Refractory pruritus caused by sintilimab and its clinical management: A case report.

Several immune related adverse events (irAEs) were reported with the wide application of immune checkpoint inhibitors (ICIs) in tumors. ICI-related skin reactions are the most common, which are manifested as maculopapules, rash, pruritus, vitiligo, psoriasis, and lichenoid rash.Among them, the incidence of pruritus is second only to maculopapule/rash, but both often co-exist. The severity of pruritus is mostly mild to moderate and can be relieved after symptomatic treatment with antihistamines. Symptoms are slightly relieved after conventional treatment in patients with severe pruritus, but it easily recurs and eventually develops into refractory pruritus.The patient's quality of life may be affected and may also be life-threatening. We report a case of a patient with postoperative recurrence of gallbladder neuroendocrine carcinoma,who developed refractory pruritus after sintilimab use, which was relieved after naloxone infusion after unsuccessful conventional drug therapy. By analyzing the treatment plan of this typical case of immune-related refractory pruritus after using sintilimab, this report discusses how clinical pharmacists can provide individualized treatment of patients by using their expertise and clinicians' cooperation and complementation in treating clinically difficult cases. This case report may be used as a reference in treating patients with refractory pruritus after the clinical use of sintilimab.

ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota.

E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here, we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. We observed that ASB3 exhibited significant upregulation in the lesions of patients with IBD. ASB3-/- mice are resistant to dextran sodium sulfate-induced colitis. IκBα phosphorylation levels and production of proinflammatory factors IL-1ß, IL-6, and TNF-α were reduced in the colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotics removed the gut commensal microbiome. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in intestinal epithelial cells. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors' production by disrupting TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis. IMPORTANCE: Ubiquitination is a key process that controls protein stability. We determined the ubiquitination of TRAF6 by ASB3 in intestinal epithelial cells during colonic inflammation. Inflammatory bowel disease patients exhibit upregulated ASB3 expression at focal sites, supporting the involvement of degradation of TRAF6, which promotes TLR-Myd88/TRIF-independent NF-κB aberrant activation and intestinal microbiota imbalance. Sustained inflammatory signaling in intestinal epithelial cells and dysregulated protective probiotic immune responses mediated by ASB3 collectively contribute to the exacerbation of inflammatory bowel disease. These findings provide insights into the pathogenesis of inflammatory bowel disease and suggest a novel mechanism by which ASB3 increases the risk of colitis. Our results suggest that future inhibition of ASB3 in intestinal epithelial cells may be a novel clinical strategy.

Novel curcumin derivatives N17 exert anti-cancer effects through the CSNK1G3/AKT axis in triple-negative breast cancer.

Curcumin, extracted from Zingiberaceae and Araceae rhizomes, is clinically used for its anti-inflammatory, antibacterial, antioxidant, and anti-cancer properties. Its safety and potential make it a promising base for designing enhanced derivatives. The focus now is on optimizing curcumin and synthesizing more potent 1,4-pentadien-3-ones, which have anti-cancer activities. In the realm of triple-negative breast cancer (TNBC), an aggressive and invasive form with high metastatic potential, the need for innovative treatments is acute. The challenges posed by chemotherapy resistance, recurrence, and TNBC's heterogeneity have emphasized the necessity for novel therapeutic approaches. Our strategy involved the integration of a quinoxaline ring into 1,4-pentadien-3-one, followed by subsequent modifications. In this study, N17 demonstrated the ability to induce cell death and effectively suppress cell proliferation in breast cancer cells. These observed anti-cancer effects were attributed to the inhibition of p-AKT(S473), a key regulator implicated in both cell apoptosis and the modulation of epithelial-mesenchymal transition process in breast cancer cells. Furthermore, our investigation indicated N17 achieves its inhibitory effects on p-AKT(S473) by specifically targeting the CSNK1G3 protein. Remarkably, N17 not only impedes the EMT process but also triggers apoptosis through the CSNK1G3/AKT signaling axis. These findings provide the critical role of CSNK1G3 as an anti-cancer regulator in TNBC, establishing N17 as a pharmacological intervention with immense promise for treating cancer metastasis.

