Asymptomatic Incidence of Monoclonal Gammopathy of Undetermined Significance and Preclinical Duration to Myeloma Diagnosis: A Modeling Study.

Background Monoclonal gammopathy of undetermined significance (MGUS) is the premalignant condition of multiple myeloma (MM). Given a lack of population-based screening for MGUS and its asymptomatic nature, the epidemiology of MGUS remains unknown. This study estimated age- and race/ethnicity-specific MGUS incidence and preclinical duration from MGUS to MM in the United States. Methods A previously published modeling approach was used to calculate national MGUS incidence using estimates of MGUS prevalence, MM incidence, MM-specific and all-cause mortality, and population age distribution from the National Health and Nutrition Examination Survey, 1999-2004, and Surveillance, Epidemiology, and End Results, 2000-2021. The estimated MGUS prevalence was divided by MGUS incidence to obtain preclinical duration of MM. Results MGUS incidence for non-Hispanic white (NHW) populations was 52, 86, 142, and 181 and for non-Hispanic black (NHB) population was 110, 212, 392, and 570 per 100,000 person-years at ages 50, 60, 70, and 80, respectively. The average preclinical duration was 20.5 (95% confidence interval, CI: 16.5, 26.1) years for the NHW population and 14.2 (95% CI: 11.5, 17.6) years for the NHB population. The cumulative risk of developing MGUS in age 50-85 was 2.8% (95% CI: 1.7%, 4.2%) for the NHW population and 6.1% (95% CI: 3.8%, 10.0%) for the NHB population. Conclusion NHB populations had a higher MGUS incidence rate at all ages and a shorter preclinical duration of MM compared to their NHW counterparts. Impact This study provides insights into the epidemiology of MGUS and enhances our understanding of the natural history of MM.

KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Development of Bivalent Aptamer-DNA Carrier-Doxorubicin Conjugates for Targeted Killing of Esophageal Squamous Cell Carcinoma Cells.

Esophageal cancer ranks the seventh in cancer incidence and the sixth in cancer death. Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of the total cases of esophageal cancer. Chemotherapy is the most effective drug-based method for treatment of esophageal cancer. However, severe side effects of traditional chemotherapy limit its treatment efficacy. Targeted chemotherapy can deliver chemotherapeutic drugs to cancer cells and specifically kill these cells with reduced side effects. In the work, the bivalent aptamer-DNA carrier (BAD) was designed by using an ESCC cell-specific aptamer as the recognition molecule and a GC base-rich DNA sequence as the drug carrier. With doxorubicin (Dox) as chemotherapeutic drugs, the bivalent aptamer-DNA-Dox conjugate (BADD) was constructed for targeted killing of ESCC cells. Firstly, the truncated A2(35) aptamer with a retained binding ability was obtained through optimization of an intact A2(80) aptamer and was used to fuse with DNA carrier sequences for constructing the BAD through simple DNA hybridization. The results of gel electrophoresis and flow cytometry analysis showed that the BAD was successfully constructed and had a stronger binding affinity than monovalent A2(35). Then, the BAD was loaded with Dox drugs to construct the BADD through noncovalent intercalation. The results of fluorescence spectra and flow cytometry assays showed that the BADD was successfully constructed and can bind to target cells strongly. Confocal imaging further displayed that the BADD can be specifically internalized into target cells and release Dox. The results of CCK-8 assays, Calcein AM/PI staining, and wound healing assays demonstrated that the BADD can specifically kill target cells, but not control cells. Our results demonstrate that the developed BADD can specifically deliver doxorubicin to target ESCC cells and selectively kill these cells, offering a potentially effective strategy for targeted chemotherapy of ESCC.

Use of Deep Neural Networks to Predict Obesity With Short Audio Recordings: Development and Usability Study.

