Primary Necrosis Research Articles

Abstract 4116603: Interleukin-33 from Necrotic Tunica Media Plays a Key Role in the Exacerbations of Coronary Arteritis in Kawasaki Disease

Objective: Alarmins resulting from cell death or oxidative stress have been shown to be involved in the development of Kawasaki disease (KD) vasculitis. In our previous study, we demonstrated the potential role of (IL)-33 as an alarmin in the development of KD vasculitis. Although edematous dissociation (necrotic change) of the tunica media is thought to be a major source of IL-33 in KD vasculitis, it has not yet been elucidated. Methods: We investigated the impact of IL-33 released from necrotic human coronary artery smooth muscle cells (HCASMCs) on human coronary artery endothelial cells (HCAECs) by a co-culture assay using the Transwell ® cell culture insert system. Subsequently, we evaluated the anti-inflammatory effects of anti-IL-33 and anti-ST2 antibodies compared to the conventional therapies of KD, such as high-dose IgG or anti-tumor necrosis factor (TNF)-α antibody. Results: Primary necrosis of HCASMCs induced significant release of IL-33. In co-cultures of necrotic HCASMCs with HCAECs, necrotic HCASMCs significantly induced the production of various proinflammatory cytokines in HCAECs. Anti-IL-33 and anti-ST2 antibodies exhibited unique inhibitory effects on the production of platelet-derived growth factor-BB or IL-12(p70) in HCAECs. Conclusion: The results of the present study suggest the potential involvement of edematous dissociation of the tunica media in the development of KD vasculitis. Furthermore, the distinctive anti-inflammatory effects of the anti-IL-33/ST2 axis drugs suggest novel therapeutic options for patients with refractory KD.

TMOD-14. ESTABLISHING A CLINICALLY RELEVANT MOUSE MODEL TO STUDY NECROSIS AS A PRIMARY VARIABLE IN GLIOBLASTOMA

Abstract All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. We suggest that necrosis is much more than a passive phenomenon related to rapid growth but rather is a driving force causing tumor microenvironment (TME) restructuring and biologic progression. yet mechanisms remain poorly understood due to a lack of animal models to study necrosis as a primary variable. In GBM, the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. To reveal spatio-temporal changes directly following vascular damage in the brain, we developed methodology to induce clinically relevant thrombosis vaso-occlusion within GBMs in immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression in real-time. We found that following Rose Bengal photothrombosis, GBMs rapidly expanded radially, with glioma migration away from central necrosis and tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increased dramatically in the peri-necrotic zones. Through the single cell tracking analysis, we found that TAMs displaying increased displacement toward necrosis and greater overall migration distances. Collectively, this model introduces necrosis as the primary variable and captures glioma growth dynamics and TME restructuring in a manner that will facilitate the development of therapies that antagonize these mechanisms to improve outcomes.

MR-guided laser interstitial thermal therapy in the treatment of brain tumors and epilepsy.

MR-guided Laser Interstitial Thermal Therapy (MRgLITT) is a minimally invasive neurosurgical technique increasingly used for the treatment of drug-resistant epilepsy and brain tumors. Utilizing near-infrared light energy delivery guided by real-time MRI thermometry, MRgLITT enables precise ablation of targeted brain tissues, resulting in limited corridor-related morbidity and expedited postoperative recovery. Since receiving CE marking in 2018, the adoption of MRgLITT has expanded to more than 40 neurosurgical centers across Europe. In epilepsy treatment, MRgLITT can be applied to various types of focal lesional epilepsy, including mesial temporal lobe epilepsy, hypothalamic hamartoma, focal cortical dysplasias, periventricular heterotopias, cavernous malformations, dysembryoplastic neuroepithelial tumors (DNET), low-grade gliomas, tuberous sclerosis, and in disconnective surgeries. In neuro-oncology, MRgLITT is used for treating newly diagnosed and recurrent primary brain tumors, brain metastases, and radiation necrosis. This comprehensive review presents an overview of the current evidence and technical considerations for the use of MRgLITT in treating various pathologies associated with drug-resistant epilepsy and brain tumors.

Necrotic Change of Tunica Media Plays a Key Role in the Development of Coronary Artery Lesions in Kawasaki Disease.

