Tremor is one of the core symptoms of Parkinson’s disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

Background Epiplakin1 (EPPK1) has been associated with disease progression and unfavorable prognosis of many cancers, but its functional involvement in esophageal squamous cell carcinoma (ESCC) remains to be uncovered. Methods The Quantitative Real‐time PCR (qPCR) assay was employed to determine the expression of EPPK1 in ESCC tissues and cells. CCK‐8 assay, colony forming assay, wound healing assay, and transwell invasion assay were utilized to evaluate the effects of EPPK1 on cell proliferation, migration, and invasion capacity in ESCC cells using small interfering ribonucleic acids. Flow cytometry was performed to estimate the cell apoptotic rate caused by silencing of EPPK1. The proteins related to epithelial‐to‐mesenchymal transition (EMT), apoptosis, and activation of the phosphatidylinositol 3‐kinase/serine threonine protein kinase 1 (PI3K/AKT) signaling pathway were measured by western blot. Results The expression of EPPK1 was dramatically increased in ESCC tissues and cells compared to that in relative controls. Additionally, silencing of EPPK1 suppressed ESCC cell growth, colony formation, migration, invasion, and EMT, while promoting ESCC cell apoptosis. Furthermore, EPPK1 induced ESCC cell progression via mediating the PI3K/AKT signaling pathway. Conclusion EPPK1 promotes ESCC progression by modulating the PI3K/AKT signaling pathway and could serve as a potential target for ESCC treatment.

Although various drugs are currently used for restless legs syndrome (RLS) in clinic, selecting appropriate drugs for patients is difficult. This network meta-analysis (NMA) aimed to compare the efficacy and safety of different drugs. After literature searching and screening, 46 trials, including 10,674 participants are included in this NMA. The pooled results showed that, compared with placebo, only levodopa is inefficient to relieve symptoms of RLS. Cabergoline decreases IRLS scores to the greatest extent among all drugs (MD −11.98, 95% CI −16.19 to −7.78). Additionally, pramipexole is superior to ropinirole in alleviating symptoms of RLS (MD −2.52, 95% CI −4.69 to −0.35). Moreover, iron supplement alleviates RLS symptoms significantly compared with placebo in patient with iron deficiency (MD −5.15, 95% CI −8.99 to −1.31), but not for RLS patients with normal serum ferritin level (MD −2.22, 95% CI −6.99 to 2.56). For primary RLS, these drugs are also effective, while there is insufficient data to analyze drug efficacy in secondary RLS. We analyzed risk of common adverse effects of drugs including nausea, somnolence, fatigue, headache and nasopharyngitis. Alpha-2-delta ligands and DAs are favorable choices for both primary and secondary RLS because of their significant efficacy and good tolerability. Iron supplement can significantly alleviate symptoms of RLS patients with iron deficiency than placebo. We recommend gabapentin, gabapentin enacarbil, and pregabalin for clinicians for first consideration mainly because that they rarely cause augmentation. Oxycodone-naloxone could be considered in patients with severe or very severe RLS who failed in treatment with above drugs.

Purpose As a third-generation EGFR TKI has been taken orally, Osimertinib effectively inhibits mutant EGFR, including T790M EGFR resistance mutations. Here, we examined real-world efficacy and tolerability of Osimertinib among Chinese patients with advanced EGFR T790M-mutant NSCLC. Patients and Methods A total of 106 advanced NSCLC patients who were taking Osimertinib following disease progression after EGFR-TKIs or other treatments were retrospectively recruited in this study. The PFS and OS after Osimertinib treatment were analyzed as the primary endpoints. Results Osimertinib was used as a second line and ≥3rd line treatment in 22.6% and 77.4% of the patients, respectively. DCR and ORR were 93.4% and 57.5%, respectively. Median PFS was 12.4 12 (95% CI, 10.5–13.5) months. The PFS was 11 (8.0, 14.0) and 12 (10.3,13.7) months ( p = 0.373), in patients with and without CNS metastasis, respectively. PFS in 2nd and ≥3rd line treatment was 11 (9.0, 13.0) and 12.4 12 (8.9, 15.1) months ( p = 0.799), respectively. In patients with EGFR exon 19 deletion and exon 21 L858 mutation, the median PFS was 11 (9.2, 12.8) and 12 (9.2, 14.8) months, respectively ( p = 0.833). Median PFS in the monotherapy group and combined anti-angiogenesis group was 11 (9.9,12.1) and 14 (11.2,16.8) months, respectively. Median OS after Osimertinib initiation was 27 (19.6, 34.4) months: 15 (6.9, 23.1) and 27 (22, 32) months in patients with and without CNS metastasis (p=0.027), 27 (20.3,33.7) months and (undefined) as second line or ≥3rd line of treatment ( p = 0.421), respectively. In patients with exon 19 deletion, the median OS was not reached, and in patients with exon 21 L858 mutations, the median OS was 23 (19.1,29.9) months (p=0.027). Median OS in the monotherapy group was 27 (21.7,32.3) months, and in combined anti-angiogenesis group was not reached (p=0.68). Conclusion Osimertinib can effectively treat advanced NSCLC with T790M mutations independently of previous treatment lines.

