A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation.

Rationale: Nucleic acid constructs are commonly used for vaccination, immune stimulation, and gene therapy, but their use in cancer still remains limited. One of the reasons is that systemic delivery to tumor-associated antigen-presenting cells (dendritic cells and macrophages) is often inefficient, while off-target nucleic acid-sensing immune pathways can stimulate systemic immune responses. Conversely, certain carbohydrate nanoparticles with small molecule payloads have been shown to target these cells efficiently in the tumor microenvironment. Yet, nucleic acid incorporation into such carbohydrate-based nanoparticles has proven challenging. Methods: We developed a novel approach using cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles to efficiently deliver nucleic acids and small-molecule immune enhancer to phagocytic cells in tumor environments and lymph nodes. Our study involved incorporating these components into the nanoparticles and assessing their efficacy in activating antigen-presenting cells. Results: The multi-modality immune stimulators effectively activated antigen-presenting cells and promoted anti-tumor immunity in vivo. This was evidenced by enhanced delivery to phagocytic cells and subsequent immune response activation in tumor environments and lymph nodes. Conclusion: Here, we describe a new approach to incorporating both nucleic acids and small-molecule immune enhancers into cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles for efficient delivery to phagocytic cells in tumor environments and lymph nodes in vivo. These multi-modality immune stimulators can activate antigen-presenting cells and foster anti-tumor immunity. We argue that this strategy can potentially be used to enhance anti-tumor efficacy.

Recommender-based bone tumour classification with radiographs-a link to the past.

OBJECTIVES: To develop an algorithm to link undiagnosed patients to previous patient histories based on radiographs, and simultaneous classification of multiple bone tumours to enable early and specific diagnosis. MATERIALS AND METHODS: For this retrospective study, data from 2000 to 2021 were curated from our database by two orthopaedic surgeons, a radiologist and a data scientist. Patients with complete clinical and pre-therapy radiographic data were eligible. To ensure feasibility, the ten most frequent primary tumour entities, confirmed histologically or by tumour board decision, were included. We implemented a ResNet and transformer model to establish baseline results. Our method extracts image features using deep learning and then clusters the k most similar images to the target image using a hash-based nearest-neighbour recommender approach that performs simultaneous classification by majority voting. The results were evaluated with precision-at-k, accuracy, precision and recall. Discrete parameters were described by incidence and percentage ratios. For continuous parameters, based on a normality test, respective statistical measures were calculated. RESULTS: Included were data from 809 patients (1792 radiographs; mean age 33.73 ± 18.65, range 3-89 years; 443 men), with Osteochondroma (28.31%) and Ewing sarcoma (1.11%) as the most and least common entities, respectively. The dataset was split into training (80%) and test subsets (20%). For k = 3, our model achieved the highest mean accuracy, precision and recall (92.86%, 92.86% and 34.08%), significantly outperforming state-of-the-art models (54.10%, 55.57%, 19.85% and 62.80%, 61.33%, 23.05%). CONCLUSION: Our novel approach surpasses current models in tumour classification and links to past patient data, leveraging expert insights. CLINICAL RELEVANCE STATEMENT: The proposed algorithm could serve as a vital support tool for clinicians and general practitioners with limited experience in bone tumour classification by identifying similar cases and classifying bone tumour entities. KEY POINTS: • Addressed accurate bone tumour classification using radiographic features. • Model achieved 92.86%, 92.86% and 34.08% mean accuracy, precision and recall, respectively, significantly surpassing state-of-the-art models. • Enhanced diagnosis by integrating prior expert patient assessments.

Pharmacological Polarization of Tumor-Associated Macrophages Toward a CXCL9 Antitumor Phenotype.

