Lymphoid organ-targeted nanomaterials for immunomodulation of cancer, inflammation, and beyond.

Nanomaterials exhibit significant potential for stimulating immune responses, offering both local and systemic modulation across a variety of diseases. The lymphoid organs, such as the spleen and lymph nodes, are home to various immune cells, including monocytes and dendritic cells, which contribute to both the progression and prevention/treatment of diseases. Consequently, many nanomaterial formulations are being rationally designed to target these organs and engage with specific cell types, thereby inducing therapeutic and protective effects. In this review, we explore crucial cellular interactions and processes involved in immune regulation and highlight innovative nano-based immunomodulatory approaches. We outline essential considerations in nanomaterial design with an emphasis on their impact on biological interactions, targeting capabilities, and treatment efficacy. Through selected examples, we illustrate the strategic targeting of therapeutically active nanomaterials to lymphoid organs and the subsequent immunomodulation for infection resistance, inflammation suppression, self-antigen tolerance, and cancer immunotherapy. Additionally, we address current challenges, discuss emerging topics, and share our outlook on future developments in the field.

A Machine Learning Application to Classify Patients at Differing Levels of Risk of Opioid Use Disorder: Clinician-Based Validation Study.

Background: Despite restrictive opioid management guidelines, opioid use disorder (OUD) remains a major public health concern. Machine learning (ML) offers a promising avenue for identifying and alerting clinicians about OUD, thus supporting better clinical decision-making regarding treatment. Objective: This study aimed to assess the clinical validity of an ML application designed to identify and alert clinicians of different levels of OUD risk by comparing it to a structured review of medical records by clinicians. Methods: The ML application generated OUD risk alerts on outpatient data for 649,504 patients from 2 medical centers between 2010 and 2013. A random sample of 60 patients was selected from 3 OUD risk level categories (n=180). An OUD risk classification scheme and standardized data extraction tool were developed to evaluate the validity of the alerts. Clinicians independently conducted a systematic and structured review of medical records and reached a consensus on a patient's OUD risk level, which was then compared to the ML application's risk assignments. Results: A total of 78,587 patients without cancer with at least 1 opioid prescription were identified as follows: not high risk (n=50,405, 64.1%), high risk (n=16,636, 21.2%), and suspected OUD or OUD (n=11,546, 14.7%). The sample of 180 patients was representative of the total population in terms of age, sex, and race. The interrater reliability between the ML application and clinicians had a weighted kappa coefficient of 0.62 (95% CI 0.53-0.71), indicating good agreement. Combining the high risk and suspected OUD or OUD categories and using the review of medical records as a gold standard, the ML application had a corrected sensitivity of 56.6% (95% CI 48.7%-64.5%) and a corrected specificity of 94.2% (95% CI 90.3%-98.1%). The positive and negative predictive values were 93.3% (95% CI 88.2%-96.3%) and 60.0% (95% CI 50.4%-68.9%), respectively. Key themes for disagreements between the ML application and clinician reviews were identified. Conclusions: A systematic comparison was conducted between an ML application and clinicians for identifying OUD risk. The ML application generated clinically valid and useful alerts about patients' different OUD risk levels. ML applications hold promise for identifying patients at differing levels of OUD risk and will likely complement traditional rule-based approaches to generating alerts about opioid safety issues.

Case report: Exploring the utility of whole-body bone scintigraphy for pediatric Langerhans cell histiocytosis: insights from clinical practice.