Bibliometric analysis and visualisation of research hotspots and frontiers on omics in osteosarcoma.

BACKGROUND/OBJECTIVE: Omics technology has become a widely applied biological science that can be used to study the etiology, pathogenesis, and treatment of osteosarcoma(OS). Bibliometric analysis is still blank in this field.This study aimed to access the trends and hotspots of omics in OS research through the bibliometric analysis method. METHODS: Relevant articles and reviews from 1999 to 2023 were retrieved from the Web of Science Core Collection. The data were processed with CiteSpace, and some graphs were generated with Graphpad, VOSviewer, Scimago Graphica, Bibliometrix and R Studio. RESULTS: A total of 1581 papers were included. China (569, 36.0%) and the United States (523, 33.1%) took the dominant position in the number of published papers, and the links between countries most frequently occurred between North America and East Asia, and between Australia and Europe. Top institutions with the highest number of publications were almost located in the United States, with The University of Texas MD Anderson Cancer Center contributing the most (44, 2.78%). Among the researchers in this field, Cleton-Jansen AM was the author with the highest number of articles in the field (20, 1.27%). According to the keyword cluster analysis, most studies focused on the "comparative genomic hybridization" before 2012. The latest surge words "tumor microenvironment" and "immune infiltration" in the keyword heatmap indicate future research directions. CONCLUSION: Our study provided the current status of the omics research in OS on a global level and the hottest directions. The field of omics in OS was developing rapidly, and the main focuses of research were revealing the characteristics of tumor microenvironment of OS and how to activate the immune system to fight cancer cells. Research on the immune microenvironment and its relationship with genetic aberrations of OS will be a priority in the future.

Current State of Targeted Therapy in Adult Langerhans Cell Histiocytosis and Erdheim-Chester Disease.

The mitogen-activated protein kinase (MAPK) pathway is a key driver in many histiocytic disorders, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). This has led to successful and promising treatment with targeted therapies, including BRAF inhibitors and MEK inhibitors. Additional novel inhibitors have also demonstrated encouraging results. Nevertheless, there are several problems concerning targeted therapy that need to be addressed. These include, among others, incomplete responsiveness and the emergence of resistance to BRAF inhibition as observed in other BRAF-mutant malignancies. Drug resistance and relapse after treatment interruption remain problems with current targeted therapies. Targeted therapy does not seem to eradicate the mutated clone, leading to inevitable relapes, which is a huge challenge for the future. More fundamental research and clinical trials are needed to address these issues and to develop improved targeted therapies that can overcome resistance and achieve long-lasting remissions.

Liver involvement with Langerhans cell histiocytosis in adults.

BACKGROUND AND AIMS: Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. METHODS: We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. RESULTS: Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). OUTCOMES: After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. CONCLUSIONS: In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

Electroacupuncture Improves Cardiac Function via Inhibiting Sympathetic Remodeling Mediated by Promoting Macrophage M2 Polarization in Myocardial Infarction Mice.

Electroacupuncture (EA) at the Neiguan acupoint (PC6) has shown significant cardioprotective effects. Sympathetic nerves play an important role in maintaining cardiac function after myocardial infarction (MI). Previous studies have found that EA treatment may improve cardiac function by modulating sympathetic remodeling after MI. However, the mechanism in how EA affects sympathetic remodeling and improves cardiac function remains unclear. The aim of this study is to investigate the cardioprotective mechanism of EA after myocardial ischemic injury by improving sympathetic remodeling and promoting macrophage M2 polarization. We established a mouse model of MI by occluding coronary arteries in male C57/BL6 mice. EA treatment was performed at the PC6 with current intensity (1 mA) and frequency (2/15 Hz). Cardiac function was evaluated using echocardiography. Heart rate variability in mice was assessed via standard electrocardiography. Myocardial fibrosis was evaluated by Sirius red staining. Levels of inflammatory factors were assessed using RT-qPCR. Sympathetic nerve remodeling was assessed through ELISA, western blotting, immunohistochemistry, and immunofluorescence staining. Macrophage polarization was evaluated using flow cytometry. Our results indicated that cardiac systolic function improved significantly after EA treatment, with an increase in fractional shortening and ejection fraction. Myocardial fibrosis was significantly mitigated in the EA group. The sympathetic nerve marker tyrosine hydroxylase and the nerve sprouting marker growth-associated Protein 43 were significantly reduced in the EA group, indicating that sympathetic remodeling was significantly reduced. EA treatment also promoted macrophage M2 polarization, reduced levels of inflammatory factors TNF-α, IL-1ß, and IL-6, and decreased macrophage-associated nerve growth factor in myocardial tissue. To sum up, our results suggest that EA at PC6 attenuates sympathetic remodeling after MI to promote macrophage M2 polarization and improve cardiac function.

