Development of small molecule drugs targeting immune checkpoints.

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.

The secondary prevention of coronary heart disease in US adults 75 Years and older in daily practice: Results from the National Health and Nutrition Examination Survey 1999-2018 survey.

Background: Pharmacologic therapies, risk factor control, and lifestyle alterations were independently proven to reduce long-term cardiovascular events. However, comprehensive research examining the extent to which individuals aged 75 and above in the United States adhere to national guidelines for the secondary prevention of coronary heart disease is limited. Therefore, the primary objective of this study was to examine the current state of secondary prevention of coronary heart disease in persons 75 years of age and older in the United States and to examine the factors that contribute to inadequate drug utilization and poor control of numerous risk factors. Methods: We identified patients over 75 years of age with coronary heart disease based on the National Health and Nutrition Examination Survey from 1999 to 2018 and analyzed the adequacy of risk factor control and adherence to lifestyle and medication recommendations to assess the effectiveness of coronary heart disease management. Logistic regression analysis was used to identify factors associated with uncontrolled risk factors or noncompliance with recommended medications. Results: We collected information from 1566 known coronary heart disease patients aged ≥75 years of age. The majority were at target goals for blood pressure (58.88%), low-density lipoprotein cholesterol (66.85%), and glycated hemoglobin (76.12%). Only 27.8% and 36.06% were at targets for body mass index and waist circumference, respectively. 91.95% reported smoking cessation, 85.98% followed recommended alcohol consumption, whereas only 10.34% reported sufficient physical activity. For ß blockers, angiotensin -converting enzyme inhibitors/angiotensin receptor blockers, statins, and antiplatelet drugs, the utilization of indicated therapy was 54.41%, 49.36%, 54.79%, and 19.03%, respectively (6.26% for all 4 medications). The results of the logistic regression analysis demonstrated that diabetes mellitus and metabolic syndrome were critical markers of numerous uncontrolled risk variables as well as noncompliance with medication regimens. Conclusions: A vast majority of coronary heart disease patients ≥75 years in the USA exhibited suboptimal overall control of critical coronary heart disease risk factors. For this patient population, more knowledge is necessary to enable patients to receive continuous support, guidance, and counseling.

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification.

BACKGROUND: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. METHODS: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis. RESULTS: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively. CONCLUSION: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Efficacy of nab­paclitaxel vs. Gemcitabine in combination with S­1 for advanced pancreatic cancer: A multicenter phase II randomized trial.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

A phase 1/2 study of pepinemab in children, adolescents, or young adults with recurrent or refractory solid tumors: A children's oncology group consortium report (ADVL1614).

PURPOSE: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma. EXPERIMENTAL DESIGN: Pepinemab was administered intravenously on Days 1 and 15 of a 28-day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2-stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood. RESULTS: Pepinemab (20 mg/kg) was well tolerated and no dose-limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults. CONCLUSIONS: Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response. CLINICAL TRIAL REGISTRY: This trial is registered as NCT03320330 at Clinicaltrials.gov. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Multi-Omics Analysis of the Oncogenic Value of Pituitary Tumor-Transforming Gene 1 (PTTG1) in Human Cancers.

BACKGROUND: The pituitary tumor-transforming gene 1 (PTTG1), also recognized as securin, plays a crucial role in diverse biological processes, such as restraining sister chromatid segregation, facilitating DNA repair, contributing to organ development, and governing angiogenesis. Additionally, it regulates the expression and secretion of transfer factors. The epigenetic characteristics of PTTG1 suggest its potential in elucidating the progression of malignant tumors in pan-cancer. Nevertheless, the current comprehension of this relationship remains limited, necessitating further comprehensive studies to delve into the underlying pathogenesis. METHODS: This investigation aimed to explore the potential functions of PTTG1 in pan-cancer by leveraging existing databases, such as TCGA and GTEx. Notably, PTTG1 was overexpressed in nearly all tumors, indicating promising prognostic and diagnostic capabilities. Moreover, the observed correlation between PTTG1 and immune cell infiltration, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), and other immune features suggests its potential utility as a guide for immunotherapy. RESULTS: The study unveils that the downregulation of PTTG1 expression in neuroblastoma results in reduced cell proliferation and increased apoptosis, substantiating the proposition that PTTG1 could serve as both a prognostic biomarker and a potential target for immunotherapy across various cancer types. CONCLUSIONS: This study centers on the exploration of the expression and role of PTTG1 in both tumors and the tumor microenvironment (TME), offering valuable insights for the development of cancer therapeutic strategies. These discoveries present potential alternative avenues for addressing clinically resistant cancers.

Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.

Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.

CT energy spectral parameters of creeping fat in Crohn's disease and correlation with inflammatory activity.

OBJECTIVES: Creeping fat is a kind of unique abnormal mesenteric tissue at the sites of diseased bowel of Crohn's disease. By using dual-energy CT enterography, this study aimed to evaluate the feasibility of spectral parameters in the quantitative analysis of mesenteric adipose tissue or creeping fat. METHODS: In this study, patients with known or suspected Crohn's disease who underwent dual-energy CT enterography from March 1, 2019, to March 31, 2021, were enrolled. Among them, 40 patients with surgery and pathology-proven creeping fat were selected as the creeping fat Crohn's disease group, and 40 normal patients were selected as the control group. The quantitative spectral parameters including the slope of the Hounsfield unit curve, normalised fat-water concentration, normalised fat-iodine concentration, and normalised fat volume fraction at the enteric phases were obtained. Mann-Whitney U test, Kruskal-Wallis H test, and receiver operating characteristic curve analysis were applied to compare quantitative parameters among various groups. RESULTS: A significant difference was observed in the slope of the Hounsfield unit curve, normalised fat-water concentration, normalised fat-iodine concentration, and normalised fat volume fraction between mesenteric adipose tissue and creeping fat with Crohn's disease at the enteric phase (all p < 0.001). The slope of the Hounsfield unit curve of creeping fat at the enteric phase had a better capability to distinguish inactive and active Crohn's disease (AUC = 0.93, p < 0.001). CONCLUSION: Dual-energy CT enterography with quantitative spectral parameters is a potentially novel noninvasive tool for evaluating creeping fat in Crohn's disease. CRITICAL RELEVANCE STATEMENT: Energy spectral parameters of creeping fat in Crohn's disease are significantly different from normal mesenteric adipose tissues and are correlated with inflammatory activity. KEY POINTS: • Dual-energy CT enterography allows quantitatively assessing creeping fat with spectral parameters. • The creeping fat has distinct spectral parameters to normal mesenteric adipose. • The spectral parameters accurately differentiate active and inactive Crohn's disease.

Percutaneous short segmental fixation combined with bone cement augmentation for stage III Kümmell's disease without nerve deformity.

The objective of this study was to evaluate the safety and efficacy of percutaneous pedicle screw fixation combined with bone cement augmentation in the management of stage III Kümmell disease without nerve deformity. A retrospective analysis was conducted on 17 patients diagnosed with stage III Kümmell disease without nerve deformity, who underwent treatment with percutaneous pedicle screw fixation combined with bone cement augmentation between April 2019 and 2022. Preoperative, postoperative, and final follow-up clinical outcome measures were collected, including Visual Analog Scale scores and Oswestry Disability Index scores. Additionally, lateral radiography was used to measure the Cobb angle and height of the anterior border of the affected vertebral body. Operative time, volume of injected bone cement, intraoperative cement leakage, and other complications were recorded. All patients underwent successful surgery, resulting in significant reductions in Visual Analog Scale scores, Oswestry Disability Index scores, and Cobb angle postoperatively; meanwhile there was a significant increase in height of the anterior border of the affected vertebral body. No major complications occurred during the follow-up period. In conclusion, percutaneous pedicle screw short-segment fixation combined with bone cement augmentation appears to be an effective surgical option for treating stage III Kümmell disease without nerve deformities.

A phase 1 trial utilizing a pharmacokinetic endpoint to determine the optimal dose of ramucirumab in children and adolescents with relapsed or refractory solid tumors, including central nervous system tumors.

BACKGROUND: Ramucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR-2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min ) ≥ 50 µg/mL was established. PROCEDURES: This phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin ) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned. RESULTS: Twenty-nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1-21] years; 22 were evaluable for the PK endpoint. Dose-limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin  ≥ 50 µg/mL. CONCLUSION: Ramucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.

Predicting coronary heart disease in Chinese diabetics using machine learning.

