Factors Affecting Life-Sustaining Treatment Decisions and Changes in Clinical Practice after Enforcement of the Life-Sustaining Treatment Decision (LST) Act: A Tertiary Hospital Experience in Korea.

Purpose: In Korea, the act on hospice and palliative care and decisions on life-sustaining treatment (LST) was implemented on February 4, 2018. We aimed to investigate relevant factors and clinical changes associated with LST decisions after law enforcement. Materials and Methods: This single-center retrospective study included patients who completed LST documents using legal forms at Asan Medical Center from February 5, 2018, to June 30, 2020. Results: 5896 patients completed LST documents, of which 2704 (45.8%) signed the documents in person, while family members of 3,192 (54%) wrote the documents on behalf of the patients. Comparing first year and following year of implementation of the act, the self-documentation rate increased (43.9% to 47.2%, p=0.014). Moreover, the number of LST decisions made during or after ICU admission decreased (37.8% vs. 35.2%, p=0.045), and the completion rate of LST documents during chemotherapy increased (6.6% vs. 8.9%, p=0.001). In multivariate analysis, age < 65 (OR, 1.724; 95% CI, 1.538-1.933; p<0.001), unmarried status (OR, 1.309; 95% CI, 1.097-1.561; p=0.003), palliative care consultation (OR, 1.538; 95% CI, 1.340-1.765; p<0.001), malignancy (OR, 1.864; 95% CI, 1.628-2.133; p<0.001), and changes in timing on the first year versus following year (OR, 1.124, 95% CI, 1.003-1.260, p=0.045) were related to a higher self-documentation rate. Conclusion: Age < 65, unmarried status, malignancy, and referral to a palliative care team were associated with patients making LST decisions themselves. Furthermore, the subject and timing of LST decisions have changed with the LST act.

Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Background: Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. Methods: We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. Results: The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). Conclusion: We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

MRI radiomics-based interpretable model and nomogram for preoperative prediction of Ki-67 expression status in primary central nervous system lymphoma.

Objectives: To investigate the value of interpretable machine learning model and nomogram based on clinical factors, MRI imaging features, and radiomic features to predict Ki-67 expression in primary central nervous system lymphomas (PCNSL). Materials and methods: MRI images and clinical information of 92 PCNSL patients were retrospectively collected, which were divided into 53 cases in the training set and 39 cases in the external validation set according to different medical centers. A 3D brain tumor segmentation model was trained based on nnU-NetV2, and two prediction models, interpretable Random Forest (RF) incorporating the SHapley Additive exPlanations (SHAP) method and nomogram based on multivariate logistic regression, were proposed for the task of Ki-67 expression status prediction. Results: The mean dice Similarity Coefficient (DSC) score of the 3D segmentation model on the validation set was 0.85. On the Ki-67 expression prediction task, the AUC of the interpretable RF model on the validation set was 0.84 (95% CI:0.81, 0.86; p < 0.001), which was a 3% improvement compared to the AUC of the nomogram. The Delong test showed that the z statistic for the difference between the two models was 1.901, corresponding to a p value of 0.057. In addition, SHAP analysis showed that the Rad-Score made a significant contribution to the model decision. Conclusion: In this study, we developed a 3D brain tumor segmentation model and used an interpretable machine learning model and nomogram for preoperative prediction of Ki-67 expression status in PCNSL patients, which improved the prediction of this medical task. Clinical relevance statement: Ki-67 represents the degree of active cell proliferation and is an important prognostic parameter associated with clinical outcomes. Non-invasive and accurate prediction of Ki-67 expression level preoperatively plays an important role in targeting treatment selection and patient stratification management for PCNSL thereby improving prognosis.

Advances in CAR-NK cell therapy for hematological malignancies.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematological malignancies, demonstrably improving patient outcomes and prognosis. However, its application has introduced new challenges, such as safety concerns, off-target toxicities, and significant costs. Natural killer (NK) cells are crucial components of the innate immune system, capable of eliminating tumor cells without prior exposure to specific antigens or pre-activation. This inherent advantage complements the limitations of T cells, making CAR-NK cell therapy a promising avenue for hematological tumor immunotherapy. In recent years, preclinical and clinical studies have yielded preliminary evidence supporting the safety and efficacy of CAR-NK cell therapy in hematological malignancies, paving the way for future advancements in immunotherapy. This review aims to succinctly discuss the characteristics, significant therapeutic progress, and potential challenges associated with CAR-NK cell therapy.