Sulfiredoxin-1 promotes the growth of hepatocellular carcinoma by inhibiting TFEB-mediated autophagy and lysosome biogenesis.

Advanced hepatocellular carcinoma (HCC) patients have poor prognosis. As an endogenous antioxidant enzyme involved in a variety of bioprocesses, sulfiredoxin-1 (SRXN1) plays an irreplaceable role in promoting the development of tumors. However, the role and working mechanism of SRXN1 in HCC remain unclear. In this study, we confirmed that SRXN1 promoted the cell proliferation of HCC at genetic and pharmacological level, respectively. Transcriptome sequencing analysis revealed SRXN1 knockdown had a significant effect on the expression of lysosome biogenesis related genes. Further experiments validated that lysosome biogenesis and autophagic flux were enhanced after SRXN1 inhibition and reduced as SRXN1 overexpression. Mechanism study revealed that ROS accumulation induced TFEB nuclear translocation, followed by increased autophagy. Following this rationale, the combination of SRXN1 inhibitor and sorafenib demonstrated noticeable synergistic antitumor effect through the boost of ROS both in vivo and in vitro. Taken together, SRXN1 could be a potential therapeutic target for HCC therapy.

Integrated biomarker-based ecological risks assessment of tadpole responses to tris(2-chloroethyl) phosphate, tris(1-chloro-2-propyl) phosphate, and their combined environmental exposure.

Tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) phosphate (TCPP) are common chlorinated organophosphorus flame retardants (OPFRs) used in industry. They have been frequently detected together in aquatic environments and associated with various hazardous effects. However, the ecological risks of prolonged exposure to these OPFRs at environmentally relevant concentrations in non-model aquatic organisms remain unexplored. This study investigated the effects of long-term exposure (up to 25 days) to TCEP and TCPP on metamorphosis, hepatic antioxidants, and endocrine function in Polypedates megacephalus tadpoles. Exposure concentrations were set at 3, 30, and 90 µg/L for each substance, conducted independently and in equal-concentration combinations, with a control group included for comparison. The integrated biomarker response (IBR) method developed an optimal linear model for predicting the overall ecological risks of TCEP and TCPP to tadpoles in potential distribution areas of Polypedates species. Results showed that: (1) Exposure to environmentally relevant concentrations of TCEP and TCPP elicited variable adverse effects on tadpole metamorphosis time, hepatic antioxidant enzyme activity and related gene expression, and endocrine-related gene expression, with their combined exposure exacerbating these effects. (2) The IBR value of TCEP was consistently greater than that of TCPP at each concentration, with an additive effect observed under their combined exposure. (3) The ecological risk of tadpoles exposed to the combined presence of TCEP and TCPP was highest in China's Taihu Lake and Vietnam's Hanoi than in other distribution locations. In summary, prolonged exposure to environmentally relevant concentrations of TCEP and TCPP presents potential ecological risks to amphibian tadpoles, offering insights for the development of policies and strategies to control TCEP and TCPP pollution in aquatic ecosystems. Furthermore, the methodology employed in establishing the IBR prediction model provides a methodological framework for assessing the overall ecological risks of multiple OPFRs.

Integrative profiling of untreated primary membranous nephropathy at the single-cell transcriptome level.