Tumor-associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9Hi TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the unique antitumor TAM phenotype, there is a lack of TAM-specific therapeutics to exploit this new biological understanding. Here, the discovery and characterization of multiple small-molecule enhancers of chemokine ligand 9 (CXCL9) and their targeted delivery in a TAM-avid systemic nanoformulation is reported. With this strategy, it is efficient encapsulation and release of multiple drug loads that can efficiently induce CXCL9 expression in macrophages, both in vitro and in vivo in a mouse tumor model. These observations provide a window into the molecular features that define TAM-specific states, an insight a novel therapeutic anticancer approach is used to discover.

Association of Serum Soluble Transferrin Receptor Concentration With Markers of Inflammation: Analysis of 1001 Patients From a Tertiary Rheumatology Center.

OBJECTIVE: Soluble transferrin receptor (sTfR) is considered to be a useful biomarker for the diagnosis of iron deficiency, especially in the setting of inflammation, as it is thought to not be affected by inflammation. We analyzed the relationship between sTfR levels and inflammatory markers in patients with known or suspected inflammatory rheumatic disease (IRD). METHODS: Blood samples of 1001 patients with known or suspected IRD referred to a tertiary rheumatology center were analyzed. Study participants were classified as patients with active IRD and patients with inactive IRD or without IRD. Correlation analyses were used to explore the relationship between sTfR levels and inflammatory markers (ie, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]). We applied multiple linear regression analysis to evaluate the predictive value of CRP levels for sTfR concentrations after adjustment for potential confounding factors. RESULTS: There were positive correlations between inflammatory markers (CRP, ESR) and serum sTfR levels (ρ 0.44, ρ 0.43, respectively; P < 0.001), exceeding the strength of correlation between inflammatory markers and the acute phase reactant ferritin (ρ 0.30, ρ 0.23, respectively; P < 0.001). Patients with active IRD demonstrated higher serum sTfR levels compared to patients with inactive or without IRD (mean 3.99 [SD 1.69] mg/L vs 3.31 [SD 1.57] mg/L; P < 0.001). After adjustment for potential confounding factors, CRP levels are predictive for serum sTfR concentrations (P < 0.001). CONCLUSION: The study provides evidence against the concept that sTfR is a biomarker not affected by inflammation.

Medically Unexplained Symptoms Are Linked to Chronic Inflammatory Diseases: Is There a Role for Frontal Cerebral Blood Oxygen Content?

INTRODUCTION: Patients often go to the physician with medically unexplained symptoms (MUS). MUS can be autonomic nervous system-related "unspecific" symptoms, such as palpitations, heart rhythm alterations, temperature dysregulation (hand, feet), anxiety, or depressive manifestations, fatigue, somnolence, nausea, hyperalgesia with varying pains and aches, dizziness, etc. Methods: In this real-world study, we investigated MUS in a cohort of unselected outpatients from general practitioners in Italy. It was our aim to increase the understanding of MUS by using principal component analyses to identify any subcategories of MUS and to check a role of chronic inflammatory diseases. Additionally, we studied cerebral blood oxygen (rCBO2) and associations with MUS and chronic inflammatory disease. RESULTS: Participants included 1,597 subjects (50.6 ± 0.4 years, 65%/35% women/men). According to ICD-10 codes, 137 subjects had chronic inflammatory diseases. MUS were checked by a questionnaire with a numeric rating scale and cerebral blood flow with optical techniques. The analyses of men and women were stratified. Psychological symptom severity was higher in the inflamed compared to the non-inflamed group (fatigue, insomnia in women and men; recent mood changes, daytime sleepiness, anxiety, apathy, cold hands only in women; abnormal appetite and heart rhythm problems only in men). Principal component analysis with MUS provided new subcategories: brain symptoms, gut symptoms, and unspecific symptoms. Brain and gut symptoms were higher in inflamed women and men. Chronic inflammatory diseases and pain were tightly interrelated in men and women (p < 0.0001). In women, not in men, average frontal rCBO2 content was higher in inflamed compared to non-inflamed subjects. In men, not in women, individuals with pain demonstrated a lower average frontal rCBO2 content compared to pain-free men. MUS did not relate to rCBO2 parameters. CONCLUSION: This study shows close relationships between MUS and chronic inflammatory diseases but not between MUS and rCBO2 parameters.