Alarmins resulting from cell death or oxidative stress are involved in the development of Kawasaki disease (KD) vasculitis. In a previous study, we demonstrated the potential role of interleukin (IL)-33 as an alarmin in the development of KD vasculitis. Although edematous dissociation (necrotic change) of the tunica media is thought to be a major source of IL-33 in KD vasculitis, it has not yet been elucidated. We investigated the impact of IL-33 released from necrotic human coronary artery smooth muscle cells (HCASMCs) on human coronary artery endothelial cells (HCAECs) using a coculture assay. Subsequently, we evaluated the anti-inflammatory effects of anti-IL-33 and anti-suppression of tumorigenicity 2 (ST2) antibodies compared with conventional therapies of KD, such as high-dose IgG or anti-tumor necrosis factor (TNF)-α antibody. Primary necrosis of HCASMCs induced significant release of IL-33. In cocultures of necrotic HCASMCs with HCAECs, the necrotic HCASMCs significantly induced the production of various proinflammatory cytokines in the HCAECs. Anti-IL-33 and anti-ST2 antibodies exhibited unique inhibitory effects on the production of platelet-derived growth factor-BB or IL-12(p70) in HCAECs. There is potential involvement of edematous dissociation of the tunica media in the development of KD vasculitis. Furthermore, the distinctive anti-inflammatory effects of the anti-IL-33/ST2 axis drugs suggest novel therapeutic options for patients with refractory KD.

Towards machine learning-based quantitative hyperspectral image guidance for brain tumor resection

BackgroundComplete resection of malignant gliomas is hampered by the difficulty in distinguishing tumor cells at the infiltration zone. Fluorescence guidance with 5-ALA assists in reaching this goal. Using hyperspectral imaging, previous work characterized five fluorophores’ emission spectra in most human brain tumors.MethodsIn this paper, the effectiveness of these five spectra was explored for different tumor and tissue classification tasks in 184 patients (891 hyperspectral measurements) harboring low- (n = 30) and high-grade gliomas (n = 115), non-glial primary brain tumors (n = 19), radiation necrosis (n = 2), miscellaneous (n = 10) and metastases (n = 8). Four machine-learning models were trained to classify tumor type, grade, glioma margins, and IDH mutation.ResultsUsing random forests and multilayer perceptrons, the classifiers achieve average test accuracies of 84–87%, 96.1%, 86%, and 91% respectively. All five fluorophore abundances vary between tumor margin types and tumor grades (p < 0.01). For tissue type, at least four of the five fluorophore abundances are significantly different (p < 0.01) between all classes.ConclusionsThese results demonstrate the fluorophores’ differing abundances in different tissue classes and the value of the five fluorophores as potential optical biomarkers, opening new opportunities for intraoperative classification systems in fluorescence-guided neurosurgery.

Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals

A disintegrin and metalloprotease 17 (ADAM17) is a membrane-tethered protease that triggers multiple signaling pathways. It releases active forms of the primary inflammatory cytokine tumor necrosis factor (TNF) and cancer-implicated epidermal growth factor (EGF) family growth factors. iRhom2, a rhomboid-like, membrane-embedded pseudoprotease, is an essential cofactor of ADAM17. Here, we present cryoelectron microscopy (cryo-EM) structures of the human ADAM17/iRhom2 complex in both inactive and active states. These reveal three regulatory mechanisms. First, exploiting the rhomboid-like hallmark of TMD recognition, iRhom2 interacts with the ADAM17 TMD to promote ADAM17 trafficking and enzyme maturation. Second, a unique iRhom2 extracellular domain unexpectedly retains the cleaved ADAM17 inhibitory prodomain, safeguarding against premature activation and dysregulated proteolysis. Finally, loss of the prodomain from the complex mobilizes the ADAM17 protease domain, contributing to its ability to engage substrates. Our results reveal how a rhomboid-like pseudoprotease has been repurposed during evolution to regulate a potent membrane-tethered enzyme, ADAM17, ensuring the fidelity of inflammatory and growth factor signaling.

Thermal Field Monitoring When Exposing Soft Tissues to Low Temperatures: Thermography Prospects and Limitations

The review analyzes the existing tools for monitoring the dynamics of thermal fi elds when exposing the soft tissues to low temperatures. Features of contact and non-contact temperature measurements have been considered, their capabilities and limitations have been noted. There was substantiated the need to develop the procedures of intra-operative temperature control. Special attention has been paid to the non-contact non-invasive infrared thermography. This method has been shown to be applied for intra-operative monitoring of the movement of the ice lump edge on the surface of tissues, detection of a disordered thermal symmetry of the ice spot, thermal fi eld dynamics on the surface of tissues inside and outside the area of the operative zone. However, thermal imaging control of the dynamics of the primary necrosis zone and the ice ball edge in the volume of tissues is possible only under certain parameters of cryoimpact, for example, with a short-term cooling of tissues with a quasi-point nitrogen cryoapplicator. The possibility of using thermography at other stages of cryosurgery is also considered, i. e. as the method of additional diagnosis at the stage of surgery planning, as well as during the post-surgery period to control healing, scarring, etc.

