Lipid Nanoparticle-mRNA Engineered Dendritic Cell Based Adoptive Cell Therapy Enhances Cancer Immune Response.

Lipid nanoparticles encapsulating mRNA (LNP-mRNA) revolutionized medicine over the past several years. While clinically approved indications currently focus on infectious disease vaccination, LNP-mRNA based treatments also hold promise for cancer immunotherapy. However, the route of dosing may impact treatment efficacy, safety, and dose. To minimize adverse effects, it is hypothesized that LNP-mRNA can be used to activate and engineer dendritic cells (DC) ex vivo before re-administration of these cells. Here, it is shown that LNP-mRNA engineered DCs can indeed vaccinate recipient mice. Vaccinated mice showed strong anti-tumor T cell responses, rejected tumor challenge, and displayed no evidence of toxicity. Further, it is found that DC specific ablation of the immune activating kinase NFkB inducing kinase (NIK) abrogated vaccination efficacy, demonstrating that adoptively transferred DCs can be functionally modified in addition to their antigen presentation capacity. Collectively, these studies show that ex vivo LNP-mRNA engineering of DCs is a feasible and robust therapeutic strategy for cancer.

Highly Active Myeloid Therapy for Cancer.

Tumor-associated macrophages (TAM) interact with cancer and stromal cells and are integral to sustaining many cancer-promoting features. Therapeutic manipulation of TAM could therefore improve clinical outcomes and synergize with immunotherapy and other cancer therapies. While different nanocarriers have been used to target TAM, a knowledge gap exists on which TAM pathways to target and what payloads to deliver for optimal antitumor effects. We hypothesized that a multipart combination involving the Janus tyrosine kinase (JAK), noncanonical nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and toll-like receptor (TLR) pathways could lead to a highly active myeloid therapy (HAMT). Thus, we devised a screen to determine drug combinations that yield maximum IL-12 production from myeloid cells to treat the otherwise highly immunosuppressive myeloid environments in tumors. Here we show the extraordinary efficacy of a triple small-molecule combination in a TAM-targeted nanoparticle for eradicating murine tumors, jumpstarting a highly efficient antitumor response by adopting a distinctive antitumor TAM phenotype and synergizing with other immunotherapies. The HAMT therapy represents a recently developed approach in immunotherapy and leads to durable responses in murine cancer models.

Hybrid LNP Prime Dendritic Cells for Nucleotide Delivery.

The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation cancer vaccines and may be able to provide anti-tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi-pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor-stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double-stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L-CANDI) delivery. This study shows that the ≈120 nm hybrid nanoparticles-in-nanoparticles effectively eradicate tumors by themselves and generate long-lasting, durable anti-tumor immunity in mouse models.

New parameters measured via preoperative tonsil photos to evaluate the post-tonsillectomy pain: an analysis assisted by machine learning.

Background: Postoperative pain is the most common complication after tonsillectomy. We aimed to explore new parameters related to post-tonsillectomy pain, as well as to construct and validate a model for the preoperative evaluation of patients' risk for postoperative pain. Methods: Data collected from patients who underwent tonsillectomy by the same surgeon at Beijing Chaoyang Hospital from January 2019 to May 2022 were analyzed. Preoperative tonsil images from all patients were taken, and the ratios of the distance between the upper pole of the tonsil and the base of the uvula (L1 for the left side and R1 for the right side) to the width of the uvula (U1) or the length of the uvula (U2) were measured. The following six ratios were calculated: L1/U1, R1/U1, LR1/U1 (the add of L1 and R1, and then divide U1), L1/U2, R1/U2, LR1/U2 (the add of L1 and R1, and then divide U2). The post-tonsillectomy pain was recorded. In addition, machine learning (ML) algorithm and feature importance analysis were used to evaluate the value of the parameters. Results: A total of 100 patients were involved and divided into the training set (60%) and the validation set (40%). All six parameters are negatively correlated with post-tonsillectomy pain. The accuracy, sensitivity, and specificity of the model were 75.0%, 72.7%, and 77.8%, respectively. LR1/U1 and LR1/U2 are the most valuable parameters to evaluate post-tonsillectomy pain. Conclusions: We have discovered new parameters that can be measured using preoperative tonsil images to evaluate post-tonsillectomy pain. ML models based on these parameters could predict whether these patients will have intolerable pain after tonsillectomy and manage it promptly.