Diabetes, a common chronic disease worldwide, can induce vascular complications, such as coronary heart disease (CHD), which is also one of the main causes of human death. It is of great significance to study the factors of diabetic patients complicated with CHD for understanding the occurrence of diabetes/CHD comorbidity. In this study, by analyzing the risk of CHD in more than 300,000 diabetes patients in southwest China, an artificial intelligence (AI) model was proposed to predict the risk of diabetes/CHD comorbidity. Firstly, we statistically analyzed the distribution of four types of features (basic demographic information, laboratory indicators, medical examination, and questionnaire) in comorbidities, and evaluated the predictive performance of three traditional machine learning methods (eXtreme Gradient Boosting, Random Forest, and Logistic regression). In addition, we have identified nine important features, including age, WHtR, BMI, stroke, smoking, chronic lung disease, drinking and MSP. Finally, the model produced an area under the receiver operating characteristic curve (AUC) of 0.701 on the test samples. These findings can provide personalized guidance for early CHD warning for diabetic populations.

Transcription factor PBX4 regulates limb development and haematopoiesis in mice.

The mammalian Pre-B cell leukaemia transcription factors 1-4 (PBX1-4) constitutes the PBC class of the homeodomain (HD)-containing proteins, which play important roles in diverse developmental processes. The functions and the underlying molecular mechanisms of PBX1-3 but not PBX4 have been extensively studied, and they have been reported to direct essential morphogenetic processes and organogenesis. In the present study, we generated knockin mice of FLAG-tagged PBX4 and the Pbx4 knockout (KO) mice and carried out in-depth characterisation of PBX4 expression and function. PBX4 was initially detected only in the testis among several organs of the adult mice and was expressed in spermatocytes and spermatids. However, no abnormality in spermatogenesis, but growth retardation and premature death after birth were observed in most adult Pbx4 KO mice. These animals were inactive and had shorter hindlimbs and lower numbers of reticulocytes and lymphocytes, probably caused by abnormalities at earlier developmental stages. Pbx4 mRNAs were indeed detected in several embryonic cell types related to limb development by in situ hybridisation and single-cell RNA-sequencing analysis. Pbx4 protein was also detected in the bone marrow of adult mice with a lower level compared with that in the testis. PBX4 preferentially binds to the promoters of a large number of genes including those for other HD-containing proteins and ribosomal proteins whose mutations are related to anaemia. PBX4-binding sites are enriched in motifs similar to those of other HD-containing proteins such as PKNOX1 indicating that PBX4 may also act as a co-transcription factor like other PBC proteins. Together, these results show that PBX4 participates in limb development and haematopoiesis while its function in spermatogenesis has not been revealed by gene KO probably due to the complementary effects of other genes.

Facilitating endoscopic full-thickness resection for gastric submucosal tumors with a novel snare traction method (with video).

BACKGROUND AND AIM: Endoscopic full-thickness resection (EFTR) is a promising technique in treating gastric submucosal tumors originating from the muscularis propria (SMT-MPs). However, it is challenging without counter-traction. METHODS: A snare was inserted through the forceps channel to grasp the part of the tumor or the mucosa connected to the tumor. The outer sheath and inner wire of snare in vitro were fixed by a pair of hemostatic forceps. The handle of snare was cut off, and the endoscope was pulled out without affecting the traction state of snare. Snare-assisted EFTR (EFTR-S) was then performed with counter-traction. One hundred and four patients with gastric SMT-MPs who received the procedure of EFTR with or without snare traction method were retrospectively analyzed using univariate and multiple regressions, and covariates were adjusted in the multiple analysis. RESULTS: Compared with EFTR group (n = 36), EFTR-S group (n = 68) showed a higher operative success rate (95.6% vs 72.2%, P = 0.001), a lower incidence of intraoperative hemorrhage (4.4% vs 16.7%, P = 0.038) and shorter operative time among operative successes (53.6 ± 16.6 min vs 67.7 ± 33.4 min, P < 0.001). Univariate logistic analysis showed that snare traction represented a significant factor, which could improve operative successful rate (odds ratio, 8.3; 95% confidence interval, 2.1 to 32.7; P = 0.002). Postoperative outcomes and adverse events among operative successes were similar between the two groups. CONCLUSIONS: This novel snare traction method may provide an effective counter-traction and reduce the difficulty of EFTR for gastric SMT-MPs.

Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation.

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.

Mechanisms of shoulder dislocation explained in the "hand as foot teaching philosophy".