[Analysis of a differentiated resuscitation room activation at a national trauma center]. / Analyse einer differenzierten Schockraumalarmierung an einem überregionalen Traumazentrum.

BACKGROUND: In order to continue to efficiently provide both personnel-intensive and resource-intensive care to severely injured patients, some hospitals have introduced individually differentiated systems for resuscitation room treatment. The aim of this study was to evaluate the concept of the A and B classifications in terms of practicability, indications, and potential complications at a national trauma center in Bavaria. METHODS: In a retrospective study, data from resuscitation room trauma patients in the year 2020 were collected. The assignment to A and B was made by the prehospital emergency physician. Parameters such as the injury severity score (ISS), Glasgow outcome scale (GOS), upgrade rate, and the indication criteria according to the S3 guidelines were recorded. Statistical data comparisons were made using t­tests, χ2-tests, or Mann-Whitney U­tests. RESULTS: A total of 879 resuscitation room treatments (A 473, B 406) met the inclusion criteria. It was found that 94.5% of resuscitation room A cases had physician accompaniment, compared to 48% in resuscitation room B assignments. In addition to significantly lower ISS scores (4.1 vs. 13.9), 29.8% of B patients did not meet the treatment criteria defined in the S3 guidelines. With a low upgrade rate of 4.9%, 98% of B patients had a GOS score of 4 or 5. CONCLUSION: The presented categorization is an effective and safe way to manage the increasing number of resuscitation room alerts in a resource-optimized manner.

Automated Prognosis Marker Assessment in Breast Cancers Using BLEACH&STAIN Multiplexed Immunohistochemistry.

Prognostic markers in routine clinical management of breast cancer are often assessed using RNA-based multi-gene panels that depend on fluctuating tumor purity. Multiplex fluorescence immunohistochemistry (mfIHC) holds the potential for an improved risk assessment. To enable automated prognosis marker detection (i.e., progesterone receptor [PR], estrogen receptor [ER], androgen receptor [AR], GATA3, TROP2, HER2, PD-L1, Ki67, TOP2A), a framework for automated breast cancer identification was developed and validated involving thirteen different artificial intelligence analysis steps and an algorithm for cell distance analysis using 11+1-marker-BLEACH&STAIN-mfIHC staining in 1404 invasive breast cancers of no special type (NST). The framework for automated breast cancer detection discriminated normal glands from malignant glands with an accuracy of 98.4%. This approach identified that five (PR, ER, AR, GATA3, PD-L1) of nine biomarkers were associated with prolonged overall survival (p ≤ 0.0095 each) and two of these (PR, AR) were found to be independent risk factors in multivariate analysis (p ≤ 0.0151 each). The combined assessment of PR-ER-AR-GATA3-PD-L1 as a five-marker prognosis score showed strong prognostic relevance (p < 0.0001) and was an independent risk factor in multivariate analysis (p = 0.0034). Automated breast cancer detection in combination with an artificial intelligence-based analysis of mfIHC enables a rapid and reliable analysis of multiple prognostic parameters. The strict limitation of the analysis to malignant cells excludes the impact of fluctuating tumor purity on assay precision.

Association of Asymmetric and Symmetric Dimethylarginine with Inflammation in the Population-Based Study of Health in Pomerania.

