Jieyu Anshen Granules (JY) is a traditional Chinese medicine formula commonly used as an adjuvant treatment for Alzheimer's disease (AD) complicated with depression. However, the specific underlying mechanisms and therapeutic targets of JY remain unclear. We used the TCMSP, TCMID, BATMAN-TCM, and other databases to screen the components and assumed targets of JY. Next, the GEO and DisGeNET databases were used to identify the related targets of both AD and Major Depressive Disorder (MDD). Enrichment analyses of core targets were performed, and the main components and core targets of JY for the comorbidity of AD and MDD were identified via protein-protein interaction (PPI) network construction and machine learning algorithms. Lastly, we verified binding affinity using the AutoDock software and molecular docking was performed. A total of 171 components were identified from JY, and 979 targets were obtained from the screening process. Bioinformatics analysis displayed 397 differentially expressed genes (DEGs) were shared by AD and MDD. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) functional enrichment analysis revealed significant enrichment of genes associated with neurotransmitter receptor activity, G protein-coupled amine receptor activity, as well as signaling pathways such as the cAMP signaling pathway, PI3K-Akt signaling pathway, and cholinergic synapses. Through the PPI network and machine learning, we identified three hub genes (Ataxia telangiectasia-mutated gene [ATM], Colony stimulating factor 1 receptor [CSF1R], EPH receptor B2 [EPHB2]) as potential therapeutic targets. Molecular docking confirmed that the components of JY (Mairin, Hederagenin, 3-Epioleanolic Acid) could effectively bind to multiple key targets. This study revealed the effective components and potential mechanisms associated with JY treatment regarding AD and MDD comorbidities, offering valuable insights into promising therapeutic targets for subsequent studies.
Hypothesis In this study, we aimed to examine the cochlear expression pattern and function of Striatin-interacting protein 2 (STRIP2) by using animal models. Background Sensorineural hearing loss often results from genetic defects in hair cell (HC) development and function. STRIP2 is a part of the striatin-interacting phosphatase and kinase (STRIPAK) complex, which plays important regulatory roles in cell fate determination, proliferation, cytoskeletal organization, and cell morphology. A recent study revealed Strip2 as the candidate gene that regulates positive selection in HC lineages. However, its role in the inner ear has not been identified. Methods Strip2 knockout mouse model was used to examine the cochlear expression pattern and function of STRIP2. Auditory brainstem response test was used to evaluate the hearing function of mice. Immunostaining and scanning electron microscope were used to study hair cells, synapses, and stereocilia of cochlea. Results Immunostaining showed that cytoplasmic STRIP2 expression in hair cells increased from postnatal day (P) 3 to P14. Despite having normal hearing thresholds, hair cell numbers, and stereocilia morphology until P90, the deletion of Strip2 resulted in a mild reduction in ribbon synapse density, suggesting a late onset of cochlear synaptic defects. Conclusion Our results revealed that STRIP2 was abundantly expressed in hair cells; however, the hearing function of Strip2 −/− mice was comparable to that of control mice until P90, and a mild decrease in ribbon synapse number was detected at P60 and P90. Further studies on STRIP2 and its associated complexes will provide new insights into the pathways involved in inner ear development and function.
Abstract High myopia (HM) is associated with impaired long-distance vision. accumulating evidences reported that abnormal visual experience leads to dysfunction in brain activity in HM even corrected. However, whether the long-term of abnormal visual experience lead to neuroanatomical changes remain unknown, the aim at this study is to investigate the alternation of cortical surface thickness in HM patients. 82 patients with HM (HM groups), 57 healthy controls (HC groups) were recruited. All participants underwent high-resolution T1 and resting-state functional magnetic resonance imaging (MRI) scans. The cortical thickness analysis was preformed to investigate the neuroanatomical changes in HM patients using computational anatomy toolbox (CAT 12) toolbox. Compare with HCs, HM patients showed decreased the cortical surface thickness in the left middle occipital gyrus (MOG), left inferior parietal lobule (IPL), right inferior temporal gyrus (ITG), right precuneus, right primary visual area 1 (V1), right superior temporal gyrus (STG), right superior parietal lobule (SPL), right occipital pole, and right the primary motor cortex (M1), and increased to the parietal operculum (OP4) (P < 0.01, FWE-corrected), the mean cortical thickness of right orbitofrontal cortex (OFC), right dorsolateral prefrontal cortex (DLPFC) and right subcallosal cortex showed negatively correlation between clinical variables (axis length (ALM), the average macular thickness (AMT), keratometer (KER) 1, KER2, the mean KER, the mean macular fovea thickness (MFK), the refractive diopter) in HM patients. Our result mainly provided an evidence of cortical thickness reduction and disconnection in visual center and visual processing area, and cortical thickness increase in left multimodal integration region in HM patients. This may provide important significance of the study of the neural mechanism of HM.