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Objective To identify risk factors for early neurological deterioration (END) in acute lacunar stroke patients, and its influence on functional outcome. Methods Consecutive acute lacunar stroke patients defined by MRI between January 2018 and June 2020 were included in the study. END was defined as any persisting increase in National Institutes of Health Stroke Scale (NIHSS) score of ≥2 points post admission, and favorable outcome was defined as a modified Rankin Scale (mRS) of 0-2 at discharge. Univariable and multivariable logistic regression were performed to identify risk factors related to END, as well as the influence of END on functional outcome. Results Among a total of 638 lacunar stroke patients (420 males (65.8%), median age 66 years (IQR:56-74)), 108 (16.9%) developed END, and 94.4% (102/108) of the END occurred within 72 h post admission. Admission NIHSS score (aOR 1.132, 95%CI 1.046-1.225, p=0.002), female (aOR 2.752, 95%CI 1.277-5.933, p=0.010), admission systolic blood pressure (SBP) (160-179mmHg) (aOR 9.395, 95%CI 4.310-20.479, p<0.001) and admission SBP (≥180mmHg) (aOR 16.030, 95%CI 5.991-42.891, p<0.001) were significantly associated with END. Delay time from onset to admission (aOR 0.995, 95%CI 0.990-1.000, p=0.031) , SBP dropping (≥20mmHg) within 3 days or when END occurred (aOR 0.037, 95%CI 0.016-0.086, p<0.001) and thalamic lacunar infarction (aOR 0.098, 95%CI 0.012-0.827, p=0.033) were inversely associated with END. END (aOR 12.374, 95%CI 6.881-22.254, p<0.001) and higher admission NIHSS score (aOR 1.488, 95%CI 1.359-1.629, p<0.001) predicted unfavorable outcome at discharge. Conclusion END in lacunar stroke patients is common and is associated with unfavorable outcome. Admission high SBP is a potentially modifiable risk factor for prevention of END, but this needs further investigation.

Background: Patients with Parkinson's disease (PD) present various responsiveness to levodopa, but the cause of such differences in levodopa responsiveness is unclear. Previous studies related the damage of brain white matter (WM) to levodopa responsiveness in PD patients, but no study investigated the relationship between the structural brain network change in PD patients and their levodopa responsiveness.Methods: PD patients were recruited and evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Each patient received a diffusion tensor imaging (DTI) scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated. PD patients were grouped into irresponsive group (improvement rate < 30%) and responsive group (improvement rate ≥ 30%). Tract-based spatial statistics (TBSS), deterministic tracing (DT), region of interest (ROI) analysis, and automatic fiber identification (AFQ) analyses were performed. The structural brain network was also constructed and the topological parameters were calculated.Results: Fifty-four PD patients were included. TBSS identified significant differences in fractional anisotropy (FA) values in the corpus callosum and other regions of the brain. DT and ROI analysis of the corpus callosum found a significant difference in FA between the two groups. Graph theory analysis showed statistical differences in global efficiency, local efficiency, and characteristic path length. Conclusion:PD patients with poor responsiveness to levodopa had WM damage in multiple brain areas, especially the corpus callosum, which might cause disruption of information integration of the structural brain network.

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