The amino acids arginine (Arg), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are related to nitric oxide (NO) metabolism and potential markers of two different disease entities: cardiovascular disease such as atherosclerosis and systemic inflammation in critically ill patients with sepsis. Although very different in their pathophysiological genesis, both entities involve the functional integrity of blood vessels. In this context, large population-based data associating NO metabolites with proinflammatory markers, e.g., white blood cell count (WBC), high-sensitivity C-reactive protein (hsCRP), and fibrinogen, or cytokines are sparse. We investigated the association of Arg, ADMA and SDMA with WBC, hsCRP, and fibrinogen in 3556 participants of the Study of Health in Pomerania (SHIP)-TREND study. Furthermore, in a subcohort of 456 subjects, 31 inflammatory markers and cytokines were analyzed. We identified Arg and SDMA to be positively associated with hsCRP (ß coefficient 0.010, standard error (SE) 0.002 and 0.298, 0.137, respectively) as well as fibrinogen (ß 5.23 × 10-3, SE 4.75 × 10-4 and 0.083, 0.031, respectively). ADMA was not associated with WBC, hsCRP, or fibrinogen. Furthermore, in the subcohort, Arg was inversely related to a proliferation-inducing ligand (APRIL). SDMA was positively associated with osteocalcin, tumor necrosis factor receptor 1 and 2, and soluble cluster of differentiation 30. Our findings provide new insights into the involvement of Arg, ADMA, and SDMA in subclinical inflammation in the general population.

Perfusion Window Chambers Enable Interventional Analyses of Tumor Microenvironments.

Intravital microscopy (IVM) allows spatial and temporal imaging of different cell types in intact live tissue microenvironments. IVM has played a critical role in understanding cancer biology, invasion, metastases, and drug development. One considerable impediment to the field is the inability to interrogate the tumor microenvironment and its communication cascades during disease progression and therapeutic interventions. Here, a new implantable perfusion window chamber (PWC) is described that allows high-fidelity in vivo microscopy, local administration of stains and drugs, and longitudinal sampling of tumor interstitial fluid. This study shows that the new PWC design allows cyclic multiplexed imaging in vivo, imaging of drug action, and sampling of tumor-shed materials. The PWC will be broadly useful as a novel perturbable in vivo system for deciphering biology in complex microenvironments.

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.

Deep Learning-Based Detection of Bone Tumors around the Knee in X-rays of Children.

Even though tumors in children are rare, they cause the second most deaths under the age of 18 years. More often than in other age groups, underage patients suffer from malignancies of the bones, and these mostly occur in the area around the knee. One problem in the treatment is the early detection of bone tumors, especially on X-rays. The rarity and non-specific clinical symptoms further prolong the time to diagnosis. Nevertheless, an early diagnosis is crucial and can facilitate the treatment and therefore improve the prognosis of affected children. A new approach to evaluating X-ray images using artificial intelligence may facilitate the detection of suspicious lesions and, hence, accelerate the referral to a specialized center. We implemented a Vision Transformer model for image classification of healthy and pathological X-rays. To tackle the limited amount of data, we used a pretrained model and implemented extensive data augmentation. Discrete parameters were described by incidence and percentage ratio and continuous parameters by median, standard deviation and variance. For the evaluation of the model accuracy, sensitivity and specificity were computed. The two-entity classification of the healthy control group and the pathological group resulted in a cross-validated accuracy of 89.1%, a sensitivity of 82.2% and a specificity of 93.2% for test groups. Grad-CAMs were created to ensure the plausibility of the predictions. The proposed approach, using state-of-the-art deep learning methodology to detect bone tumors on knee X-rays of children has achieved very good results. With further improvement of the algorithm, enlargement of the dataset and removal of potential biases, this could become a useful additional tool, especially to support general practitioners for early, accurate and specific diagnosis of bone lesions in young patients.

[Role of the sympathetic nervous system in chronic inflammation]. / Rolle des sympathischen Nervensystems bei chronischen Entzündungen.