Background Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort ( NCT02383212 ) and the pivotal Phase 2 study ( NCT02760498 ). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study ( NCT02760498 ). Methods The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability. Results For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%). Conclusion In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses. Trial registration number Clinicaltrials.gov, NCT02760498 . Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498
The process of skeletal regeneration initiated by stem cells following injury, especially in fractures, is significantly impaired by aging and adverse factors. Nicotinamide mononucleotide (NMN), a critical endogenous precursor of nicotinamide adenine dinucleotide (NAD), has garnered extensive attention for its multifaceted regulatory functions in living organisms and its wide-ranging therapeutic potential. However, whether NMN contributes to trauma-induced skeletal regeneration remains unclear.
Sensorineural hearing loss (SNHL) affects approximately 466 million people worldwide, which is projected to reach 900 million by 2050. Its histological characteristics are lesions in cochlear hair cells, supporting cells, and auditory nerve endings. Neurological disorders cover a wide range of diseases affecting the nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), autism spectrum disorder (ASD), etc. Many studies have revealed that neurological disorders manifest with hearing loss, in addition to typical nervous symptoms. The prevalence, manifestations, and neuropathological mechanisms underlying vary among different diseases. In this review, we discuss the relevant literature, from clinical trials to research mice models, to provide an overview of auditory dysfunctions in the most common neurological disorders, particularly those associated with hearing loss, and to explain their underlying pathological and molecular mechanisms.
9519 Background: CSCC is rivaled only by basal cell carcinoma as the most common cancer in the US. There is no standard of care for patients with mCSCC; hence there is a significant unmet need in these patients. Cemiplimab (REGN2810) treatment at 3 mg/kg Q2W demonstrated encouraging preliminary activity in CSCC in a phase 1 study (ASCO 2017, #9503). We present the primary analysis of the mCSCC cohort from the pivotal phase 2 study (NCT02760498; data cutoff date Oct 27, 2017). Methods: Patients with mCSCC (defined as nodal and/or distant) received cemiplimab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks (Q2W). Tumor measurements were performed every 8 weeks. The primary objective was to evaluate overall response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Duration of response (DOR) was a key secondary endpoint. Durable disease control rate (DDCR) was defined as stable disease or response for ≥16 weeks. Results: 59 patients were enrolled (54 M/ 5 F; median age: 71.0 years [range: 38–93]; ECOG performance status: 0 and 1 in 23 and 36 patients, respectively). 33 patients (55.9%) had received prior systemic therapy and 50 (84.7%) had received prior radiotherapy. Median duration of follow-up was 7.9 months (range: 1.1–15.6). ORR by central review was 47.5% (95% CI: 34.3–60.9; 4 CRs and 24 PRs). Responses were observed irrespective of prior systemic therapy. Median DOR has not been reached. Only 3 responding patients had subsequent disease progression at the time of data cut-off. DDCR was 61% (95% CI: 47.4–73.5). Median time to response was 1.9 months (range: 1.7–6.0). The most common adverse events (AEs) regardless of attribution (all grades, ≥Grade 3) were diarrhea (27.1%, 1.7%), fatigue (23.7%, 1.7%), and nausea (16.9%, 0.0%). Immune-related AEs ≥Grade 3 (per investigator assessment) occurred in 10.2% of patients. Conclusions: In the largest prospective study reported in patients with mCSCC, cemiplimab 3 mg/kg Q2W showed substantial activity and durable responses with an acceptable safety profile. Clinical trial information: NCT02760498.
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