T cell-dependent bispecific antibodies alter organ-specific endothelial cell-T cell interaction.

Preclinical and clinical studies demonstrate that T cell-dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an in-depth characterization of acute responses to TDBs in tumor-bearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation and endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ-specific ECs may account for the differential responses in normal tissues and tumors, and we identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM-1 to support T cell-EC interaction in response to soluble factors released from a TDB-mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB-mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy.

NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity.

BACKGROUND: Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required. METHODS: We identified the co-stimulatory receptor NKG2D as a target based on its expression on a large proportion of CD8+ tumor infiltrating lymphocytes (TILs) from breast cancer patient samples. Human and murine surrogate NKG2D co-stimulatory receptor-bispecifics (CRB) that bind NKG2D on NK and CD8+ T cells as well as HER2 on breast cancer cells (HER2-CRB) were developed as a proof of concept for targeting this signaling axis in vitro and in vivo. RESULTS: HER2-CRB enhanced NK cell activation and cytokine production when co-cultured with HER2 expressing breast cancer cell lines. HER2-CRB when combined with a T cell-dependent-bispecific (TDB) antibody that synthetically activates T cells by crosslinking CD3 to HER2 (HER2-TDB), enhanced T cell cytotoxicity, cytokine production and in vivo antitumor activity. A mouse surrogate HER2-CRB (mHER2-CRB) improved in vivo efficacy of HER2-TDB and augmented NK as well as T cell activation, cytokine production and effector CD8+ T cell differentiation. CONCLUSION: We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. Given the large number of ongoing clinical trials leveraging NK and T cells for cancer immunotherapy, NKG2D-bispecifics have broad combinatorial potential.

Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat.

Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring. Preliminary genome-wide analyses of gene transcription and DNA methylation of the molecular basis for such maternal effects suggested differences in the epigenetic state and transcriptional activity of the Grm1 gene in the rat as a function of maternal care. Grm1 encodes the type I metabotropic glutamate receptor (mGluR1), and we found increased mGluR1 mRNA and protein in hippocampus from the adult offspring of mothers showing an increased frequency of pup licking/grooming (i.e., high-LG mothers) that was associated with a decrease in the methylation of Grm1. ChIP assays showed increased levels of histone 3 lysine 9 acetylation and histone 3 lysine 4 trimethylation of Grm1 in hippocampus from the adult offspring of high-LG compared with low-LG mothers. These histone posttranslational modifications were highly correlated, and both associate inversely with DNA methylation and positively with transcription. Studies of mGluR1 function showed increased hippocampal mGluR1-induced long-term depression in the adult offspring of high-LG compared with low-LG mothers, as well as increased paired-pulse depression (PPD). PPD is an inhibitory feedback mechanism that prevents excessive glutamate release during high-frequency stimulation. The maternal effects on both long-term depression and PPD were eliminated by treatment with an mGluR1-selective antagonist. These findings suggest that variations in maternal care can influence hippocampal function and cognitive performance through the epigenetic regulation of genes implicated in glutamatergic synaptic signaling.

BM-BronchoLC - A rich bronchoscopy dataset for anatomical landmarks and lung cancer lesion recognition.

Flexible bronchoscopy has revolutionized respiratory disease diagnosis. It offers direct visualization and detection of airway abnormalities, including lung cancer lesions. Accurate identification of airway lesions during flexible bronchoscopy plays an important role in the lung cancer diagnosis. The application of artificial intelligence (AI) aims to support physicians in recognizing anatomical landmarks and lung cancer lesions within bronchoscopic imagery. This work described the development of BM-BronchoLC, a rich bronchoscopy dataset encompassing 106 lung cancer and 102 non-lung cancer patients. The dataset incorporates detailed localization and categorical annotations for both anatomical landmarks and lesions, meticulously conducted by senior doctors at Bach Mai Hospital, Vietnam. To assess the dataset's quality, we evaluate two prevalent AI backbone models, namely UNet++ and ESFPNet, on the image segmentation and classification tasks with single-task and multi-task learning paradigms. We present BM-BronchoLC as a reference dataset in developing AI models to assist diagnostic accuracy for anatomical landmarks and lung cancer lesions in bronchoscopy data.

Insulin signaling and its application.

The discovery of insulin in 1921 introduced a new branch of research into insulin activity and insulin resistance. Many discoveries in this field have been applied to diagnosing and treating diseases related to insulin resistance. In this mini-review, the authors attempt to synthesize the updated discoveries to unravel the related mechanisms and inform the development of novel applications. Firstly, we depict the insulin signaling pathway to explain the physiology of insulin action starting at the receptor sites of insulin and downstream the signaling of the insulin signaling pathway. Based on this, the next part will analyze the mechanisms of insulin resistance with two major provenances: the defects caused by receptors and the defects due to extra-receptor causes, but in this study, we focus on post-receptor causes. Finally, we discuss the recent applications including the diseases related to insulin resistance (obesity, cardiovascular disease, Alzheimer's disease, and cancer) and the potential treatment of those based on insulin resistance mechanisms.

Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells.

The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that ß-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.

Notch signaling in thyrocytes is essential for adult thyroid function and mammalian homeostasis.

The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism1, and thyroid diseases comprise the most common endocrine disorders2. Nevertheless, high-resolution views of the cellular composition and signals that govern the thyroid have been lacking3,4. Here, we show that Notch signalling controls homeostasis and thermoregulation in adult mammals through a mitochondria-based mechanism in a subset of thyrocytes. We discover two thyrocyte subtypes in mouse and human thyroids, identified in single-cell analyses by different levels of metabolic activity and Notch signalling. Therapeutic antibody blockade of Notch in adult mice inhibits a thyrocyte-specific transcriptional program and induces thyrocyte defects due to decreased mitochondrial activity and ROS production. Thus, disrupting Notch signalling in adult mice causes hypothyroidism, characterized by reduced levels of circulating thyroid hormone and dysregulation of whole-body thermoregulation. Inducible genetic deletion of Notch1 and 2 in thyrocytes phenocopies this antibody-induced hypothyroidism, establishing a direct role for Notch in adult murine thyrocytes. We confirm that hypothyroidism is enriched in children with Alagille syndrome, a genetic disorder marked by Notch mutations, suggesting that these findings translate to humans.

Genetic predisposition to depression and inflammation impacts symptom burden and survival in patients with head and neck cancer: A longitudinal study.

OBJECTIVE: The primary purpose of this study was to investigate the contribution of genetic predispositions to depression and inflammation, as measured through polygenic risk scores, on symptom burden (physical and psychological) in patients with head and neck cancer in the immediate post-treatment period (i.e., at three months post-diagnosis), as well as on 3-, 6-, 12-, 24- and 36-month survival. METHODS: Prospective longitudinal study of 223 adults (72 % participation) newly diagnosed with a first occurrence of primary head and neck cancer, paired with genetic data (Illumina PsychArray), validated psychometric measures, Structured Clinical Interviews for DSM Disorders (SCID-I), and medical chart reviews. RESULTS: Symptom burden at 3 months was predicted by (R2 adj. = 0.38, p < 0.001): a baseline SCID-I Anxiety Disorder (b = 1.69, B = 0.23, 95%CI = 0.43-2.94; p = 0.009), baseline levels of HADS anxiety (b = 0.20, B = 0.29, 95%CI = 0.07-0.34; p = 0.003), the polygenic risk score (PRS) for depression (b = 0.66, B = 0.18, 95%CI = 0.003-1.32; p = 0.049), and cumulated dose of radiotherapy (b = 0.002, B = 0.46, 95%CI = 0.001-0.003; p < 0.001). When controlling for factors known to be associated with cancer survival, patients with a higher PRS associated with depression and inflammation, respectively, presented higher risk of death within 36 months (b = 1.75, Exp(B) = 5.75, 95%CI = 1.55-21.27, p = 0.009 and b = 0.14, Exp(B) = 1.15, 95%CI = 1.01-1.30, p = 0.03). CONCLUSIONS: Our results outline three potential pathways of symptom burden in patients with head and neck cancer: a genetic predisposition towards depression; an initial anxiety disorder upon being diagnosed with cancer or high levels of anxiety upon diagnosis; and a dose-related response to radiotherapy. One may want to investigate early interventions in these areas to alleviate symptom burden in patients faced with a life-threatening disease, as well as consider targeting genetic predisposition towards depression and inflammation implicated in survival. The high prevalence of distress in patients with head and neck cancer is an opportunity to study genetic predispositions, which could potentially be broadly generalized to other cancers and diseases.

Moisturizing effectiveness of immediate compared with delayed moisturization.

INTRODUCTION: Moisturizers play an essential role in maintaining the integrity of the skin barrier by increasing stratum corneum hydration (SCH) and reducing transepidermal water loss (TEWL). According to dermatology and allergy guidelines, moisturizers should be applied on the skin within 3 min after bathing or showering. However, there is very little evidence supporting this recommendation. This study aimed to investigate the effectiveness of immediate and delayed moisturizing after bathing/washing on the improvement of SCH and TEWL. METHODS: This was a crossover study of 60 healthy Vietnamese volunteers aged 18-25 years. In each subject, SCH and TEWL levels were measured at three areas: non-moisturized, immediate moisturizing after washing, and delayed moisturizing at 30 min after washing. RESULTS: In non-moisturized skin, SCH and TEWL levels were significantly different from the baseline at 60 min after washing, while significantly decreased TEWL levels were observed immediately after moisturizing. In addition, moisturized skin had significantly higher SCH and lower TEWL levels compared with non-moisturized areas at every time point (p < 0.05). Interestingly, the percentage changes of SCH and TEWL levels from baseline did not differ between immediately and delayed moisturized areas. CONCLUSIONS: Tested moisturizer helped increase SCH and decrease TEWL; however, there was no difference in moisturizing effectiveness between immediate and delayed moisturizing in healthy skin. The recommendation of immediate application of moisturizers after bathing/washing should be reconsidered, and more studies are needed to establish a stronger recommendation.

