichotomized into the normal sleep and poor sleep group, according to Pittsburgh sleep quality index (PSQI). Baseline characteristics, cognitive performance, and cerebral blood flow (CBF) were measured and compared between the two groups. The association or correlation between cerebral perfusion, cognition, and insomnia was analyzed using binary logistic regression. RESULTS: Our study found that declined MoCA score (P = .0317) was more prevalent in those with poor sleep. There was a statistical difference in the recall (P = .0342) of MMSE, the delayed recall (P = .0289) of MoCA between the two groups. Logistic regression analysis showed educational background (P < .001) and insomnia severity index (ISI) score (P = .039) were independently correlated with MoCA scores. Arterial spin labeling demonstrated that left hippocampal gray matter perfusion was significantly reduced (P = .0384) in the group with poor sleep. And, negative correlation was found between left hippocampal perfusion and PSQI scores. CONCLUSIONS: In the patients with CSVDs, insomnia severity was associated with cognitive decline. Left hippocampal gray matter perfusion was correlated with PSQI scores in CSVDs.

Characterization of neuroinflammation pattern in anti-LGI1 encephalitis based on TSPO PET and symptom clustering analysis.

PURPOSE: TSPO PET with radioligand [18F]DPA-714 is an emerging molecular imaging technique that reflects cerebral inflammation and microglial activation, and it has been recently used in central nervous system diseases. In this study, we aimed to investigate the neuroinflammation pattern of anti-leucine-rich glioma-inactivated 1 (LGI1) protein autoimmune encephalitis (AIE) and to evaluate its possible correlation with clinical phenotypes. METHODS: Twenty patients with anti-LGI1 encephalitis from the autoimmune encephalitis cohort in Huashan Hospital and ten with other AIE and non-inflammatory diseases that underwent TSPO PET imaging were included in the current study. Increased regional [18F]DPA-714 retention in anti-LGI1 encephalitis was detected on a voxel basis using statistic parametric mapping analysis. Multiple correspondence analysis and hierarchical clustering were conducted for discriminate subgroups in anti-LGI1 encephalitis. Standardized uptake value ratios normalized to the cerebellum (SUVRc) were calculated for semiquantitative analysis of TSPO PET features between different LGI1-AIE subgroups. RESULTS: Increased regional retention of [18F]DPA-714 was identified in the bilateral hippocampus, caudate nucleus, and frontal cortex in LGI1-AIE patients. Two subgroups of LGI1-AIE patients were distinguished based on the top seven common symptoms. Patients in cluster 1 had a high frequency of facio-brachial dystonic seizures than those in cluster 2 (p = 0.004), whereas patients in cluster 2 had a higher frequency of general tonic-clonic (GTC) seizures than those in cluster 1 (p < 0.001). Supplementary motor area and superior frontal gyrus showed higher [18F]DPA-714 retention in cluster 2 patients compared with those in cluster 1 (p = 0.024; p = 0.04, respectively). CONCLUSIONS: Anti-LGI1 encephalitis had a distinctive molecular imaging pattern presented by TSPO PET scan. LGI1-AIE patients with higher retention of [18F]DPA-714 in the frontal cortex were more prone to present with GTC seizures. Further studies are required for verifying its value in clinical application.

Decreased water exchange rate across blood-brain barrier in hereditary cerebral small vessel disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased kw in the whole brain (ß = -0.634, P = 0.001), normal-appearing white matter (ß = -0.599, P = 0.002) and temporal lobe (ß = -0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (ß = 0.458, P = 0.001; ß = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.

Outcome Prediction of Unconscious Patients Based on Weighted Sparse Brain Network Construction.

It is quite challenging to establish a prompt and reliable prognosis assessment for acquired brain injury (ABI) patients with persistent severe disorders of consciousness (DOC) like unconscious comatose and unresponsive wakefulness syndrome (a.k.a., vegetative state). Recent advances in brain functional imaging and functional net-work analysis have demonstrated its potential in determining the consciousness level and prognostic outcome for ABI patients with DOC. However, the diagnostic and prognostic usefulness of the whole-brain functional connectome based on advanced machine learning techniques has not been fully evaluated. The first aim of this study is to predict the outcome of individual unconscious ABI patients during a three-month follow-up. The second aim is to conduct precise individualized differentiation among different consciousness levels for exploring the neurobiological mechanisms underlying DOC. Based on resting-state fMRI, we construct large-scale functional networks by using a weighted sparse model, which ensures sparsity and interpretability by preserving strong functional connections. The functional connection strengths are exploited as features for outcome prediction and consciousness level differentiation. We achieve significantly improved consciousness level classification (accuracy: 84.78%) and recovery outcome prediction (accuracy: 89.74%) compared to other network construction methods. More importantly, we reveal the contributive connections across the entire brain in both tasks. These connections could serve as the potential biomarkers for better understanding of consciousness and further provide new insight into the development of diagnostic, prognostic, and effective therapeutic guidelines for ABI patients with DOC.