Polystyrene Microplastics Causes Diarrhea and Impairs Intestinal Angiogenesis through the ROS/METTL3 Pathway.

Due to the immature intestinal digestion, immunity, and barrier functions, weaned infants are more susceptible to pathogens and develop diarrhea. Microplastics (MPs), pervasive contaminants in food, water, and air, have unknown effects on the intestinal development of weaned infants. This study explored the impact of polystyrene MPs on intestinal development using a weaned piglet model. Piglets in the control group received a basal diet, and those in the experimental groups received a basal diet contaminated with 150 mg/kg polystyrene MPs. The results showed that exposure to polystyrene MPs increased the diarrhea incidence and impaired the intestinal barrier function of weaned piglets. Notably, the exposure led to oxidative stress and inflammation in the intestine. Furthermore, polystyrene MPs-treated weaned piglets showed a reduced level of intestinal angiogenesis. Mechanistically, polystyrene MPs suppressed methyltransferase-like 3 (METTL3) expression by increasing reactive oxygen species (ROS) production, consequently destabilizing angiogenic factors' mRNA and hindering intestinal angiogenesis. In summary, polystyrene MPs contamination in the diet increases diarrhea and compromises intestinal angiogenesis through the ROS/METTL3 pathway, demonstrating their toxic effects on the intestine health of weaned infants.

An interpretable artificial intelligence model based on CT for prognosis of intracerebral hemorrhage: a multicenter study.

OBJECTIVES: To develop and validate a novel interpretable artificial intelligence (AI) model that integrates radiomic features, deep learning features, and imaging features at multiple semantic levels to predict the prognosis of intracerebral hemorrhage (ICH) patients at 6 months post-onset. MATERIALS AND METHODS: Retrospectively enrolled 222 patients with ICH for Non-contrast Computed Tomography (NCCT) images and clinical data, who were divided into a training cohort (n = 186, medical center 1) and an external testing cohort (n = 36, medical center 2). Following image preprocessing, the entire hematoma region was segmented by two radiologists as the volume of interest (VOI). Pyradiomics algorithm library was utilized to extract 1762 radiomics features, while a deep convolutional neural network (EfficientnetV2-L) was employed to extract 1000 deep learning features. Additionally, radiologists evaluated imaging features. Based on the three different modalities of features mentioned above, the Random Forest (RF) model was trained, resulting in three models (Radiomics Model, Radiomics-Clinical Model, and DL-Radiomics-Clinical Model). The performance and clinical utility of the models were assessed using the Area Under the Receiver Operating Characteristic Curve (AUC), calibration curve, and Decision Curve Analysis (DCA), with AUC compared using the DeLong test. Furthermore, this study employs three methods, Shapley Additive Explanations (SHAP), Grad-CAM, and Guided Grad-CAM, to conduct a multidimensional interpretability analysis of model decisions. RESULTS: The Radiomics-Clinical Model and DL-Radiomics-Clinical Model exhibited relatively good predictive performance, with an AUC of 0.86 [95% Confidence Intervals (CI): 0.71, 0.95; P < 0.01] and 0.89 (95% CI: 0.74, 0.97; P < 0.01), respectively, in the external testing cohort. CONCLUSION: The multimodal explainable AI model proposed in this study can accurately predict the prognosis of ICH. Interpretability methods such as SHAP, Grad-CAM, and Guided Grad-Cam partially address the interpretability limitations of AI models. Integrating multimodal imaging features can effectively improve the performance of the model. CLINICAL RELEVANCE STATEMENT: Predicting the prognosis of patients with ICH is a key objective in emergency care. Accurate and efficient prognostic tools can effectively prevent, manage, and monitor adverse events in ICH patients, maximizing treatment outcomes.

Clinical study of immediate implant placement in posterior maxillary region assisted by dynamic real-time navigation: A randomized controlled trial.

OBJECTIVE: To evaluate the accuracy of the implant accuracy and clinical effect of navigation-assisted immediate implant placement (IIP) in the posterior maxillary tooth region. METHODS: This study included 60 patients with 96 implants undergoing IIP in the posterior maxillary region from January 2021 to December 2022, stratified into dynamic navigation and freehand implant groups. All clinical indicators, including initial stability, implant deviation (entry point deviation, end point deviation, depth deviation and angle deviation), marginal bone resorption and implant success rate, were systematically recorded. RESULTS: All implants were successfully placed with an average torque of (24.38 ± 1.84)N.cm. The mean entry point deviation, apex point deviation and angular deviation in the navigation group were significantly smaller than that of the freehand group (P < 0.05). Marginal bone resorption was significantly less in the navigated group than in the freehand group (P < 0.05). All dental implants were considered an operational success and the mean follow-up time was (27.8 ± 8.4) months. CONCLUSION: The application of dynamic navigation-assisted immediate implant placement in the maxillary posterior region can achieve good implant accuracy and satisfactory clinical results.

