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This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure‐response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2‐compartment model with time‐dependent nonlinear elimination. The prediction‐corrected visual predictive check was used to evaluate the model's predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure‐response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation‐based methods. [ABSTRACT FROM AUTHOR]

Summary: Understanding the molecular regulation of plant cold response is the basis for cold resistance germplasm improvement. Here, we revealed that the apple histone deacetylase MdHDA6 can perform histone deacetylation on cold‐negative regulator genes and repress their expression, leading to the positive regulation of cold tolerance in apples. Moreover, MdHDA6 directly interacts with the transcription factor MdTCP15. Phenotypic analysis of MdTCP15 transgenic apple lines and wild types reveals that MdTCP15 negatively regulates cold tolerance in apples. Furthermore, we found that MdHDA6 can facilitate histone deacetylation of MdTCP15 and repress the expression of MdTCP15, which positively contributes to cold tolerance in apples. Additionally, the transcription factor MdTCP15 can directly bind to the promoter of the cold‐negative regulator gene MdABI1 and activate its expression, and it can also directly bind to the promoter of the cold‐positive regulator gene MdCOR47 and repress its expression. However, the co‐expression of MdHDA6 and MdTCP15 can inhibit MdTCP15‐induced activation of MdABI1 and repression of MdCOR47, suggesting that MdHDA6 suppresses the transcriptional regulation of MdTCP15 on its downstream genes. Our results demonstrate that histone deacetylase MdHDA6 plays an antagonistic role in the regulation of MdTCP15‐induced transcriptional activation or repression to positively regulate cold tolerance in apples, revealing a new regulatory mechanism of plant cold response. [ABSTRACT FROM AUTHOR]

Hybrid complex anions of ginsenosides resulted from direct infusion-tandem mass spectrometry Energy-resolved MS (ER-MS)7 was utilized to discriminate noncovalent binding from covalent linkage I via i building breakdown graphs for ions of interest. In our previous study,5 we discussed the I pros i and I cons i of DI-MS/MS toward in-depth chemical characterization of complex matrices, in comparison to liquid chromatography-MS/MS (LC-MS/MS). [Extracted from the article]

Compared with healthy controls, heroin users (HUs) show evidence of structural and functional brain alterations. However, little is known about the possibility of brain recovery after protracted heroin abstinence. The purpose of this study was to investigate whether brain recovery is possible after protracted abstinence in HUs. A total of 108 subjects with heroin addiction completed structural and functional scans, and 61 of those subjects completed 8‐month follow‐up scans. Resting‐state data and 3D‐T1 MR images were collected for all participants, first at baseline and again after 8 months. Cognitive function and craving were measured by the Trail Making Test‐A (TMT‐A) and Visual Analog Scale for Craving, respectively. The cortical thickness and resting‐state functional connectivity (RSFC) differences were then analyzed and compared between baseline and follow‐up, and correlations were obtained between neuroimaging and behavioral changes. HUs demonstrated improved cognition (shorter TMT‐A time) and reduced craving at the follow‐up (HU2) relative to baseline (HU1), and the cortical thickness in the bilateral superior frontal gyrus (SFG) was significantly greater at HU2 than at HU1. Additionally, the RSFC of the left SFG with the inferior frontal gyrus (IFG), insula, and nucleus accumbens and that of the right SFG with the IFG, insula and orbitofrontal cortex (OFC) were increased at HU2. The changes in TMT‐A time were negatively correlated with the RSFC changes between the left SFG and the bilateral IFG, the bilateral caudate, and the right insula. The changes in craving were negatively correlated with the RSFC changes between the left OFC and the bilateral SFG. Our results demonstrated that impaired frontal‐limbic neurocircuitry can be partially restored, which might enable improved cognition as well as reduced craving in substance‐abusing individuals. We provided novel scientific evidence for the partial recovery of brain circuits implicated in cognition and craving after protracted abstinence. Highlights: Improved cognition and reduced craving were observed in heroin users (HUs) after 8 months of abstinence.HUs demonstrated increased superior frontal gyrus (SFG) cortical thickness after 8 months of abstinence.Increased resting‐state functional connectivity within SFG circuits was correlated with improved cognition and reduced craving; Brain circuit recovery was detected as a result of protracted abstinence in HUs. [ABSTRACT FROM AUTHOR]

Background. Alcoholism is known to cause liver toxicity and is extensively researched. On the other hand, stress, depression, and obesity are interrelated conditions with alcoholism, and their medications would affect the liver itself. In this study, we investigated the effects of the drugs fluoxetine and atorvastatin on the liver and compared with those of alcohol in a mouse model. Methods. Comparisons of animals treated with the three drugs were carried out: serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin were measured; liver tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta-1) levels were evaluated; proliferative cells were detected via immunohistochemistry (IHC) targeting on proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2); for apoptosis, IHC targeting on activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were employed; and histopathology was also documented in all groups. Results. For ALT, AST, albumin, and liver TNF alpha, only the ethanol group surged to significantly higher levels. For TGF beta-1, both ethanol and atorvastatin groups reached a significantly higher level. PCNA and MCM2 showed increased proliferation in the livers of all three groups, with the ethanol group having the highest number of positive cells followed by atorvastatin and then the fluoxetine group. As for cell death, both ethanol and fluoxetine groups showed significantly more apoptosis than control in TUNEL and activated caspase-3, while in the atorvastatin group, activated caspase-3 positive cells increased significantly, but the increase in TUNEL-positive cells did not reach statistical significance. [ABSTRACT FROM AUTHOR]

As a critical component of cortico‐striato‐thalamo‐cortical loop in addiction, our understanding of the thalamus in impaired cognition of heroin users (HU) has been limited. Due to the complex thalamic connection with cortical and subcortical regions, thalamus was divided into prefrontal (PFC), occipital (OC), premotor, primary motor, sensory, temporal, and posterior parietal association subregions according to white matter tractography. We adopted seven subregions of bilateral thalamus as regions of interest to systematically study the implications of distinct thalamic nuclei in acute abstinent HU. The volume and resting‐state functional connectivity (RSFC) differences of the thalamus were investigated between age‐, gender‐, and alcohol‐matched 37 HU and 33 healthy controls (HCs). Trail making test‐A (TMT‐A) was adopted to assess cognitive function deficits, which were then correlated with neuroimaging findings. Although no significant different volumes were found, HU group showed decreased RSFC between left PFC_thalamus and middle temporal gyrus as well as between left OC_thalamus and inferior frontal gyrus and supplementary motor area relative to HCs. Meanwhile, the higher TMT‐A scores in HU were negatively correlated with PFC_thalamic RSFC with inferior temporal gyrus, fusiform, and precuneus. Craving scores were negatively correlated with OC_thalamic RSFC with accumbens, hippocampus, and insula. Opiate Withdrawal Scale scores were negatively correlated with left PFC/OC_thalamic RSFC with orbitofrontal cortex and medial PFC. We indicated two thalamus subregions separately involvement in cognitive control and craving to reveal the implications of thalamic subnucleus in pathology of acute abstinent HU. [ABSTRACT FROM AUTHOR]