Background: Primary membranous nephropathy (PMN) is an autoimmune kidney disease. Despite the identification of certain autoantigens, the etiology and pathophysiology of PMN are still largely unknown. Methods: Five patients with biopsy-proven PMN were enrolled in this study. Their blood, kidney and urine samples were collected respectively to profile cellular, molecular and immunological alterations by using single-cell RNA sequencing (scRNA-seq). Experimental verifications were also implemented in kidney tissue. Results: In the peripheral blood mononuclear cell (PBMC) samples, portions of B cells and plasma cells were increased in PMN patients. Cell-cell communication analysis suggests that APRIL (a proliferation-inducing ligand from B cells) might be a potential molecule that regulates the activity of plasma cells. In the kidney samples, scRNA-seq analysis showed that the infiltration of T cells, as well as the myeloid cells, appears abundant compared with healthy controls, suggesting that immune cells are actively recruited to kidney. Furthermore, we observed an enhanced interaction between inflammatory cells and podocytes, which might contribute to kidney injury. Accordingly, scRNA-seq analysis of urinary samples is partially reminiscent of the kidney cell landscape, especially T cells and myeloid cells, suggesting monitoring urinary samples is a promising method to monitor PMN development. Additionally, integrative analysis across the blood, kidney and urine identified LTB, HERP1, ANXA1, IL1RN and ICAM1 as common regulators of PMN. Finally, immune repertoire in PBMC also showed an elevated diversity of clonal type, implying the existence of autoreactive T-cell receptor/B-cell receptor. Conclusion: Our study comprehensively profiled the transcriptomic landscapes of blood, kidney and urine in patients with PMN using scRNA-seq. We depicted the alterations including cell compositions and cell-cell communication in PMN. These results offer important clues with regard to the diagnosis and pathogenesis of PMN and potential intervention of PMN progression.

Hernandezine acts as a CDK4 suppressor inhibiting tumor growth by the CDK4/PKM2/NRF2 axis in colon cancer.

BACKGROUND: The cyclin-dependent kinase 4 (CDK4) interacts with its canonical and non-canonical substrates modulating the cell cycle in tumor cells. However, the potential substrates and the beyond-cell-cycle-regulated functions of CDK4 in colon cancer (CC) are still unknown. Hernandezine (HER) is previously verified to induce G0/G1 phase arrest and autophagic cell death in human cancer cells, which implies that HER might target G0/G1 phase-related proteins, including CDK4. PURPOSE: The present study tried to investigate the glycolytic metabolism and oxidative stress functions of CDK4 in colon cancer. Furthermore, the inhibitory effects and potential binding sites of HER on CDK4, as well as its anti-tumor activity were investigated in CC cells. METHODS: The mass spectrometry assay was performed to identify potential endogenous substrates of CDK4 and the correlation between glycolytic metabolic rate and CDK4 level in COAD patient tissues. Meanwhile, after inhibiting the activity or the expression of CDK4, the binding capacity of CDK4 to PKM2 and NRF2 and the latter two protein distributions in cytoplasm and nucleus were detected in CC cells. In vitro, the regulatory effects of the CDK4-PKM2-NRF2 axis on glycolysis and oxidative stress were performed by ECAR, OCR, and ROS assay. The inhibitory effect of HER on CDK4 activity was explored in CC cells and the potential binding sites were predicted and testified in vitro. Furthermore, tumor growth inhibition of HER by suppressing the CDK4-PKM2-NRF2 axis was also investigated in vitro and in vivo. RESULTS: PKM2 and NRF2 were identified as endogenous substrates of CDK4 and, high-expressed CDK4 was associated with low-level glycolysis in COAD. In vitro, inactivated CDK4 facilitated CDK4-PKM2-NRF2 complex formation which resulted in 1) inhibited PKM2 activity and retarded the glycolytic rate; 2) cytoplasm-detained NRF2 failed to transcript anti-oxidative gene expressions and induced oxidant stress. Additionally, as a CDK4 inhibitor, HER developed triple anti-tumor effects including induced G0/G1 phase arrest, suppressed glycolysis, and disrupted the anti-oxidative capacity of CC cells. CONCLUSION: The results first time revealed that CDK4 modulated glycolytic and anti-oxidative capacity of CC cells via bound to its endogenous substrates, PKM2 and NRF2. Additionally, 140Asp145Asn amino acid sites of CDK4 were potential targets of HER. HER exerts anti-tumor activity by inhibited the activity of CDK4, promoted the CDK4-PKM2-NRF2 complex formation in the CC cells.