Endogenous Neural Stem Cell-induced Neurogenesis after Ischemic Stroke: Processes for Brain Repair and Perspectives.

Ischemic stroke is a very common cerebrovascular accident that occurred in adults and causes higher risk of neural deficits. After ischemic stroke, patients are often left with severe neurological deficits. Therapeutic strategies for ischemic stroke might mitigate neuronal loss due to delayed neural cell death in the penumbra or seek to replace dead neural cells in the ischemic core. Currently, stem cell therapy is the most promising approach for inducing neurogenesis for neural repair after ischemic stroke. Stem cell treatments include transplantation of exogenous stem cells but also stimulating endogenous neural stem cells (NSCs) proliferation and differentiation into neural cells. In this review, we will discuss endogenous NSCs-induced neurogenesis after ischemic stroke and provide perspectives for the therapeutic effects of endogenous NSCs in ischemic stroke. Our review would inform future therapeutic development not only for patients with ischemic stroke but also with other neurological deficits.

Changing handedness after nerve reconstruction in brachial plexus birth palsy.

Purpose: Right obstetric brachial plexus injuries (OBPI) often lead to left-handedness before limb function is restored post-surgery. A pertinent question arises about promoting a transition from left to right-handedness. We hypothesized that, with the decrease in neuroplasticity, handedness switching is not only difficult, but also reduces handedness-speech lateralization, impaired motor adaptability, and compromised language proficiency. Methods: We retrospectively analyzed clinical data from January 1996 to January 2012 at our hospital. Participants were divided into intervention or control groups based on handedness switching. We compared handedness and computed lateral quotient (LQ) and lateralization index (LI) for handedness-speech center. Additionally, we assessed dominant hand's writing speed, language function, and IQ. Associations between absolute LI and LQ values, writing speed, language scores, and IQ were examined. Results: Nineteen extended Erb's palsy participants were enrolled, eight in the intervention group, and 11 in the control. No right-handed individuals were found in either cohort. The intervention group had significantly lower LQ and LI values, and fewer achieved normal writing speed. Yet, no notable disparities in language scores or IQ emerged. Notably, we established correlations between motor finesse, handedness degree, and handedness-speech lateralization. Conclusion: For right extended Erb's palsy, shifting handedness is nearly unfeasible, and such an endeavor could trigger a reduction in handedness-speech lateralization magnitude and diminished motor finesse.

DYRK2 downregulation in colorectal cancer leads to epithelial-mesenchymal transition induction and chemoresistance.

Colorectal cancer (CRC) is among the most prominent causes of cancer-associated mortality in the world, with chemoresistance representing one of the leading causes of treatment failure. However, the mechanisms governing such chemoresistance remain incompletely understood. In this study, the role of DYRK2 as a mediator of CRC cell drug resistance and the associated molecular mechanisms were assessed by evaluating human tumor tissue samples, CRC cell lines, and animal model systems. Initial analyses of The Cancer Genome Atlas database and clinical tissue microarrays revealed significant DYRK2 downregulation in CRC in a manner correlated with poor prognosis. We further generated LoVo CRC cells that were resistant to the chemotherapeutic drug 5-FU, and found that such chemoresistance was associated with the downregulation of DYRK2 and a more aggressive mesenchymal phenotype. When DYRK2 was overexpressed in these cells, their proliferative, migratory, and invasive activities were reduced and they were more prone to apoptotic death. DYRK2 overexpression was also associated with enhanced chemosensitivity and the inhibition of epithelial-mesenchymal transition (EMT) induction in these LoVo 5-FUR cells. Co-immunoprecipitation assays revealed that DYRK2 bound to Twist and promoted its proteasomal degradation. In vivo studies further confirmed that the overexpression of DYRK2 inhibited human CRC xenograft tumor growth with concomitant Twist downregulation. Overall, these results thus highlight DYRK2 as a promising therapeutic target in CRC worthy of further investigation.

Low Regional Homogeneity of Intrinsic Cerebellar Activity in Ankle Instability: An Externally Validated rs-fMRI Study.