BACKGROUND: The escalating global prevalence of obesity has necessitated the exploration of novel diagnostic approaches. Recent scientific inquiries have indicated potential alterations in voice characteristics associated with obesity, suggesting the feasibility of using voice as a noninvasive biomarker for obesity detection. OBJECTIVE: This study aims to use deep neural networks to predict obesity status through the analysis of short audio recordings, investigating the relationship between vocal characteristics and obesity. METHODS: A pilot study was conducted with 696 participants, using self-reported BMI to classify individuals into obesity and nonobesity groups. Audio recordings of participants reading a short script were transformed into spectrograms and analyzed using an adapted YOLOv8 model (Ultralytics). The model performance was evaluated using accuracy, recall, precision, and F1-scores. RESULTS: The adapted YOLOv8 model demonstrated a global accuracy of 0.70 and a macro F1-score of 0.65. It was more effective in identifying nonobesity (F1-score of 0.77) than obesity (F1-score of 0.53). This moderate level of accuracy highlights the potential and challenges in using vocal biomarkers for obesity detection. CONCLUSIONS: While the study shows promise in the field of voice-based medical diagnostics for obesity, it faces limitations such as reliance on self-reported BMI data and a small, homogenous sample size. These factors, coupled with variability in recording quality, necessitate further research with more robust methodologies and diverse samples to enhance the validity of this novel approach. The findings lay a foundational step for future investigations in using voice as a noninvasive biomarker for obesity detection.

Selective inhibition of c-Met signaling pathways with a bispecific DNA nanoconnector for the targeted therapy of cancer.

Hepatocyte growth factor receptor (c-Met) is a suitable molecular target for the targeted therapy of cancer. Novel c-Met-targeting drugs need to be developed because conventional small-molecule inhibitors and antibodies of c-Met have some limitations. To synthesize such drugs, we developed a bispecific DNA nanoconnector (STPA) to inhibit c-Met function. STPA was constructed by using DNA triangular prism as a scaffold and aptamers as binding molecules. After c-Met-specific SL1 and nucleolin-specific AS1411 aptamers were integrated with STPA, STPA could bind to c-Met and nucleolin on the cell membrane. This led to the formation of the c-Met/STPA/nucleolin complex, which in turn blocked c-Met activation. In vitro experiments showed that STPA could not only inhibit the c-Met signaling pathways but also facilitate c-Met degradation through lysosomes. STPA also inhibited c-Met-promoted cell migration, invasion, and proliferation. The results of in vivo experiments showed that STPA could specifically target to tumor site in xenograft mouse model, and inhibit tumor growth with low toxicity by downregulating c-Met pathways. This study provided a novel and simple strategy to develop c-Met-targeting drugs for the targeted therapy of cancer.

Tracheostomy care of non-ventilated patients and COVID considerations: A scoping review of clinical practice guidelines and consensus statements.

BACKGROUND: The purpose of this study is to examine and evaluate the existing clinical practice guidelines and consensus statements regarding tracheostomy care for non-mechanically ventilated patients. METHODS: A systematic search of databases, and professional organisations was conducted from inception to 19 March 2023. Two appraisers evaluated each guideline using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Text and Opinion Papers. RESULTS: No specific clinical guidelines exist on airway management in non-mechanically ventilated patients. Of 6318 articles identified, we included 12 clinical practice guidelines, and 9 consensus statements, which were from China, the US, the UK, South Korea, Australia, France and Belgium. The AGREE II scores in six domains are (1) the scope and purpose, 70.30%; (2) stakeholder involvement, 37.61%; (3) rigor of development, 33.97%; (4) clarity of presentation, 68.16%; (5) applicability, 44.23% and (6) editorial independence, 40.06%. The overall quality of evidence was level B. The summarised recommendations for clinical practice encompass the following six areas: airway humidification, management of the trach cuff, management of inner cannula, tracheostoma care, tracheostomy suctioning and management and prevention of common post-operative complications. CONCLUSIONS: The overall quality of the clinical guidelines on non-ventilated tracheostomy care was moderate, and further improvements are needed in domains of stakeholder involvement, applicability, clarity of presentation and editorial independence. Recommendations on non-ventilated tracheostomy care are often embedded in the guidelines on ventilated tracheostomy. Specific clinical guidelines are needed to provide a standardised approach to tracheostomy care for non-ventilated patients. RELEVANCE TO CLINICAL PRACTICE: Patients with non-ventilated tracheostomy need specialised airway management. Improving patient outcomes requires standardised protocols, patient involvement, quality evaluation, and interdisciplinary approaches. NO PATIENT OR PUBLIC CONTRIBUTION: The study reviewed clinical practice guidelines and consensus statements, therefore patient or public input was not needed.

