Humanized CD36 (hCD36) mouse model supports the preclinical evaluation of therapeutic candidates targeting CD36.

CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates lipid uptake, advanced oxidation protein products, and immunological recognition, and has roles in lipid accumulation, apoptosis, as well as in metastatic colonization in cancer. CD36 is involved in tumor immunity, metastatic invasion, and therapy resistance through various molecular mechanisms. Targeting CD36 has emerged as an effective strategy for tumor immunotherapy. In this study, we have successfully generated a novel hCD36 mouse (Unless otherwise stated, hCD36 mouse below refer to homozygous hCD36 mouse) strain where the sequences encoding the extracellular domains of the mouse Cd36 gene were replaced with the corresponding human sequences. The results showed that the hCD36 mice only expressed human CD36, and the proportion of each lymphocyte was not significantly changed compared with wild-type mice. Furthermore, CD36 monoclonal antibody could significantly inhibit tumor growth after treatment. Therefore, the hCD36 mouse represent a validated preclinical mouse model for the evaluation of tumor immunotherapy targeting CD36.

The establishment of B cell-deficient Igh-J KO mouse model by gene editing and efficacy evaluation.

Over the last few years, immunotherapy has made significant progress in treating various cancers with therapeutic antibodies. However, therapeutic antibodies have been validated for inducing an unintended immune response in human and animal models, which leads to the emergence of anti-drug antibodies (ADAs) and affects their effectiveness and safety. In preclinical research, ADAs production by B cells may accelerate antibody metabolism and result in missing potential candidate molecules. Thus, it is urgent to develop preclinical models that remove only B cells without affecting the function of T and NK cells. Rearrangement of immunoglobulin heavy chain J gene fragment (Igh-J) is the first link in B cell development, and immunotherapies are currently leaning toward combination treatments with PD-1/PD-L1 antibodies, here we created humanized PD-1, PD-L1 and Igh-J knockout (hPD-1/hPD-L1, Igh-J KO) mice and validated by using the reported high immunogenicity drug M7824 (a protein designed to simultaneously block PD-L1 and TGF-ß pathways, poorly anti-tumor efficacy in immunocompetent mice). Phenotypic analysis revealed that human PD-1 and PD-L1 were detectable in hPD-1/hPD-L1, Igh-J KO mice, but not mouse IgM and IgD. Igh-J KO depleted B cells while increased the percentage of other immune cell types. Meanwhile, the humanization of PD-1/PD-L1 and Igh-J KO had neither effect on the overall development, differentiation, or distribution of T cell subtypes, nor on the activation of NK and T cells, indicating that mice can be used for T and NK-related immunotherapies. Furthermore, M7824 treatment of these B cell-deficient mice inhibited tumor growth significantly, with higher M7824 analog concentrations and lower ADA-positive rates. These findings demonstrate that Igh-J KO mice are an effective and stable preclinical model for testing drugs based on T and NK cells with high immunogenicity in vivo.

Research progress on immunogenicity of therapeutic antibodies / 中国生物制品学杂志

@#Therapeutic antibodies have achieved ideal results in clinical practice,while the immunogenicity of antibody drugs may trigger anti-drug immune response in the body,thus inducing the formation of anti-drug antibody(ADA).ADA affects the clearance and bioavailability of drugs through neutralizing/non-neutralizing drug activities,and changes the pharmacokinetic and pharmacodynamic characteristics of drugs,which can interfere or block the therapeutic effect of drugs and may lead to adverse reactions to varying degrees in clinical practice,and can interfere with the effectiveness evaluation and screening of candidate molecules in preclinical studies.Therefore,this paper reviewed the factors affecting immunogenicity,the types and formation mechanism of ADA,the detection methods of ADA,the strategies to mitigate immunogenicity and the development of preclinical animal models for highly immunogenic drugs,so as to provide a reference for the development of therapeutic antibodies.

Machine learning with magnetic resonance imaging for prediction of response to neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis.

PURPOSE: The aim of this meta-analysis was to determine the diagnostic accuracy of machine learning (ML) models with MRI in predicting pathological response to neoadjuvant chemotherapy in patients with breast cancer. Furthermore, we compared the pathologic complete response (pCR) prediction performance of ML + radiomics with that of a deep learning (DL) algorithm. METHODS: A search for relevant studies published until December 20, 2021 was conducted in MEDLINE and EMBASE databases. The quality of the studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies -2 criteria. The I2 value assessed the heterogeneity of the included studies as well as the decision to adopt a random effects model. The area under the receiver operating characteristic curves (AUC) was pooled to quantify the predictive accuracy. Subgroup analysis, meta-regression analysis, and sensitivity analysis were performed to detect potential sources of study heterogeneity. A funnel plot was used to investigate publication bias. The PROSPERO ID of our study was CRD42022284071. RESULT: Seventeen eligible studies encompassing 3392 patients were evaluated in the analysis. ML + MRI showed high accuracy (AUC = 0.87, 95% CI = 0.84-0.91) in predicting response to neoadjuvant therapy. In subgroup analysis, the AUC of the DL subgroup (AUC = 0.92, 95% CI = 0.88-0.97) was higher than that of the ML + radiomics subgroup (AUC = 0.85, 95% CI = 0.82-0.90) (P = 0.030). In the ML + radiomics subgroup, the studies using MRI combined with other parameters (clinical or histopathologic information; AUC = 0.90, 95% CI = 0.85-0.96) reported better performance than studies using only MRI parameters (AUC = 0.82, 95% CI = 0.78-0.86) (P = 0.009). CONCLUSIONS: ML applied to MRI enabled moderate accuracy in predicting pathological response to neoadjuvant therapy in patients with breast cancer. Furthermore, the meta-analysis showed that DL had higher predictive accuracy than ML + radiomics.