Toxicity comparison and risk assessment of two chlorinated organophosphate flame retardants (TCEP and TCPP) on Polypedates megacephalus tadpoles.

Tris(2-chloroethyl) phosphate (TCEP) and tris(1­chloro-2-propyl) phosphate (TCPP) are widely used as chlorinated organophosphate flame retardants (OPFRs) due to their fire-resistance capabilities. However, their extensive use has led to their permeation and pollution in aquatic environments. Using amphibians, which are non-model organisms, to test the toxic effects of OPFRs is relatively uncommon. This study examined the acute and chronic toxicity differences between TCEP and TCPP on Polypedates megacephalus tadpoles and evaluated the potential ecological risks to tadpoles in different aquatic environments using the risk quotient (RQ). In acute toxicity assay, the tadpole survival rates decreased with increased exposure time and concentrations, with TCEP exhibiting higher LC50 values than TCPP, at 305.5 mg/L and 70 mg/L, respectively. In the chronic assay, prolonged exposure to 300 µg/L of both substances resulted in similar adverse effects on tadpole growth, metamorphosis, and hepatic antioxidant function. Based on RQ values, most aquatic environments did not pose an ecological risk to tadpoles. However, the analysis showed that wastewater presented higher risks than rivers and drinking water, and TCPP posed a higher potential risk than TCEP in all examined aquatic environments. These findings provide empirical evidence to comprehend the toxicological effects of OPFRs on aquatic organisms and to assess the safety of aquatic environments.

Accurate identification of 8-oxoguanine in RNA with single-nucleotide resolution using ligase-dependent qPCR.

8-oxoguanine (o8G), a prevalent oxidative modification in RNA induced by reactive oxygen species (ROS), plays a pivotal role in regulating RNA functions. Accurate detection and quantification of o8G modifications is critical to understanding their biological significance and potential as disease biomarkers, but effective detection methods remain limited. Here, we have developed a highly specific T3 DNA ligase-dependent qPCR assay that exploits the enzyme's ability to discriminate o8G from guanine (G) with single-nucleotide resolution. This method can detect o8G in RNA at levels as low as 500 fM, with an up to 18-fold higher selectivity for discriminating o8G from G. By simulating oxidative stress conditions in SH-SY5Y and HS683 cell lines treated with rotenone, we successfully identified site-specific o8G modifications in key miRNAs associated with neuroprotective responses, including miR-124, let-7a and miR-29a. The developed assay holds significant promise for the practical identification of o8G, facilitating its potential for detailed studies of o8G dynamics in various biological contexts and diseases.

Co-occurrence of Erdheim-Chester disease and clonally evolving acute myeloid leukemia with FLT3-ITD and PTPN11 mutations.

Erdheim-Chester disease (ECD) is a rare histiocytosis that tends to co-exist with other myeloid malignancies. Here, we use genetic and transcriptomic sequencing to delineate a case of co-occurring BRAFV600E-mutated ECD and acute myeloid leukemia (AML), followed by AML remission and relapse. The AML relapse involved the extinction of clones with KMT2A-AFDN and FLT3-ITD, and the predominance of PTPN11-mutated subclones with distinct transcriptomic features. This case report has highlighted the screening for other myeloid malignancies at the diagnosis of ECD and the clinical significance of PTPN11-mutated AML subclones that require meticulous monitoring.

Patterns and organ treatment response of Erdheim-Chester disease with cardiac involvement.