Purpose: This mini-review delves into the realm of Langerhans cell histiocytosis (LCH) in children, focusing on its skeletal involvement. By synthesizing pertinent literature, we sought to provide a comprehensive understanding of LCH's clinical and radiographic spectrum. Our study then demonstrates the diagnostic prowess of whole-body 99mTc-methyl diphosphonate (MDP) scintigraphy in LCH cases, underscoring its value in tandem with existing knowledge. Methods: Our approach involved an extensive literature review that contextualized LCH within the current medical landscape. Subsequently, we presented a case series featuring five pediatric instances of skeletal LCH, one accompanied by soft tissue infiltration. The principal aim was to illuminate the diagnostic and staging potential of whole-body 99mTc-MDP scintigraphy, augmenting existing insights. Results: Through meticulous literature synthesis, we highlighted pediatric LCH's protean clinical manifestations and radiological variability. Aligning with this spectrum, our case series underscored the role of 99mTc-MDP scintigraphy in diagnosing and staging LCH. Among the five pediatric cases, one demonstrated concurrent soft tissue involvement. This aligns with the multifaceted nature of LCH presentations. Conclusion: Pediatric LCH can present with a wide range of clinical and radiologic features. By amalgamating our cases with extant literature, we stress the necessity of a multimodal strategy. 99mTc-MDP scintigraphy emerged as an indispensable tool for accurate staging and soft tissue detection. Our findings collectively advocate for a holistic approach to managing LCH, ensuring informed therapeutic decisions for optimal patient outcomes.

Evaluating the effect of body mass index and 25-hydroxy-vitamin D level on basal cell carcinoma using Mendelian randomization.

Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum 25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),[0.81,0.99]; p = 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,[- 0.22, - 0.03], p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, [0.94,1.09], p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.

Decoding the metastatic potential and optimal postoperative adjuvant therapy of melanoma based on metastasis score.

Metastasis is a formidable challenge in the prognosis of melanoma. Accurately predicting the metastatic potential of non-metastatic melanoma (NMM) and determining effective postoperative adjuvant treatments for inhibiting metastasis remain uncertain. In this study, we conducted comprehensive analyses of melanoma metastases using bulk and single-cell RNA sequencing data, enabling the construction of a metastasis score (MET score) through diverse machine-learning algorithms. The reliability and robustness of the MET score were validated using various in vitro assays and in vivo models. Our findings revealed a distinct molecular landscape in metastatic melanoma characterized by the enrichment of metastasis-related pathways, intricate cell-cell communication, and heightened infiltration of pro-angiogenic tumor-associated macrophages compared to NMM. Importantly, patients in the high MET score group exhibited poorer prognoses and an immunosuppressive microenvironment, featuring increased infiltration of regulatory T cells and decreased infiltration of CD8+ T cells, compared to the low MET score patient group. Expression of PD-1 was markedly higher in patients with low MET scores. Anti-PD-1 (aPD-1) therapy profoundly affected antitumor immunity activation and metastasis inhibition in these patients. In summary, our study demonstrates the effectiveness of the MET score in predicting melanoma metastatic potential. For patients with low MET scores, aPD-1 therapy may be a potential treatment strategy to inhibit metastasis. Patients with high MET scores may benefit from combination therapies.

The association between gut microbiota and postoperative delirium in patients.

Postoperative delirium is a common postoperative complication in older patients, and its pathogenesis and biomarkers remain largely undetermined. The gut microbiota has been shown to regulate brain function, and therefore, it is vital to explore the association between gut microbiota and postoperative delirium. Of 220 patients (65 years old or older) who had a knee replacement, hip replacement, or laminectomy under general or spinal anesthesia, 86 participants were included in the data analysis. The incidence (primary outcome) and severity of postoperative delirium were assessed for two days. Fecal swabs were collected from participants immediately after surgery. The 16S rRNA gene sequencing was used to assess gut microbiota. Principal component analyses along with a literature review were used to identify plausible gut microbiota, and three gut bacteria were further studied for their associations with postoperative delirium. Of the 86 participants [age 71.0 (69.0-76.0, 25-75% percentile of quartile), 53% female], 10 (12%) developed postoperative delirium. Postoperative gut bacteria Parabacteroides distasonis was associated with postoperative delirium after adjusting for age and sex (Odds Ratio [OR] 2.13, 95% Confidence Interval (CI): 1.09-4.17, P = 0.026). The association between delirium and both Prevotella (OR: 0.59, 95% CI: 0.33-1.04, P = 0.067) and Collinsella (OR: 0.57, 95% CI: 0.27-1.24, P = 0.158) did not meet statistical significance. These findings suggest that there may be an association between postoperative gut microbiota, specifically Parabacteroides distasonis, and postoperative delirium. However, further research is needed to confirm these findings and better understand the gut-brain axis's role in postoperative outcomes.