Chitotriosidase attenuates brain inflammation via HDAC3/NF-κB pathway in D-galactose and aluminum-induced rat model with cognitive impairments.

Chitotriosidase (CHIT1, chitinase 1) is increased in the cerebrospinal fluid and peripheral blood of Alzheimer's disease (AD) patients. Our previous study has shown that CHIT1 provides potential protection through microglial polarization and reduction of ß-amyloid (Aß) oligomers on rat models of AD. Histone deacetylase 3 (HDAC3) plays a significant role in the expression and regulation of proteins related to the pathophysiology of AD. In addition, nuclear factor-kappa B (NF-κB) signaling pathway activation in neurons is associated with the progression of AD. NF-κB activation is regulated by HDAC3 deacetylation. In the present study, we researched the role of CHIT1 in HDAC3/NF-κB signaling in D-galactose (D-gal) and aluminum-exposed rat model with cognitive impairments. Following CHIT1 treatment, we found that the protein and mRNA levels of HDAC3 and NF-κB were reduced, the expression level of IκBα increased, anti-inflammatory factors (Arg-1, IL-10, and CD206) were elevated while pro-inflammatory factors (TNF-a, iNOS, and IL-1ß) were decreased in D-gal/aluminum-induced AD rats. These results indicate that CHIT1 can regulate brain inflammation via HDAC3/NF-κB p65 pathway, contributing to improvement of cognitive impairment.

Usage and adherence of antidementia drugs in a memory clinic cohort in Chongqing, Southwest China.

BACKGROUND: To investigate the use and adherence of antidementia drugs in elderly patients with dementia from the Memory Clinic of The First Affiliated Hospital of Chongqing Medical University. METHODS: Patients were recruited from the Memory Clinic of The First Affiliated Hospital of Chongqing Medical University from December 2010 to December 2018. Medical charts were reviewed, including diagnosis, dosage of antidementia medicines, neuropsychological testing scores, and the further questionnaires were conducted via face-to-face or telephone, included duration of treatment, types of antidementia drugs, and reasons for treatment discontinuation. RESULTS: The data from 422 patients were analysed retrospectively for this study. Three hundred and fifteen were diagnosed with Alzheimer's disease (AD), 67 with mild cognitive impairment (MCI), and 40 with other types of dementia. From the 422 patients, 26.8% were treated with original donepezil (n = 113), 11.6% with generic donepezil (n = 49), 24.6% with memantine (n = 104), 13.3% with huperzine A (n = 56), and 23.7% with a combination of drugs (n = 100). However, 73% of patients discontinued treatment within 1 year of initiation. Patients treated for more than 36 months (37.8%) were more likely to choose combined medication, as compared with patients treated for less than 36 months. Patients with less than 9 years of education (odds ratio (OR): 2.394; 95% CI: 1.508-3.801) were more likely to discontinue treatment than patients with more than 9 years of education. Patients with elevated physical self-maintenance scale (PSMS) scores (OR: 1.195; 95% CI: 1.086-1.316) had a high risk of discontinuation. CONCLUSIONS: Overall treatment compliance is relatively poor in memory clinics in Chongqing. Our study demonstrates that higher education may lead to better treatment adherence in dementia care. Combination therapy may increase treatment time. However, poorer PSMS scores are a significant risk factor for treatment discontinuation.

Increased plasma sestrin2 concentrations in patients with chronic heart failure and predicted the occurrence of major adverse cardiac events: A 36-month follow-up cohort study.

BACKGROUND: Previous study had demonstrated that sestrin2 (Sesn2) expression was increased in human failing heart. Although, the circulating Sesn2 concentrations in patients with chronic heart failure (CHF) remains unknown. This study investigated plasma Sesn2 concentrations in patients with CHF and the role between Sesn2 and the occurrence of major adverse cardiac events. METHODS: A total of 80 control subjects and 220 CHF patients were enrolled and the Sesn2 concentrations of each sample were measured. Additionally, the occurrence of major adverse cardiac events in each CHF patient were followed prospectively for 36 months. RESULTS: Increased plasma Sesn2 concentrations were found in CHF patients and gradually increased from New York Heart Association (NYHA) functional class II to IV. The Sesn2 concentrations were positively correlated with N-terminal B-type natriuretic peptide (NT-pro BNP) but negatively correlated with left ventricular ejection fraction (LVEF) in CHF patients. The ROC curve suggested that Sesn2 had a certain value in predicting major adverse cardiac events during CHF patients, although, the predictive role of Sesn2 is not as good as NT-pro BNP. In addition, the multivariate Cox hazard analysis was performed after the CHF patients were divided into 3 groups (low, middle, and high) base on the plasma Sesn2 concentrations category, and the results showed that both high and middle Sesn2 concentrations increased the incidence of major adverse cardiac events when compared with low Sesn2 group. Furthermore, CHF patients with major adverse cardiac events showed higher Sesn2 concentrations when compared with CHF without major adverse cardiac events. The Kaplan-Meier analysis was performed after the CHF patients were divided into 2 groups according to the median Sesn2 concentrations and the results revealed that patients with high Sesn2 concentrations had a higher risk of major adverse cardiac events compared with those with low Sesn2. CONCLUSIONS: Plasma Sesn2 concentrations were increased in CHF patients and positively correlated with the severity of CHF. Increased Sesn2 concentrations significantly increased the occurrence of major adverse cardiac events and suggested poor outcome in CHF patients.