OBJECTIVE: To evaluate the heart response of Erdheim-Chester disease (ECD) through continuous follow-up within our large cohort, for which there is a lack of understanding. METHODS: We conducted a retrospective analysis of clinical data from patients with ECD with cardiac involvement diagnosed at our centre between January 2010 and August 2023. We assessed the heart response by integrating pericardial effusion and metabolic responses. RESULTS: A total of 40 patients were included, with a median age of 51.5 years (range: 29-66) and a BRAFV600E mutation rate of 56%. The most common imaging manifestations observed were pericardial effusion (73%), right atrium (70%) and right atrioventricular sulcus infiltration (58%). Among 21 evaluable patients, 18 (86%) achieved a heart response including 5 (24%) complete response (CR) and 13 (62%) partial response (PR). The CR rate of pericardial effusion response was 33%, while the PR rate was 56%. Regarding the cardiac mass response, 33% of patients showed PR. For cardiac metabolic response, 32% and 53% of patients achieved complete and partial metabolic response, respectively. There was a correlation between pericardial effusion response and cardiac metabolic response (r=0.73 (95% CI 0.12 to 0.83), p<0.001). The median follow-up was 50.2 months (range: 1.0-102.8 months). The estimated 5-year overall survival was 78.9%. The median progression-free survival was 59.4 months (95% CI 26.2 to 92.7 months). Patients who received BRAF inhibitors achieved better heart response (p=0.037) regardless of treatment lines. CONCLUSION: We pioneered the evaluation of heart response of ECD considering both pericardial effusion and cardiac metabolic response within our cohort, revealing a correlation between these two indicators. BRAF inhibitors may improve heart response, regardless of the treatment lines.

MRI-based vertebral bone quality score as a novel bone status marker of patients with adolescent idiopathic scoliosis.

To investigate the application of MRI-based vertebral bone quality (VBQ) score in assessing bone mineral density (BMD) for patients with adolescent idiopathic scoliosis (AIS). We reviewed the data of AIS patients between January 2021 and October 2023 with MRI, whole-spine plain radiographs, quantitative computed tomography (QCT) and general information. VBQ score was calculated using T1-weighted MRI. Univariate analysis was applied to present the differences between variables of patients with normal BMD group (QCT Z-score > - 2.0) and low BMD group (QCT Z-score ≤ - 2.0). The correlation between VBQ score and QCT Z-score was analyzed with Pearson correlation test. A multivariate logistic regression model was used to determine the independent factors related to low BMD. Receiver operating characteristic curve (ROC) was drawn to analyze the diagnostic performance of VBQ score in distinguishing low BMD. A total of 136 AIS patients (mean age was 14.84 ± 2.10 years) were included, of which 41 had low BMD. The low BMD group had a significantly higher VBQ score than that in normal group (3.48 ± 0.85 vs. 2.62 ± 0.62, P < 0.001). The VBQ score was significantly negative correlated with QCT Z score (r = - 0.454, P < 0.001). On multivariate analysis, VBQ score was independently associated with low BMD (OR: 4.134, 95% CI 2.136-8.000, P < 0.001). The area under the ROC curve indicated that the diagnostic accuracy of the VBQ score for predicting low BMD was 81%. A sensitivity of 65.9% with a specificity of 88.4% could be achieved for distinguishing low BMD by setting the VBQ score cutoff as 3.18. The novel VBQ score was a promising tool in distinguishing low BMD in patients with AIS and could be useful as opportunistic assessment for screening and complementary evaluation to QCT before surgery.

Clinical characteristics, radiological features and outcomes in pulmonary involvement of cryoglobulinemia.

BACKGROUND: Cryoglobulinemia with pulmonary involvement is rare, and its characteristics, radiological findings, and outcomes are still poorly understood. METHODS: Ten patients with pulmonary involvement of 491 cryoglobulinemia patients at Peking Union Medical College Hospital were enrolled in this retrospective study. We analyzed the characteristics, radiological features and management of pulmonary involvement patients, and compared with those of non-pulmonary involvement with cryoglobulinemia. RESULTS: The 10 patients with pulmonary involvement (2 males; median age, 53 years) included three patients with type I cryoglobulinemia and seven patients with mixed cryoglobulinemia. All of 10 patients were IgM isotype cryoglobulinemia. All type I patients were secondary to B-cell non-Hodgkin lymphoma. Four mixed patients were essential, and the remaining patients were secondary to infections (n = 2) and systemic lupus erythematosus (n = 1), respectively. Six patients had additional affected organs, including skin (60%), kidney (50%), peripheral nerves (30%), joints (20%), and heart (20%). The pulmonary symptoms included dyspnea (50%), dry cough (30%), chest tightness (30%), and hemoptysis (10%). Chest computed tomography (CT) showed diffuse ground-glass opacity (80%), nodules (40%), pleural effusions (30%), and reticulation (20%). Two patients experienced life-threatening diffuse alveolar hemorrhage. Five patients received corticosteroid-based regimens, and four received rituximab-based regimens. All patients on rituximab-based regimens achieved clinical remission. The estimated two-year overall survival (OS) was 40%. Patients with pulmonary involvement had significantly worse OS and progression-free survival than non-pulmonary involvement patients of cryoglobulinemia (P < 0.0001). CONCLUSIONS: A diagnosis of pulmonary involvement should be highly suspected for patients with cryoglobulinemia and chest CT-indicated infiltrates without other explanations. Patients with pulmonary involvement had a poor prognosis. Rituximab-based treatment may improve the outcome.