The association between gut microbiota and postoperative delirium in patients.

Postoperative delirium is one of the most common postoperative complications in older patients. Its pathogenesis and biomarkers, however, remain largely undetermined. Majority of human microbiota is gut microbiota and gut microbiota has been shown to regulate brain function. Therefore, this study aimed to determine the association between gut microbiota and postoperative delirium in patients. Of 220 patients (65 years old or older) who had a knee replacement, hip replacement, or laminectomy under general or spinal anesthesia, 86 participants were included in the data analysis. The incidence (primary outcome) and severity of postoperative delirium was assessed for two days. Fecal swabs were collected from participants immediately after surgery. The 16S rRNA gene sequencing was used to assess gut microbiota. Using principal component analyses along with a literature review to identify biologically plausible mechanisms, and three bacterials were studied for their associations with postoperative delirium. Of the 86 participants [age 71.0 (69.0-76.0, 25%-75% percentile of quartile), 53% female], ten (12%) developed postoperative delirium. Postoperative gut bacteria Parabacteroides distasonis (Odds Ratio [OR] 2.13, 95% Confidence Interval (CI): 1.09-4.17, P = 0.026) was associated with postoperative delirium after adjusting for age and sex. The association between delirium and both Prevotella (OR: 0.59, 95% CI: 0.33-1.04, P = 0.067) and Collinsella (OR: 0.57, 95% CI: 0.27-1.24, P = 0.158) did not meet statistical significance. These findings suggest that postoperative gut microbiota (e.g., Parabacteroides distasonis ) may serve as biomarkers in the pathogenesis of postoperative delirium, pending confirmative studies.

Transcatheter tricuspid valve-in-valve implantation for degenerated surgical bioprosthesis.

BACKGROUND: Isolated redo surgery for degenerated tricuspid bioprosthesis is of very high risk. We aimed to evaluate the safety and efficacy of transcatheter valve-in-valve (TVIV) implantation using a novel balloon expandable Renato valve. METHODS: A prospective multicenter study was conducted to enroll patients with degenerated tricuspid bioprostheses. A total of 12 patients underwent TVIV implantation using the Renato valve system via transfemoral, transjugular, or transatrial approaches at three institutions from May 2021 to October 2021. All-cause mortality and hemodynamic performance were evaluated up to 6 months after procedure. RESULTS: The median age was 68.2 years, and 75.0% were female. Six patients had a history of rheumatic left-sided valve surgery and late tricuspid valve replacement. The median preoperative Society of Thoracic Surgeons score was 9.9%. The procedures were successful in all cases. Tricuspid regurgitation and paravalvular leak were none or mild in all patients. The median transvalvular gradient decreased from 7.8 mmHg preoperatively to 4.5 mmHg at 6 months after TVIV, respectively. No death occurred and all patients recovered to New York Heart Association functional class I or II during a 6-month follow-up. CONCLUSIONS: TVIV implantation with the Renato valve was a safe and effective treatment for degenerated bioprostheses in high-risk patients.

Single-cell transcriptome analysis identifies Versican(+) myofibroblast as a hallmark for thoracic aortic aneurysm marked by activation of PI3K-AKT signaling pathway.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a silent but dangerous cardiovascular disease. Understanding molecular mechanisms of TAA on single-cell level might provide new strategies for preventing and treating TAA. METHODS: Single-cell RNA sequencing was performed on control and aneurysmal thoracic aorta to find out specific cell clusters and cell types. Western blot and histological staining were used to verify the findings of single-cell transcriptome analysis. Characteristics of Versican (VCAN) overexpressed myofibroblast was evaluated through bioinformatic methods and experimental validation. RESULTS: A total of 3 control and 8 TAA specimens were used for single-cell transcriptome analysis including 48,128 thoracic aortic cells. Among these cells, we found out a specific cell cluster containing both hallmarks of smooth muscle cell (SMC) and fibroblast. Thus, we defined these cells as myofibroblast. Further single-cell transcriptome analysis identified VCAN as a cellular marker of myofibroblast. Western blot and histological staining revealed that VCAN(+) myofibroblast was significantly increased in TAA specimens compared with control individuals. Differential analysis, functional, pathway enrichment analysis and cell-cell communication analysis demonstrated that VCAN(+) myofibroblast was closely associated with previous reported TAA associated pathological process including SMC proliferation, SMC migration and extracellular matrix (ECM) disruption. Pathway analysis found out significant activation of PI3K-AKT signaling pathway within VCAN(+) myofibroblast, which was further confirmed by experimental validation. CONCLUSIONS: Single-cell RNA sequencing identified VCAN(+) myofibroblast as a typical cellular hallmark of TAA. These cells might participate in the pathogenesis of TAA through activation of PI3K-AKT signaling pathway to link SMC proliferation, SMC migration and ECM disruption.