PURPOSE: Joint deafferentation after post-ankle sprain ligament healing can disrupt sensory input from the ankle and induce maladaptive neuroplasticity, especially in the cerebellum. This study aimed to determine whether the regional homogeneity of intrinsic cerebellar activity differs between patients with ankle instability and healthy controls without a history of ankle injury. METHODS: The current study used a primary data set of 18 patients and 22 healthy controls and an external UK Biobank data set of 16 patients with ankle instability and 69 healthy controls for a cross-database, cross-sectional investigation. All participants underwent resting-state functional magnetic resonance imaging to calculate their regional homogeneity (ReHo) value. Between-group comparisons of the sensorimotor-related subregions of the cerebellum were first performed in the primary data set to identify low cerebellar ReHo in patients with multiple comparison corrections, and the surviving subregions were then externally validated in the UK Biobank data set. Correlation analyses between the ReHo values and clinical features were also performed. RESULTS: The ReHo value of cerebellar lobule VIIIb was significantly lower in the ankle instability group than in the controls (0.170 ± 0.016 vs 0.184 ± 0.019 in the primary data set, 0.157 ± 0.026 vs 0.180 ± 0.042 in the UK Biobank data set). The ReHo values of this subregion showed a significant positive correlation with the Cumberland Ankle Instability Tool scores in the ankle instability group (r = 0.553, P-corrected = 0.0348). CONCLUSIONS: Patients with ankle instability had lower intraregional coherence in cerebellar lobule VIIIb than that of controls, which was also positively correlated with the intensity of self-reported ankle instability.

Biological functions of RNA modification patterns that define tumor microenvironment and survival outcomes in testicular germ cell tumors.

BACKGROUND: Accumulating evidence has indicated that aberrant RNA modifications are associated with malignant progression and the immune microenvironment in various tumors. However, the function of RNA modification regulators in testicular germ cell tumors (TGCTs) remains to be discovered. This study aimed to investigate the biological functions of RNA modification regulators in testicular germ cell tumors and identify their potential clinical predictive value. METHODS: Expression level of 75 RNA modification regulators was acquired to generate differential expression patterns. RNA modification regulatory genes were applied to construct a progression-free survival (PFS) risk model. Meanwhile, three RNA modification clusters were identified using consensus clustering. Subsequently, the infiltration characteristics of cells in the microenvironment as well as the antitumor drug candidates have been further analyzed. Finally, to further validate our results, we examined the expression and biological behavior of seven selected RNA modification regulators both in TGCT cell lines and clinical tissues. RESULTS: We collected the differentially expressed regulators of RNA modification. RNA modification risk signature was developed to stratify the prognosis of TGCT patients. Furthermore, we found significant differences in immune microenvironment between subgroups. Ultimately, seven selected RNA modification regulators were further verified. CONCLUSIONS: We generated and validated a risk signature related to RNA modification which could accurately predict the relapse risk in TGCT patients. This risk signature was correlated with immune cells infiltration among tumor microenvironments. Furthermore, we screened antitumor drug candidates and evaluated the sensitivity and efficacy of class chemotherapeutic drugs, which could provide reference for clinical drug use.

A regulatory circuit of lncRNA NLGN1-AS1 and Wnt signalling controls clear cell renal cell carcinoma phenotypes through FZD4-modulated pathways.

BACKGROUND: Recent evidence has indicated that long non-coding RNAs (lncRNAs) were emerged as key molecules in clear cell renal cell carcinoma (ccRCC). TCGA database showed that the expression level of lncRNA NLGN1-AS1 was up-regulated in ccRCC; However, whether NLGN1-AS1 implicated in the malignant progression of ccRCC remained unclear. METHODS: Based on TCGA database, candidate lncRNAs were selected and quantitative real-time PCR (qRT-PCR) was utilized to verify the expression levels of candidate lncRNAs in human ccRCC tissues. Loss-of-function experiments were performed to examine the biological functions of NLGN1-AS1 both in vitro and in vivo. According to bioinformatics analysis, fluorescence reporter assays and rescue experiments, the underlying mechanisms of NLGN1-AS1 in ccRCC cell lines were so clearly understood. RESULTS: As a novel lncRNA, NLGN1-AS1 was up-regulated in ccRCC cell lines and associated with poor prognosis of and ccRCC patients, which was correlated with the progression of ccRCC. Functionally, the down-regulation of NLGN1-AS1 significantly decreased the proliferation of ccRCC cells both in vitro and in vivo. Bioinformatics analysis and luciferase report assays identified that miR-136-5p was a direct target of NLGN1-AS1. We also determined that FZD4 were inhibitory targets of miR-136-5p, and that Wnt/ß-catenin signaling was inhibited by both NLGN1-AS1 knockdown and miR-136-5p over-expression. In addition, we found that the suppression of proliferation and the inhibition of Wnt/ß-catenin pathway induced by NLGN1-AS1 knockdown would require the over-expression of FZD4. CONCLUSIONS: Our findings suggested that lncRNA NLGN1-AS1 could promote the progression of ccRCC by targeting miR-136-5p/FZD4 and Wnt/ß-catenin pathway, and might serve as a novel potential therapeutic target to inhibit the progression of ccRCC.