In this review article the current model of the interaction between the sympathetic nervous system (SNS) and the immune system in the context of chronic inflammation is presented. Mechanisms in the interaction between the SNS and the immune system are shown, which are similar for all disease entities: 1) the biphasic effect of the sympathetic system on the inflammatory response with a proinflammatory, stimulating effect before and during the activation of the immune system (early) and a more inhibitory effect in late phases of immune activation (chronic). 2) The interruption of communication between immune cells and the brain by withdrawal of sympathetic nerve fibers from areas of inflammation, such as the spleen, lymph nodes or peripheral foci of inflammation. 3) The local replacement of catecholamines by neurotransmitter-producing cells to fine-tune the local immune response independently of the brain. 4) Increased activity of the SNS due to an imbalance of the autonomic nervous system at the systemic level, which provides an explanation for known disease sequelae and comorbidities due to the long duration of chronic inflammatory reactions, such as increased cardiovascular risk with hypertension, diabetes mellitus and catabolic metabolism. The understanding of neuroimmune interactions can lead to new therapeutic approaches, e.g., a stimulation of beta-adrenergic and even more an inhibition of alpha-adrenergic receptors or a restoration of the autonomic balance in the context of arthritis ) can make an anti-inflammatory contribution (more influence of the vagus nerve); however, in order to translate the theoretical findings into clinical action that is beneficial for the patient, controlled interventional studies are required.

[Energy metabolism of the immune system : Consequences in chronic inflammation]. / Energiemetabolismus des Immunsystems : Konsequenzen bei chronischen Entzündungen.

BACKGROUND: Energy is the currency of life. The systemic and intracellular energy metabolism plays an essential role for the energy supply of the resting and activated immune system and this also applies to chronic inflammatory diseases. OBJECTIVE: This presentation examines both components of the systemic and cellular energy metabolism in health and chronic inflammation. MATERIAL AND METHODS: A literature search was conducted using PubMed, Embase and the Cochrane Library. The information is presented in the form of a narrative review. RESULTS: A chronically activated immune system acquires large amounts of energy-rich substrates that are lost for other functions of the body. In particular, the immune system and the brain are in competition. The consequences of this competition are many known diseases, such as fatigue, anxiety, depression, anorexia, sleep problems, sarcopenia, osteoporosis, insulin resistance, hypertension and others. The permanent change in the brain causes long-term alterations that stimulate disease sequelae even after disease remission. In the intracellular energy supply, chronic inflammation typically involves a conversion to glycolysis (to lactate, which has its own regulatory functions) and the pentose phosphate pathway in disorders of mitochondrial function. The chronic changes in immune cells of patients with rheumatoid arthritis (RA) lead to a disruption of the citric acid cycle (Krebs cycle). The hypoxic situation in the inflamed tissue stimulates many alterations. A differentiation is made between effector functions and regulatory functions of immune cells. CONCLUSION: Based on the energy changes mentioned, novel treatment suggestions can be made in addition to those already known in energy metabolism.

Heat of the night: sleep disturbance activates inflammatory mechanisms and induces pain in rheumatoid arthritis.

Sleep has a homeostatic role in the regulation of the immune system and serves to constrain activation of inflammatory signalling and expression of cellular inflammation. In patients with rheumatoid arthritis (RA), a misaligned inflammatory profile induces a dysregulation of sleep-wake activity, which leads to excessive inflammation and the induction of increased sensitivity to pain. Given that multiple biological mechanisms contribute to sleep disturbances (such as insomnia), and that the central nervous system communicates with the innate immune system via neuroendocrine and neural effector pathways, potential exists to develop prevention opportunities to mitigate the risk of insomnia in RA. Furthermore, understanding these risk mechanisms might inform additional insomnia treatment strategies directed towards steering and reducing the magnitude of the inflammatory response, which together could influence outcomes of pain and disease activity in RA.

Retroperitoneal arterial bleeding caused by an undisplaced conservatively treated hyperextension injury of the lumbar spine - A case report.