Patient Characteristics Associated With Reactions to Mrgprx2-Activating Drugs in an Electronic Health Record-Linked Biobank.

BACKGROUND: Mas-related G protein-couple receptor x2 (Mrgprx2) activation underlies many common non-IgE-mediated adverse drug reactions (ADRs), yet the features of patients with reactions to Mrgprx2-activating drugs are unknown. OBJECTIVE: To characterize the patient-specific comorbidities and laboratory characteristics associated with listed reactions to Mrgprx2-activating drugs, including fluoroquinolones, morphine, neuromuscular blockade agents, vancomycin, and leuprolide. METHODS: We used a retrospective, observational cohort study design using electronic health record data from adults with an Mrgprx2-activating drug exposure recorded within a hospital system clinical Biobank. Odds ratios (ORs) and incidence rate ratios for clinical characteristics associated with ADRs, including immediate hypersensitivity reactions, were calculated using multivariable logistic regression. RESULTS: Among 59,763 patients exposed to Mrgprx2-activating drugs, 4846 had a listed ADR. Female sex, White race, asthma (OR: 1.81, 95% confidence interval [CI]: 1.68-1.94), chronic urticaria (OR: 1.73, 95% CI: 1.46-2.05), and mastocytosis (OR: 12.79, 95% CI: 5.98-27.02) were associated with increased odds of a reaction. Overall, patients with allergic disease had 1.21 times the rate of an ADR compared with patients without allergic disease. Elevated absolute eosinophil count was inversely associated with reactions, and there was no association with elevated total IgE. Observed associations were similar in a patient subgroup with immediate-type hypersensitivity reactions. CONCLUSION: Specific allergic diseases and common allergic biomarkers are differentially associated with ADRs to Mrgprx2-activating drugs. These findings from a large, "real world" drug-exposed population highlight clinical factors that may contribute to non-IgE-mediated drug allergy.

Enhancing Photothermal Therapy Efficacy by In Situ Self-Assembly in Glioma.

The residence time of some small molecular imaging and therapeutic agents in tumor tissue is short and the molecules can be easily dispersed, which decreases treatment efficacy. Therefore, methods that enhance oncotherapy performance are of significant importance. Here, we report an in situ self-assembly strategy aimed at enhancing the photothermal therapy of glioblastomas. The probe, ICG-PEP-c(RGD)fk, consisted of a glutathione-reactive self-assembling polypeptide as the skeleton, indocyanine green (ICG) as a theranostic agent, and cyclic Arg-Gly-Asp [c(RGD)fk] peptides as the targeting group. ICG-PEP-c(RGD)fk was synthesized and found to be assembled in the glutathione environment at 9.446 µM in vitro. Human glioblastoma cell line U87MG-luc with high integrin αvß3 expression was applied to invivo experiments. ICG-PEP-c(RGD)fk provided clearer tumor imaging and had a tumor retention time of 6.12 times longer than that of ICG-c(RGD)fk. In therapeutic experiments, ICG-PEP-c(RGD)fk significantly suppressed glioblastoma growth and the tumor volume was 2.61 times smaller than in the ICG-c(RGD)fk group at the end of the observation period. Moreover, the median survival time of ICG-PEP-c(RGD)fk group was significantly improved by 2.78 times compared with that of the control group. In conclusion, glutathione-reactive self-assembling peptides are capable of increasing the tumor retention time and improving the photothermal therapeutic effect. The in situ self-assembly strategy is a potential and feasible method to enhance oncotherapy.

