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End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2’-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI.

Abstract Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer–immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

Abstract SARS-CoV-2 vaccine booster dose can induce a robust humoral immune response, however, its cellular mechanisms remain elusive. Here, we investigated the durability of antibody responses and single-cell immune profiles following booster dose immunization, longitudinally over 6 months, in recipients of a homologous BBIBP-CorV/BBIBP-CorV or a heterologous BBIBP-CorV/ZF2001 regimen. The production of neutralizing antibodies was dramatically enhanced by both booster regimens, and the antibodies could last at least six months. The heterologous booster induced a faster and more robust plasmablast response, characterized by activation of plasma cells than the homologous booster. The response was attributed to recall of memory B cells and the de novo activation of B cells. Expanded B cell clones upon booster dose vaccination could persist for months, and their B cell receptors displayed accumulated mutations. The production of antibody was positively correlated with antigen presentation by conventional dendritic cells (cDCs), which provides support for B cell maturation through activation and development of follicular helper T (Tfh) cells. The proper activation of cDC/Tfh/B cells was likely fueled by active energy metabolism, and glutaminolysis might also play a general role in promoting humoral immunity. Our study unveils the cellular mechanisms of booster-induced memory/adaptive humoral immunity and suggests potential strategies to optimize vaccine efficacy and durability in future iterations.

Abstract Cell migration is a pivotal step in metastatic process, which requires cancer cells to navigate a complex spatially‐confined environment, including tracks within blood vessels and in the vasculature of target organs. Here it is shown that during spatially‐confined migration, the expression of insulin‐like growth factor‐binding protein 1 (IGFBP1) is upregulated in tumor cells. Secreted IGFBP1 inhibits AKT1‐mediated phosphorylation of mitochondrial superoxide dismutase (SOD2) serine (S) 27 and enhances SOD2 activity. Enhanced SOD2 attenuates mitochondrial reactive oxygen species (ROS) accumulation in confined cells, which supports tumor cell survival in blood vessels of lung tissues, thereby accelerating tumor metastasis in mice. The levels of blood IGFBP1 correlate with metastatic recurrence of lung cancer patients. This finding reveals a unique mechanism by which IGFBP1 sustains cell survival during confined migration by enhancing mitochondrial ROS detoxification, thereby promoting tumor metastasis.

BackgroundLittle is known about the role of interleukin (IL) in patients with acute myocardial infarction (MI), especially soluble IL-2 receptor (sIL-2R) and IL-8. We aim to evaluate, in MI patients, the predictive value of serum sIL-2R and IL-8 for future major adverse cardiovascular events (MACEs), and compare them with current biomarkers reflecting myocardial inflammation and injury.MethodsThis was a prospective, single-center cohort study. We measured serum concentrations of IL-1β, sIL-2R, IL-6, IL-8 and IL-10. Levels of current biomarkers for predicting MACEs were measured, including high-sensitivity C reactive protein, cardiac troponin T and N-terminal pro-brain natriuretic peptide. Clinical events were collected during 1-year and a median of 2.2 years (long-term) follow-up.ResultsTwenty-four patients (13.8%, 24/173) experienced MACEs during 1-year follow-up and 40 patients (23.1%, 40/173) during long-term follow-up. Of the five interleukins studied, only sIL-2R and IL-8 were independently associated with endpoints during 1-year or long-term follow-up. Patients with high sIL-2R or IL-8 levels (higher than the cutoff value) had a significantly higher risk of MACEs during 1-year (sIL-2R: HR 7.7, 3.3–18.0, p

A common event upon receptor–ligand engagement is the formation of receptor clusters on the cell surface, in which signaling molecules are specifically recruited or excluded to form signaling hubs to regulate cellular events. These clusters are often transient and can be disassembled to terminate signaling. Despite the general relevance of dynamic receptor clustering in cell signaling, the regulatory mechanism underlying the dynamics is still poorly understood. As a major antigen receptor in the immune system, T cell receptors (TCR) form spatiotemporally dynamic clusters to mediate robust yet temporal signaling to induce adaptive immune responses. Here we identify a phase separation mechanism controlling dynamic TCR clustering and signaling. The TCR signaling com- ponent CD3ε chain can condensate with Lck kinase through phase separation to form TCR signalosomes for active antigen signaling. Lck-mediated CD3ε phosphorylation, however, switched its binding preference to Csk, a functional suppressor of Lck, to cause the dissolvement of TCR signalosomes. Modulating TCR/Lck condensation by target- ing CD3ε interactions with Lck or Csk directly affects T cell activation and function, highlighting the importance of the phase separation mechanism. The self-programmed condensation and dissolvement is thus a built-in mechanism of TCR signaling and might be relevant to other receptors. [ABSTRACT FROM AUTHOR]