OBJECTIVE: To continuously absorb new teaching concepts and try new teaching methods in the process of clinical practice teaching for medical students to improve the teaching effect. METHODS: In the process of clinical practice teaching of orthopedic, the teaching concept of "hand and foot" was adopted. RESULTS: In the process of clinical practice teaching for medical students, the "hand as foot teaching philosophy" was used to explain the abstract anatomical structures, which greatly stimulated students' interest in classroom learning and achieved good teaching effects. CONCLUSION: The "hand as foot teaching philosophy" is a new teaching concept, which is worth exploring and applying in clinical practice, so as to continuously optimize and improve the theoretical system and better serve for teaching.

Exosome-mediated delivery of miR-519e-5p promotes malignant tumor phenotype and CD8+ T-cell exhaustion in metastatic PTC.

CONTEXT: Distant metastases are the primary cause of therapy failure and mortality in patients with papillary thyroid carcinomas (PTCs). However, the underlying mechanism responsible for the initiation of tumor cell dissemination and metastasis in PTCs has rarely been investigated. OBJECTIVE: The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs. METHODS: The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT‒PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases. RESULTS: We identified that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1 mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2. CONCLUSION: Our findings highlighted the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms.

Ferroptosis and tumor immunity: In perspective of the major cell components in the tumor microenvironment.

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation, which is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. Mounting studies on the essential role of ferroptosis have been published in the progression of solid tumors, metastasis, therapy, and therapy resistance. Studies showed that ferroptosis is a "double-edged sword" in tumor immunity, which means it may have both tumor-antagonizing and tumor-promoting functions. The tumor microenvironment (TME) comprises not only tumor cells but also surrounding immune cells, stromal cells, as well as noncellular components such as the extracellular matrix (ECM), cytokines, growth factors, and extracellular vesicles (EVs). In the complex and diverse condition in TME where tumor cells grow, changes in each constituent may impact tumor destiny differently. Recently, several studies have revealed the interaction between ferroptosis and different constituents in TME. Both tumor cells and nontumor cells have a dual role in tumor immunity and influence tumor progression through ferroptosis. Herein, this review aims at summarizing the role of ferroptosis in tumor immunity based on TME, focusing on the mechanisms of the interaction between the ferroptosis and the different constituents in TME, illuminating how ferroptosis plays its role in promoting or antagonizing tumors by acting with varying components in TME and proposing several questions in immunomodulatory effects of ferroptosis and ferroptosis-associated immunotherapy.

Serotonin syndrome caused by a CYP2C19-mediated interaction between low-dose escitalopram and clopidogrel: a case report.

Background: Serotonin syndrome has been recognized as a serious adverse reaction to antidepressants and is characterized by sudden or severe autonomic nerve dysfunction and neuromuscular symptoms. Without an accurate diagnosis and prompt treatment, serotonin syndrome progresses rapidly and can be life-threatening. It is usually related to the dose of 5-hydroxytryptamine drugs, and the dose is the basis for diagnosis. Therefore, serotonin syndrome induced by low-dose antidepressants rarely occurs, and clinicians are more likely to misdiagnose patients who take low-dose antidepressants with similar symptoms. Here, we present a case study of serotonin syndrome caused by a relatively low dose of escitalopram, which is not common in past references. Case summary: The patient was a 74-year-old Asian woman with a 42-year history of schizophrenia. After 6 weeks of antidepressant treatment, our patient presented with characteristic myoclonus in the lower limbs and closed eyes with fluttering. Initially, she was misdiagnosed with neuroleptic malignant syndrome (NMS) due to antipsychotic medication and was treated accordingly, even with discontinuation of clozapine. However, her symptoms persisted, and then therapeutic drug monitoring was initiated with the involvement of a clinical pharmacist. Eventually, she was diagnosed with serotonin syndrome due to escitalopram levels reaching the warning level. Subsequently, the patient's treatment was modified, and her clinical outcome was satisfactory without any other serious adverse reactions. Gene detection was also performed, and a cytochrome P450 enzyme (CYP) 2C19-mediated interaction between low-dose escitalopram and clopidogrel seems to be a possible mechanism. Conclusion: Data on this is extremely scarce, and to the best of our knowledge, serotonin syndrome caused by low-dose antidepressants has not yet been discussed to any great extent in the literature. Our case provides more clinical experience in the treatment of serotonin syndrome.