Automatic scan range for dose-reduced multiphase CT imaging of the liver utilizing CNNs and Gaussian models.

Multiphase CT scanning of the liver is performed for several clinical applications; however, radiation exposure from CT scanning poses a nontrivial cancer risk to the patients. The radiation dose may be reduced by determining the scan range of the subsequent scans by the location of the target of interest in the first scan phase. The purpose of this study is to present and assess an automatic method for determining the scan range for multiphase CT scans. Our strategy is to first apply a CNN-based method for detecting the liver in 2D slices, and to use a liver range search algorithm for detecting the liver range in the scout volume. The target liver scan range for subsequent scans can be obtained by adding safety margins achieved from Gaussian liver motion models to the scan range determined from the scout. Experiments were performed on 657 multiphase CT volumes obtained from multiple hospitals. The experiment shows that the proposed liver detection method can detect the liver in 223 out of a total of 224 3D volumes on average within one second, with mean intersection of union, wall distance and centroid distance of 85.5%, 5.7 mm and 9.7 mm, respectively. In addition, the performance of the proposed liver detection method is comparable to the best of the state-of-the-art 3D liver detectors in the liver detection accuracy while it requires less processing time. Furthermore, we apply the liver scan range generation method on the liver CT images acquired from radiofrequency ablation and Y-90 transarterial radioembolization (selective internal radiation therapy) interventions of 46 patients from two hospitals. The result shows that the automatic scan range generation can significantly reduce the effective radiation dose by an average of 14.5% (2.56 mSv) compared to manual performance by the radiographer from Y-90 transarterial radioembolization, while no statistically significant difference in performance was found with the CT images from intra RFA intervention (p = 0.81). Finally, three radiologists assess both the original and the range-reduced images for evaluating the effect of the range reduction method on their clinical decisions. We conclude that the automatic liver scan range generation method is able to reduce excess radiation compared to the manual performance with a high accuracy and without penalizing the clinical decision.

Identifying transcriptional programs underlying cancer drug response with TraCe-seq.

Genetic and non-genetic heterogeneity within cancer cell populations represent major challenges to anticancer therapies. We currently lack robust methods to determine how preexisting and adaptive features affect cellular responses to therapies. Here, by conducting clonal fitness mapping and transcriptional characterization using expressed barcodes and single-cell RNA sequencing (scRNA-seq), we have developed tracking differential clonal response by scRNA-seq (TraCe-seq). TraCe-seq is a method that captures at clonal resolution the origin, fate and differential early adaptive transcriptional programs of cells in a complex population in response to distinct treatments. We used TraCe-seq to benchmark how next-generation dual epidermal growth factor receptor (EGFR) inhibitor-degraders compare to standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells. We identified a loss of antigrowth activity associated with targeted degradation of EGFR protein and an essential role of the endoplasmic reticulum (ER) protein processing pathway in anti-EGFR therapeutic efficacy. Our results suggest that targeted degradation is not always superior to enzymatic inhibition and establish TraCe-seq as an approach to study how preexisting transcriptional programs affect treatment responses.

Hierarchical self-assembly of heparin-PEG end-capped porous silica as a redox sensitive nanocarrier for doxorubicin delivery.

Porous nanosilica (PNS) has been attracting a great attention in fabrication carriers for drug delivery system (DDS). However, unmodified PNS-based carriers exhibited the initial burst release of loaded bioactive molecules, which may limit their potential clinical application. In this study, the surface of PNS was conjugated with adamantylamine (A) via disulfide bonds (PNS-SS-A) which was functionalized with cyclodextrin-heparin-polyethylene glycol (CD-HPEG) for redox triggered doxorubicin (DOX) delivery. The modified PNS was successfully formed with spherical shape and diameter around 50nm determined by transmission electron microscopy (TEM). DOX was efficiently trapped in the PNS-SS-A@CD-HPEG and slowly released in phosphate buffered saline (PBS) without any initial burst effect. Importantly, the release of DOX was triggered due to the cleavage of the disulfide bonds in the presence of dithiothreitol (DTT). In addition, the MTT assay data showed that PNS-SS-A@CD-HPEG was a biocompatible nanocarrier and reduced the toxicity of DOX. These results demonstrated that PNS-SS-A@CD-HPEG has great potential as a novel nanocarrier for anticancer drug in cancer therapy.