Aims: The aim was to quantify the relationship between pharmacist intervention and vancomycin‐associated acute kidney injury (AKI). Methods: Electronic databases were searched up to August 2020 for meta‐analyses of cohort studies and/or randomized controlled trials. Studies that compared the incidence of AKI in patients between post‐ and prepharmacist intervention were investigated. The primary outcome was incidence of AKI. We also evaluated the influence of pharmacist intervention in risk factors of vancomycin‐associated AKI. Results: The search strategy retrieved 1744 studies and 34 studies with 19 298 participants were included (22 published articles and 12 abstracts from conference proceedings). Compared with the preintervention group, the postintervention group patients had a significantly lower incidence of vancomycin‐associated AKI: 7.3% for post‐ and 9.6% for preintervention (odds ratio [OR] 0.52, 95% confidence interval [CI]; 0.41, 0.67], P <.00001). The rate of attaining target concentration was significantly higher in the post‐ than preintervention group (OR 2.86, 95% CI [2.23, 3.67], P <.00001). The postintervention group significantly improved the percentage of serum creatinine laboratory tests than preintervention group (OR = 3.24, 95% CI 2.02, 5.19], P <.00001). Patients postintervention had markedly lower risk of mortality than preintervention patients (OR 0.47, 95% CI [0.31, 0.72], P =.0004). Conclusion: Pharmacist intervention in vancomycin treatment significantly decreased the rate of vancomycin‐associated AKI, while improving efficacy and reducing mortality. We speculate that this is because the pharmacist interventions optimized the rationality of vancomycin therapy, monitoring of vancomycin trough concentration and the monitoring of patients' renal function. [ABSTRACT FROM AUTHOR]

Background/Aims: At present, there are relatively few reports on the treatment consisting of transarterial chemoembolization (TACE) combined with lenvatinib, and there is no unified conclusion on the curative effect. The objective of this research was to assess the efficacy and safety of combining TACE with lenvatinib for the treatment of unresectable hepatocellular carcinoma (uHCC). Materials and Methods: This study was a retrospective analysis of the patient’s medical records. In this study, 249 patients (uHCC) in our hospital from 2020 to 2021 were divided into 2 groups, including the TACE-alone group (198 patients received TACE alone) and the TACE-LEN group (51 patients were treated with TACE combined with lenvatinib). According to the propensity score matching method, there were TACE-LEN group (51 patients) and TACE-alone group (51 patients). With the help of surgical experts, the overall survival (OS), progression-free survival (PFS), and tumor response (according to mRECIST) of the 2 groups were sorted and recorded, and then analyzed. Survival curves were established, the prognostic factors of OS and PFS were analyzed by univariate and multivariate analyses, and the independent prognostic factors were recorded. The adverse reactions of patients after treatment were recorded. Results: The 1-year and 2-year OS rates were 50.98% and 19.48% for the TACE-LEN group, 27.45% and 8.55% for the TACE-alone group (P = .042), respectively. The PFS of patients in the TACE-LEN group was also longer (1-year PFS rate: 25.49% vs. 11.76%, 2-year PFS rate: 19.17% vs. 5.88%; P = .0069). The disease control rate (68.63% vs. 49.10%, P = .044) of the TACE-LEN group was significantly higher. In the subgroup analysis, the OS of the TACE-LEN group was better than TACE-alone group in patients with Barcelona Clinic Liver Cancer stage C (1-year OS rate: 44.44% vs. 17.14%, 2-year OS rate: 8.67% vs. 0%; P = .009). Factor analysis concluded that serum alkaline phosphatase and treatment protocol (TACE-LEN vs. TACE) were independent influencing factors of OS. The most common treatment-related AEs included decreased albumin (n = 28, 54.9%), hypertension (n = 23, 45.1%), elevated aspartate transaminase (n = 21, 41.2%) and elevated total bilirubin (n = 18, 35.2%) in TACE-LEN group. Conclusion: Compared with TACE monotherapy, TACE combined with lenvatinib effectively prolonged the OS time with a controllable safety profile for patients with uHCC.

Ketamine compound was firstly synthesized for more than 60 years. It is widely used in clinical anesthesia due to its potent analgesic effect and lower deleterious impacts on circulatory and respiratory functions. Very recently, its rapid and long-lasting antidepressant effect attracted increasing attentions in the topic field. We therefore reviewed the pharmacological properties of ketamine, its clinical application as a narcotic analgesic, and antidepressant effect of its metabolites.