DNMT1-Mediated the Downregulation of FOXF1 Promotes High Glucose-induced Podocyte Damage by Regulating the miR-342-3p/E2F1 Axis.

Podocyte damage plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Accumulating evidence suggests that dysregulation of transcription factors plays a crucial role in podocyte damage in DN. However, the biological functions and underlying mechanisms of most transcription factors in hyperglycemia-induced podocytes damage remain largely unknown. Through integrated analysis of data mining, bioinformatics, and RT-qPCR validation, we identified a critical transcription factor forkhead box F1 (FOXF1) implicated in DN progression. Moreover, we discovered that FOXF1 was extensively down-regulated in renal tissue and serum from DN patients as well as in high glucose (HG)-induced podocyte damage. Meanwhile, our findings showed that FOXF1 might be a viable diagnostic marker for DN patients. Functional experiments demonstrated that overexpression of FOXF1 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and fibrosis in HG-induced podocytes damage. Mechanistically, we found that the downregulation of FOXF1 in HG-induced podocyte damage was caused by DNMT1 directly binding to FOXF1 promoter and mediating DNA hypermethylation to block FOXF1 transcriptional activity. Furthermore, we found that FOXF1 inhibited the transcriptional expression of miR-342-3p by binding to the promoter of miR-342, resulting in reduced sponge adsorption of miR-342-3p to E2F1, promoting the expression of E2F1, and thereby inhibiting HG-induced podocytes damage. In conclusion, our findings showed that blocking the FOXF1/miR-342-3p/E2F1 axis greatly alleviated HG-induced podocyte damage, which provided a fresh perspective on the pathogenesis and therapeutic strategies for DN patients.

Anticancer Prodrug Capable of Mitochondria-Targeting, Light-Triggered Release, and Fluorescence Monitoring.

Mitigating the adverse effects of anticancer agents requires innovative prodrug engineering. In this study, we showcase the potential of our o-quinone methide-based trigger-release-conjugation platform as a versatile tool for constructing advanced prodrug systems. Using this platform, we achieved the light-triggered release of an anticancer drug mechlorethamine, targeting mitochondrial DNA. The entire process was adeptly tracked through the emission of fluorescence signals, revealing notable effects across various cancer cell lines compared to a normal cell line. Exploring alternative cancer-associated triggers, including enzymes, and incorporating cancer/tumor-specific targeting elements could lead to effective prodrugs with reduced cytotoxicity.

A highly neutralizing human monoclonal antibody targeting a novel linear epitope on staphylococcal enterotoxin B.

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138-147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

A Retrospective Investigation of a Case of Dual Infection by Avian-Origin Influenza A (H10N5) and Seasonal Influenza A (H3N2) Viruses - Anhui Province, China, December 2023-January 2024.

What is known about this topic?: H10 avian influenza viruses circulate in wild birds and can reassort with other subtypes. H10N8 and H10N3 have previously caused sporadic human infections in China. What is added by this report?: This report documents the first human case of co-infection with avian-origin H10N5 and seasonal H3N2 influenza viruses. Epidemiological investigations identified H10N5 in environmental samples linked to the patient, but no transmission to close contacts occurred. What are the implications for public health practice?: Enhanced surveillance of avian influenza in live poultry markets and poultry populations is crucial for thoroughly characterizing the epidemiology, transmission, and pathogenesis of H10N5 viruses. Strengthening assessments of outbreak control measures is essential to guide effective management.

Acceleration of Photoinduced Electron Transfer by Modulating Electronegativity of Substituents in Stable Zr-Metal-Organic Frameworks to Boost Photocatalytic CO2 Reduction.