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. METHODS: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. RESULTS: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. CONCLUSION: mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

Advances in aptamer-based nuclear imaging.

Aptamers are short oligonucleotides that bind to specific target molecules. They have been extensively explored in biomedical applications, including biosensing, medical imaging, and disease treatment. Their adjustable affinity for specific biomarkers stimulates more translational efforts, such as nuclear imaging of tumors in preclinical and clinical settings. In this review, we present recent advances of aptamer-based nuclear imaging and compare aptamer tracers with other biogenic probes in forms of peptides, nanobodies, monoclonal antibodies, and antibody fragments. Fundamental properties of aptamer-based radiotracers are highlighted and potential directions to improve aptamer's imaging performance are discussed. Despite many translational obstacles to overcome, we envision aptamers to be a versatile tool for cancer nuclear imaging in the near future.

Sequential coupling of dry and wet COVID-19 screening to reduce the number of quarantined individuals.

INTRODUCTION: Currently, several countries are facing severe public health and policy challenges when designing their COVID-19 screening strategy. A quantitative analysis of the potential impact that combing the Rapid Antigen Test (RAT; Wet screening) and digital checker (Dry screening) can have on the healthcare system is lacking. METHOD: We created a hypothetical COVID-19 cohort for the analysis. The population size was set as 10 million with three levels of disease prevalence (10%, 1%, or 0.1%) under the assumption that a positive test result will lead to quarantine. A digital checker and two RATs are used for analysis. We further hypothesized two scenarios: RAT only and RAT plus digital checker. We then calculated the number of quarantined in both scenarios and compared the two to understand the benefits of sequential coupling of a digital checker with a RAT. RESULT: Sequential coupling of the digital checker and RAT can significantly reduce the number of individuals quarantined to 0.95-1.33M, 0.86-1.29M, and 0.86-1.29M, respectively, under the three different prevalence levels. CONCLUSION: Sequential coupling of digital checker and RAT at a population level for COVID-19 positive test to reduce the number of people who require quarantine and alleviating stress on the overburdened healthcare systems during the COVID-19 pandemic.

18F-PFPN PET: A New and Attractive Imaging Modality for Patients with Malignant Melanoma.

18F-FDG PET has limited diagnostic applications in malignant melanoma (MM). 18F-N-(2-(diethylamino)ethyl)-5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)picolinamide (18F-PFPN) is a novel PET probe with high affinity and selectivity for melanin. We conducted a clinical study with 2 aims, first to investigate the biodistribution and radiation dosimetry of 18F-PFPN in healthy volunteers, and second, to examine the diagnostic utility of 18F-PFPN PET imaging in patients with MM. Methods: 18F-PFPN was synthesized through a fluoro-for-tosyl exchange reaction. Five healthy volunteers were enrolled to investigate the biodistribution, pharmacokinetics, radiation dosimetry, and safety of the tracer. Subsequently, a total of 21 patients with clinically suspected or confirmed MM underwent both 18F-PFPN PET/MRI and 18F-FDG PET/CT scans. The normalized SUVmax of selected lesions was determined for both tracers and compared in patient- and lesion-based analyses. Results: 18F-PFPN has an elevated radiochemical yield and was highly stable in vivo. In healthy volunteers, 18F-PFPN was safe and well tolerated, and its effective absorbed dose was comparable to that of 18F-FDG. In patient-based analysis, 18F-PFPN uptake was higher than 18F-FDG for both primary tumors and nodal metastases. In lesion-based analysis,18F-PFPN PET imaging could detect 365 metastases that were missed on 18F-FDG PET. Additionally, 18F-PFPN PET imaging had clinical value in distinguishing false-positive lesions on 18F-FDG PET. Conclusion: 18F-PFPN is a safe and well-tolerated melanin PET tracer. In a pilot clinical study, 18F-PFPN PET imaging outperformed traditional 18F-FDG PET in identifying both primary MM and its distant spread.