Background: Hyperextension fractures of the thoracolumbar spine are commonly seen in ankylotic disorders due to the rigidity of the spine. The known complications include instability, neurological deficits and posttraumatic deformity but there is no report of a hemodynamic relevant arterial bleeding in undisplaced hyperextension fractures. An arterial bleeding poses a life-threatening complication and may be difficult to recognize in an ambulatory or clinical setting. Case presentation: A 78-year-old male was brought to the emergency department after suffering a domestic fall with incapacitating lower back pain. X-rays and a CT scan revealed an undisplaced L2 hyperextension fracture which was treated conservatively. 9 days after admission, the patient complained about unprecedented abdominal pain with a CT scan disclosing a 12 × 9 × 20 cm retroperitoneal hematoma on grounds of an active arterial bleeding from a branch of the L2 lumbar artery. Subsequently, access via lumbotomy, evacuation of the hematoma and insertion of a hemostatic agent was performed. The therapy concept of the L2 fracture remained conservatively. Conclusions: A secondary, retroperitoneal arterial bleeding after a conservatively treated undisplaced hyperextension fracture of the lumbar spine is a rare and severe complication that has not been described in literature yet and may be difficult to recognize. An early CT scan is recommended in case of a sudden onset of abdominal pain in these fractures to fasten treatment and hence decrease morbidity and mortality. Thus, this case report contributes to the awareness of this complication in a spine fracture type with increasing incidence and clinical relevance.

Impact of a Femoral Fracture on Outcome after Traumatic Brain Injury-A Matched-Pair Analysis of the TraumaRegister DGU®.

Traumatic brain injury (TBI) is the leading cause of death and disability in polytrauma and is often accompanied by concomitant injuries. We conducted a retrospective matched-pair analysis of data from a 10-year period from the multicenter database TraumaRegister DGU® to analyze the impact of a concomitant femoral fracture on the outcome of TBI patients. A total of 4508 patients with moderate to critical TBI were included and matched by severity of TBI, American Society of Anesthesiologists (ASA) risk classification, initial Glasgow Coma Scale (GCS), age, and sex. Patients who suffered combined TBI and femoral fracture showed increased mortality and worse outcome at the time of discharge, a higher chance of multi-organ failure, and a rate of neurosurgical intervention. Especially those with moderate TBI showed enhanced in-hospital mortality when presenting with a concomitant femoral fracture (p = 0.037). The choice of fracture treatment (damage control orthopedics vs. early total care) did not impact mortality. In summary, patients with combined TBI and femoral fracture have higher mortality, more in-hospital complications, an increased need for neurosurgical intervention, and inferior outcome compared to patients with TBI solely. More investigations are needed to decipher the pathophysiological consequences of a long-bone fracture on the outcome after TBI.

Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity.

BACKGROUND: Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy. METHODS: We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor. RESULTS: IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development. CONCLUSIONS: By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.

Chronic Effects of the Sympathetic Nervous System in Inflammatory Models.

The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research has revealed several aspects of these interactions over the past decades, e.g., between the autonomic nervous system and the immune system. This review will focus on evidence revealing the role of the sympathetic nervous system (SNS) in chronic inflammation, like colitis, multiple sclerosis, systemic sclerosis, lupus erythematodes, and arthritis with a focus on animal models supported by human data. A theory of the contribution of the SNS in chronic inflammation will be presented that spans these disease entities. One major finding is the biphasic nature of the sympathetic contribution to inflammation, with proinflammatory effects until the point of disease outbreak and mainly anti-inflammatory influence thereafter. Since sympathetic nerve fibers are lost from sites of inflammation during inflammation, local cells and immune cells achieve the capability to endogenously produce catecholamines to fine-tune the inflammatory response independent of brain control. On a systemic level, it has been shown across models that the SNS is activated in inflammation as opposed to the parasympathetic nervous system. Permanent overactivity of the SNS contributes to many of the known disease sequelae. One goal of neuroendocrine immune research is defining new therapeutic targets. In this respect, it will be discussed that at least in arthritis, it might be beneficial to support ß-adrenergic and inhibit α-adrenergic activity besides restoring autonomic balance. Overall, in the clinical setting, we now need controlled interventional studies to successfully translate the theoretical knowledge into benefits for patients.