Photoreduction of CO2 with water into chemical feedstocks of fuels provides a green way to help solve both the energy crisis and carbon emission issues. Metal-organic frameworks (MOFs) show great potential for CO2 photoreduction. However, poor water stability and sluggish charge transfer could limit their application. Herein, three water-stable MOFs functionalized with electron-donating methyl groups and/or electron-withdrawing trifluoromethyl groups are obtained for the CO2 photoreduction. Compared with UiO-67-o-CF3-CH3 and UiO-67-o-(CF3)2, UiO-67-o-(CH3)2 achieves excellent performance with an average CO generation rate of 178.0 µmol g-1 h-1 without using any organic solvent or sacrificial reagent. The superior photocatalytic activity of UiO-67-o-(CH3)2 is attributed to the fact that compared with trifluoromethyl groups, methyl groups could not only elevate CO2 adsorption capacity and reduction potential but also promote photoinduced charge separation and migration. These are evidenced by gas physisorption, photoluminescence, time-resolved photoluminescence, electrochemical impedance spectroscopy, transient photocurrent characteristics, and density functional theory calculations. The possible working mechanisms of electron-donating methyl groups are also proposed. Moreover, UiO-67-o-(CH3)2 demonstrates excellent reusability for the CO2 reduction. Based on these results, it could be affirmed that the strategy of modulating substituent electronegativity could provide guidance for designing highly efficient photocatalysts.

Nitroreductase-Triggered Fluorophore Labeling of Cells and Tissues under Hypoxia.

Several reductases, including nitroreductase, are upregulated under hypoxic conditions characterized by an oxygen-deficient microenvironment. Given that hypoxia is a prominent feature of solid tumors, our investigation focused on developing a bioconjugative probe designed for staining tissue under hypoxic conditions, particularly activated by nitroreductase. This probe, developed using our trigger-release-bioconjugation system rooted in the ortho-quinone methide chemistry, exhibited selective activation by nitroreductase and fluorophore labeling within mitochondria and endoplasmic reticulum. As a result, it displayed sustained fluorescence that persisted even after washing steps in cells and tissues. We applied this innovative probe to stain mouse kidney tissue in an acute kidney injury model induced by inadequate oxygen supply. Among various organ tissues examined, only kidney tissue showed significantly higher fluorescence in the injury model compared with the control tissue, as revealed by two-photon microscopic imaging. This research presents a promising avenue for the development of practical staining agents for image-guided tumor surgery.

Analysis of the aging-related biomarker in a nonhuman primate model using multilayer omics.

BACKGROUND: Aging is a prominent risk factor for diverse diseases; therefore, an in-depth understanding of its physiological mechanisms is required. Nonhuman primates, which share the closest genetic relationship with humans, serve as an ideal model for exploring the complex aging process. However, the potential of the nonhuman primate animal model in the screening of human aging markers is still not fully exploited. Multiomics analysis of nonhuman primate peripheral blood offers a promising approach to evaluate new therapies and biomarkers. This study explores aging-related biomarker through multilayer omics, including transcriptomics (mRNA, lncRNA, and circRNA) and proteomics (serum and serum-derived exosomes) in rhesus monkeys (Macaca mulatta). RESULTS: Our findings reveal that, unlike mRNAs and circRNAs, highly expressed lncRNAs are abundant during the key aging period and are associated with cancer pathways. Comparative analysis highlighted exosomal proteins contain more types of proteins than serum proteins, indicating that serum-derived exosomes primarily regulate aging through metabolic pathways. Finally, eight candidate aging biomarkers were identified, which may serve as blood-based indicators for detecting age-related brain changes. CONCLUSIONS: Our results provide a comprehensive understanding of nonhuman primate blood transcriptomes and proteomes, offering novel insights into the aging mechanisms for preventing or treating age-related diseases.

Polystyrene microplastics exposure reduces meat quality and disturbs skeletal muscle angiogenesis via thrombospondin 1.

Microplastics (MPs) pose a significant threat to livestock health. Yet, the roles of polystyrene MPs (PS-MPs) on meat quality and skeletal muscle development in pigs have not been fully determined. To investigate the effect of PS-MPs on skeletal muscle, piglets were given diets supplementation with 0 mg/kg (CON group), 75 mg/kg (75 mg/kg PS-MPs group), and 150 mg/kg PS-MPs (150 mg/kg PS-MPs group), respectively. The results indicated that the average daily gain (ADG) of piglets in the 150 mg/kg PS-MPs group was significantly lower than that in the CON group. No significant differences were observed in the final body weight and ADG between the CON group and the 75 mg/kg PS-MPs group. Piglets in the 150 mg/kg PS-MPs group exhibited decreased meat redness index and type I muscle fiber density. Metabolomic analysis revealed that the contents of meat flavor compounds carnosine, beta-alanine, palmitic acid, and niacinamide in muscle were lower in the 150 mg/kg PS-MPs group than in the CON group. Additionally, piglets subjected to 150 mg/kg PS-MPs exhibited impaired muscle angiogenesis. Further analysis indicated that PS-MPs exposure up-regulated thrombospondin 1 (THBS1) expression by inhibiting THBS1 mRNA and protein degradation, thereby disrupting skeletal muscle angiogenesis. These findings indicate that PS-MPs exposure adversely affects meat quality and hinders skeletal muscle angiogenesis in pigs, providing deeper insights into the detrimental effects of PS-MPs on meat quality and skeletal muscle development.