Effect of Cold-Water Irrigation on the Coblation Site for Post-Tonsillectomy Pain: A Prospective Randomized Clinical Study.

OBJECTIVE: To explore the effect of cold-water irrigation on post-tonsillectomy pain after coblation. METHODS: Data from 61 adult patients who underwent coblation tonsillectomy in our hospital from January 2019 to December 2020 were collected, and the patients were randomly divided into the cold-water irrigation group (Group 1) and the room-temperature irrigation group (Group 2). Group 1 was irrigated with ice water mixed saline with the help of a pressure band, and Group 2 was irrigated with room-temperature saline. During the operation, we monitored the temperature of the operating cavity in real time. We recorded the postoperative pain for 11 consecutive days from the day and the 10th day after the operation. RESULTS: The postoperative pain score was significantly lower than that in Group 2, except on the 2nd, 3rd and 7th and 8th days after the operation. CONCLUSION: The perfusion of cold water during coblation tonsillectomy is helpful to reduce postoperative pain.

[Extracellular Signal-regulated Kinase 1/2 Signaling Regulates Cell Invasion:a Review].

Extracellular signal-regulated kinase 1/2 (ERK1/2) is a serine/threoninekinase involved in the signal transduction cascade of Ras-Raf-mitogen-activated protein kinase (MEK)-ERK.It participates in the cell growth,proliferation and even invasion by regulating gene transcription and expression.The occurrence of a variety of diseases such as lung cancer,liver cancer,ovarian cancer,cervical cancer,endometriosis,and preeclampsia,as well the metastasis and disease progression,is closely associated with the regulation of cell invasion by ERK1/2 signaling pathway.Therefore,exploring the regulation of ERK1/2 signaling on cell invasion and its role in pathogenesis of diseases may help to develop more effective treatment schemes.This article introduces recent progress in the regulation of ERK1/2 signaling on cell invasion and the role of such regulation in diseases,with a view to give new insights into the clinical treatment of ERK 1/2-related diseases.

Mini-review: The neural circuits of the non-lemniscal inferior colliculus.

The inferior colliculus (IC) is a critical hub of the central auditory system (CAS), and a majority of the ascending and descending auditory synapses converge in the IC. With considerable methodological advances in neural tract tracing techniques, one can clearly visualize various sub-compartments of the IC. Herein, we compared the inputs and outputs between the two sub-regions of the non-lemniscal IC, namely, the dorsal and external cortex of the IC. The non-lemniscal IC plays a crucial role in multisensory integration and animal behavior, and the dorsal and external regions are distinct in many aspects, including molecular expression and neural circuits. They may serve integration and regulation functions via parallel pathways. As previous studies have mostly treated these two parts as a whole, we suggest that the two sub-regions of the non-lemniscal IC should be studied separately in future IC functional investigations.

[Endolymphatic sac tumor with symptoms of endolymphatic hydrops: a case report and reviews].

A 38-year-old woman had suffered from recurrent vertigo, deafness and tinnitus for 2 years. After treatment for Meniere's disease, her symptoms did not improve. The threshold of pure tone audiometry was 68dBHL SNHL. High resolution CT of the temporal bone showed that a mass is behind the posterior semicircular canal. MRI showed that mixed signals are in the center of the mass and long T1T2 signal around the mass. The mass was surgically resected. Pathology report showed: endolymphatic sac tumor.

The Potential Role of Serum Exosomes in Preeclampsia.

Preeclampsia is a serious pregnancy-specific disease that affects about 5%-8% of pregnant women and is the main reason for the increase in maternal and perinatal mortality. Due to unknown etiology, preeclampsia is still the main cause of increased mortality in maternal and perinatal infants, which is mainly manifested by new hypertension after 20 weeks of pregnancy. As the pathogenesis has not been fully elucidated, early diagnosis and full treatment are lacking. Exosomes secreted from the placenta to the peripheral circulation may be involved in the pathogenesis of preeclampsia and can be detected from the plasma of pregnant women after 6 weeks of pregnancy. Related studies have shown that the levels of exosomes in preeclampsia have changed, and the protein and miRNA expression profiles are also different. Therefore, monitoring changes in plasma exosomes and expression profiles may provide new ideas and new perspectives for the prediction, diagnosis and treatment of preeclampsia.