Landscape of human organoids: Ideal model in clinics and research.

In the last decade, organoid research has entered a golden era, signifying a pivotal shift in the biomedical landscape. The year 2023 marked a milestone with the publication of thousands of papers in this arena, reflecting exponential growth. However, amid this burgeoning expansion, a comprehensive and accurate overview of the field has been conspicuously absent. Our review is intended to bridge this gap, providing a panoramic view of the rapidly evolving organoid landscape. We meticulously analyze the organoid field from eight distinctive vantage points, harnessing our rich experience in academic research, industrial application, and clinical practice. We present a deep exploration of the advances in organoid technology, underpinned by our long-standing involvement in this arena. Our narrative traverses the historical genesis of organoids and their transformative impact across various biomedical sectors, including oncology, toxicology, and drug development. We delve into the synergy between organoids and avant-garde technologies such as synthetic biology and single-cell omics and discuss their pivotal role in tailoring personalized medicine, enhancing high-throughput drug screening, and constructing physiologically pertinent disease models. Our comprehensive analysis and reflective discourse provide a deep dive into the existing landscape and emerging trends in organoid technology. We spotlight technological innovations, methodological evolution, and the broadening spectrum of applications, emphasizing the revolutionary influence of organoids in personalized medicine, oncology, drug discovery, and other fields. Looking ahead, we cautiously anticipate future developments in the field of organoid research, especially its potential implications for personalized patient care, new avenues of drug discovery, and clinical research. We trust that our comprehensive review will be an asset for researchers, clinicians, and patients with keen interest in personalized medical strategies. We offer a broad view of the present and prospective capabilities of organoid technology, encompassing a wide range of current and future applications. In summary, in this review we attempt a comprehensive exploration of the organoid field. We offer reflections, summaries, and projections that might be useful for current researchers and clinicians, and we hope to contribute to shaping the evolving trajectory of this dynamic and rapidly advancing field.

Endoscopic resection of extra-luminal gastric gastrointestinal stromal tumors using a snare assisted external traction technique (with video).

OBJECTIVE: The primary purpose of the study was to explore the clinical efficacy of the novel snare assisted endoscopic resection of extraluminal growing gastric gastrointestinal stromal tumors (gastric GISTs) using external traction, and the secondary purpose was to compare the novel snare assisted endoscopic resection of extraluminal GISTs with the standard laparoscopic procedure. METHODS: We retrospectively analyzed the patients who underwent novel external traction assisted endoscopic resection or laparoscopic resection for their extraluminal gastric GIST ≤5 cm in diameter. RESULTS: A total of 111 patients (27 in the endoscopic group and 84 in the laparoscopic group) were included in this study. There was no significant difference in tumor diameter and complication rate between the two groups. The overall procedure time was slightly higher in the endoscopic group compared to the laparoscopic group (P = 0.034). However, postoperative hospitalization time (P < 0.001) and postoperative fasting time (P = 0.005) were shorter in the endoscopic group compared to the laparoscopic group. CONCLUSION: Snare external traction-assisted endoscopic resection of extraluminal growing gastric GISTs is safe and effective, and it provides a new adjunctive method for endoscopic resection of GIST.