Risk factors for the recurrence of left atrioventricular valvular regurgitation after surgical repair of partial and transitional atrioventricular septal defect.

Background: Left atrioventricular valvular regurgitation (LAVVR) recurrence after partial and transitional atrioventricular septal defect (AVSD) repair is the main risk factor associated with reoperation or mortality. The purpose of this study was to identify risk factors associated with the recurrence of LAVVR after surgical repair of transitional and partial AVSD at a single institution. Methods: A hundred and fifty-seven patients who underwent anatomical repair for partial and transitional AVSD from January 2013 to December 2021 were included in our institutional database. Demographic characteristics, operative information, comorbidities, complications, and outcomes were retrieved from electronic medical records. Echocardiographic evaluations included cardiac dimensions, the degree of LAVVR, and the anatomy of the atrioventricular valve. Results: After a median follow-up period of 5.8 years, 40 patients had recurrent moderate or even more severe LAVVR. Compared with patients without recurrent LAVVR, those experiencing LAVVR recurrence were more likely to have larger preoperative left atrial (LA) size and larger left ventricular (LV) size after standardization, larger left atrioventricular valve (LAVV) cleft width, higher proportions of preoperative moderate or even more severe LAVVR, and immediately postoperative mild to moderate or even more severe LAVVR. Univariate Cox regression analysis showed that age at first repair, height, LA size after standardization, LV size after standardization, the severity of preoperative LAVVR, immediately postoperative LAVVR, and the LAVV cleft width more than 1cm were risk factors for recurrent LAVVR (P<0.05 for all). Multivariable Cox regression analysis showed that mild to moderate or even more severe LAVVR postoperatively [hazard ratio (HR) 9.53, 95% confidence interval (CI): 3.78-24.01; P<0.001], the width of LAVV cleft more than 1 cm (HR: 3.90, 95% CI: 1.80-8.48; P<0.001) and age at first repair (HR: 0.45, 95% CI: 0.31-0.66; P<0.001) were independently associated with the recurrence of LAVVR. Conclusions: The width of LAVV cleft, mild to moderate or even more severe LAVVR immediately after surgery, and age at initial surgery are risk factors for recurrent LAVVR. The presence of recurrent LAVVR necessitates proactive surveillance to facilitate timely reintervention.

Analysis of the functional role and mRNA expression of GABABR in the nucleus accumbens of cocaine-addicted rats.

BACKGROUND: Drug addiction is a social and medical problem that must be urgently addressed. The nucleus accumbens (NAc) is closely related to addiction-related learning memory, and γ-aminobutyric acid type B receptor (GABABR) is a potential target for the treatment of drug addiction. However, the role of GABABR activity levels in the NAc in cocaine addiction is unclear. METHODS: In this study, we established an animal model of cocaine dependence, modulated the level of GABABR activity, applied a conditioned place preference assay (CPP) to assess the role of the NAc in reconsolidation of addiction memory, evaluated learning and memory functions by behavioral experiments, examined the expression of GB1, GB2, CREB, p-CREB, PKA, ERK, and BDNF in the NAc by molecular biology experiments, and screened differentially significantly expressed genes by transcriptome sequencing. RESULTS: Our study showed that the GABAB receptor agonist BLF had a significant effect on locomotor distance in rats, promoted an increase in GABA levels and significantly inhibited the PKA and ERK1/2/CREB/BDNF signaling pathways. Moreover, transcriptome sequencing showed that GABABR antagonist intervention identified a total of 21 upregulated mRNAs and 21 downregulated mRNAs. The DE mRNA genes were mainly enriched in tyrosine metabolism; however, further study is needed. CONCLUSION: GABABR activity in the NAc is involved in the regulation of cocaine addiction and may play an important role through key mRNA pathways.