Effects of low protein feed on hepato-intestinal health and muscle quality of grass carp (Ctenopharyngodon idellus).

In this study, grass carp (33.28 ± 0.05 g) were fed three diets for 8 weeks: control (crude protein [CP] 30%, crude lipid [CL] 6%), low protein (LP; CP16%, CL6%), and low protein with high-fat (LPHF; CP16%, CL10%). The final body weight decreased in the LP and LPHF groups compared to the Control (P < 0.05). Liver triglycerides, total cholesterol, and nonesterified fatty acids were higher in the LP group than the Control, whereas these indexes in the LPHF group were higher than those in the LP group (P < 0.05). The LP group had intestinal barrier damage, while the LPHF group had a slight recovery. TNF-α, IL-8, and IL-1ß content were lower in the LP group than in the Control (P < 0.05), and even higher in the LPHF group (P < 0.05). The expressions of endoplasmic reticulum stress-related genes Activating transcription factor 6 (ATF-6) and Glucose-regulated protein (GRP78) were higher in the LPHF group against the LP group (P < 0.05). The IL-1ß and TNF-α content negatively correlated with intestinal Actinomycetes and Mycobacterium abundance (P < 0.05). The muscle fiber diameter was smaller in both the LP and LPHF groups than the control (P < 0.05), with the LP group showing metabolites related to protein digestion and absorption, and LPHF group exhibiting metabolites related to taste transmission. The results demonstrate reducing dietary protein affects growth, causing liver lipid accumulation, reduced enteritis response, and increased muscle tightness, while increasing fat content accelerates fat accumulation and inflammation.

Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification. According to the mutational status of RHOA, TET2, histone-modifying, and immune-related genes, PTCL is divided into 4 molecular subtypes with discrete patterns of gene expression, biological aberrations, and vulnerabilities to targeted agents. We also perform an unsupervised clustering on the microenvironment transcriptional signatures and categorize PTCL into 4 lymphoma microenvironment subtypes based on characteristic activation of oncogenic pathways and composition of immune communities. Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL.

Inhibition of SFTSV replication in humanized mice by a subcutaneously administered anti-PD1 nanobody.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease's mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection.

Computed tomography-based radiomics model to predict adverse clinical outcomes in acute pulmonary embolism.

This preliminary study investigated the feasibility of a combined model constructed using radiomic features based on computed tomography (CT) and clinical features to predict adverse clinical outcomes in acute pulmonary embolism (APE). Currently, there is no widely recognized predictive model. Patients with confirmed APE who underwent CT pulmonary angiography were retrospectively categorized into good and poor prognosis groups. Seventy-four patients were randomized into a training (n = 51) or validation (n = 23) cohort. Feature extraction was performed using 3D-Slicer software. The least absolute shrinkage and selection operator regression was used to identify the optimal radiomics features and calculate the radiomics scores; subsequently, the radiomics model was developed. A combined predictive model was constructed based on radiomics scores and selected clinical features. The predictive efficacy of the three models (radiomics, clinical and combined) was assessed by plotting receiver operating characteristic curves. Furthermore, the calibration curves were graphed and the decision curve analysis was performed. Four radiomic features were screened to calculate the radiomic score. Right ventricular to left ventricular ratio (RV/LV) ≥ 1.0 and radiomics score were independent risk factors for adverse clinical outcomes. In the training and validation cohorts, the areas under the curve (AUCs) for the RV/LV ≥ 1.0 (clinical) and radiomics score prediction models were 0.778 and 0.833 and 0.907 and 0.817, respectively. The AUCs for the combined model of RV/LV ≥ 1.0 and radiomics score were 0.925 and 0.917, respectively. The combined and radiomics models had high clinical assessment efficacy for predicting adverse clinical outcomes in APE, demonstrating the clinical utility of both models. Calibration curves exhibited a strong level of consistency between the predictive and observed probabilities of poor and good prognoses in the combined model. The combined model of RV/LV ≥ 1.0 and radiomics score based on CT could accurately and non-invasively predict adverse clinical outcomes in patients with APE.

Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis.

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.

Selection and identification of a prohibitin 2-binding DNA aptamer for tumor tissue imaging and targeted chemotherapy.

Tumor cell-targeting molecules play a vital role in cancer diagnosis, targeted therapy, and biomarker discovery. Aptamers are emerging as novel targeting molecules with unique advantages in cancer research. In this work, we have developed several DNA aptamers through cell-based systematic evolution of ligands by exponential enrichment (Cell-SELEX). The selected SYL-6 aptamer can bind to a variety of cancer cells with high signal. Tumor tissue imaging demonstrated that SYL-6-Cy5 fluorescent probe was able to recognize multiple clinical tumor tissues but not the normal tissues, which indicates great potential of SYL-6 for clinical tumor diagnosis. Meanwhile, we identified prohibitin 2 (PHB2) as the molecular target of SYL-6 using mass spectrometry, pull-down and RNA interference assays. Moreover, SYL-6 can be used as a delivery vehicle to carry with doxorubicin (Dox) chemotherapeutic agents for antitumor targeted chemotherapy. The constructed SYL-6-Dox can not only selectively kill tumor cells in vitro, but also inhibit tumor growth with reduced side effects in vivo. This work may provide a general tumor cell-targeting molecule and a potential biomarker for cancer diagnosis and targeted therapy.

Cell Membrane-Anchored DNA Nanoinhibitor for Inhibition of Receptor Tyrosine Kinase Signaling Pathways via Steric Hindrance and Lysosome-Induced Protein Degradation.

Receptor tyrosine kinase (RTK) plays a crucial role in cancer progression, and it has been identified as a key drug target for cancer targeted therapy. Although traditional RTK-targeting drugs are effective, there are some limitations that potentially hinder the further development of RTK-targeting drugs. Therefore, it is urgently needed to develop novel, simple, and general RTK-targeting inhibitors with a new mechanism of action for cancer targeted therapy. Here, a cell membrane-anchored RTK-targeting DNA nanoinhibitor is developed to inhibit RTK function. By using a DNA tetrahedron as a framework, RTK-specific aptamers as the recognition elements, and cholesterol as anchoring molecules, this DNA nanoinhibitor could rapidly anchor on the cell membrane and specifically bind to RTK. Compared with traditional RTK-targeting inhibitors, this DNA nanoinhibitor does not need to bind at a limited domain on RTK, which increases the possibilities of developing RTK inhibitors. With the cellular-mesenchymal to epithelial transition factor (c-Met) as a target RTK, the DNA nanoinhibitor can not only induce steric hindrance effects to inhibit c-Met activation but also reduce the c-Met level via lysosome-mediated protein degradation and thus inhibition of c-Met signaling pathways and related cell behaviors. Moreover, the DNA nanoinhibitor is feasible for other RTKs by just replacing aptamers. This work may provide a novel, simple, and general RTK-targeting nanoinhibitor and possess great value in RTK-targeted cancer therapy.

Application of Speckle Tracking Echocardiography for Evaluating Ventricular Function after Transcatheter Pulmonary Valve Replacement.

Pulmonary regurgitation usually leads to right heart dilatation and eventually right heart dysfunction, which is associated with a poor prognosis. Transcatheter pulmonary valve replacement is a developing treatment for pulmonary valve dysfunction that can take the place of traditional surgery and make up for the shortcomings of a large injury. Echocardiography plays a significant role in assessing ventricular function; however, conventional echocardiographic parameters have several limitations. Speckle tracking echocardiography has been regarded as a more accurate tool for quantifying cardiac function than conventional echocardiography. Therefore, the aim of this review was to summarize the application of speckle tracking echocardiography for evaluating right and left ventricular functions in patients after transcatheter pulmonary valve replacement.