GCN-Based Risk Prediction for Necrosis Slide of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which ranks fourth in cancer deaths. Primary pathological necrosis is an effective prognostic indicator for hepatocellular carcinoma. We propose a GCN-based approach that mimics the pathologist's perspective for global assessment of necrosis tissue distribution to analyze patient survival. Specifically, we introduced a graph convolutional neural network to construct a spatial map with necrotic tissue and tumor tissue as graph nodes, aiming to mine the contextual information between necrotic tissue in pathological sections. We used 1381 slides from 303 patients from the First Affiliated Hospital of Zhejiang University School to train the model and used TCGA-LIHC for external validation. The C-index of our method outperforms the baseline by about 4.45%, which proves that the information about the spatial distribution of necrosis learned by GCN is meaningful for guiding patient prognosis.

Identification of predictors for short-term recurrence: comprehensive analysis of 296 retroperitoneal liposarcoma cases

BackgroundThe short-term (≤ 1 year) recurrence (STR) is the primary determinant impacting both the life quality and survival duration in patients who have undergone surgical resection for retroperitoneal liposarcoma (RPLS), a condition with intricate and ambiguous pathogenesis. The purpose of this study was to analyze the risk factors associated with STR in cases of RPLS and primary retroperitoneal liposarcoma (PRPLS).MethodsFor this retrospective observational study, a total of 296 RPLS cases were selected as research subjects, who experienced tumor recurrence during the follow-up period. The Local recurrence-free survival (LRFS) rates were estimated using the Kaplan–Meier method and subsequently compared between groups utilizing the log-rank test. The subsequent analyses involved univariate and multivariate logistic regression to identify predictors of STR in RPLS cases. Additionally, a logistic regression model was constructed for PRPLS.ResultsThe 1-, 3-, and 5-year LRFS rates of the 296 RPLS cases were 51.7%, 16.9%, and 7.1%, respectively. In the univariate analysis, several factors were found to be associated with STR, including preoperative neutrophil/lymphocyte ratio (NLR), smoking history, surgical frequency, combined organ excision, operative time, intraoperative bleeding, transfer to the intensive care unit (ICU), multiple primary tumors, tumor shape and capsule characteristics, histological subtype, and presence of tumor necrosis. The elevated preoperative NLR, surgical frequency of ≥ 3 times, transfer to the ICU, presence of multiple primary tumors, and tumor necrosis were identified as independent risk factors for STR in surgically resected RPLS. Conversely, diabetes, intact tumor capsule, and well-differentiated histological subtype appeared to be independent protective factors. Analysis for PRPLS revealed that tumor capsule and tumor necrosis were independent predictors of STR.ConclusionsThe elevated preoperative NLR, surgical frequency of ≥ 3 times, transfer to the ICU, presence of multiple primary tumors, tumor necrosis, and tumor capsule were expected to serve as predictive factors of STR for surgical resected RPLS and PRPLS.

Immunohistochemical expression of anaplastic lymphoma kinase in neuroblastoma and its relations with some clinical and histopathological features.

Anaplastic lymphoma kinase (ALK) mutations have been identified as a prominent cause of some familial and sporadic neuroblastoma (NB). ALK expression in NB and its relationship with clinical and histopathological features remains controversial. This study investigated ALK expression and its potential relations with these features in NB. Ninety cases of NB at the Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam from 01/01/2018 to 12/31/2021, were immunohistochemically stained with ALK (D5F3) antibody. The ALK expression and its relations with some clinical and histopathological features were investigated. The rate of ALK expression in NB was 91.1%. High ALK expression (over 50% of tumor cells were positive with moderate-strong intensity) accounted for 65.6%, and low ALK expression accounted for 34.4%. All the MYCN-amplified NB patients had ALK immunohistochemistry positivity, most cases had high ALK protein expression. The undifferentiated subtype of NB had a lower ALK-positive rate than the poorly differentiated and differentiated subtype. The percentages of ALK positivity were significantly higher in more differentiated histological types of NB (p = .024). There was no relation between ALK expression and: age group, sex, primary tumor location, tumor stage, MYCN status, clinical risk, Mitotic-Karyorrhectic Index, prognostic group, necrosis, and calcification. ALK was highly expressed in NB. ALK expression was not related to several clinical and histopathological features. More studies are needed to elucidate the association between ALK expression and ALK gene status and to investigate disease progression, especially the oncogenesis of ALK-positive NB.

INNV-24. MACHINE LEARNING-BASED SPECTROSCOPIC TISSUE DIFFERENTIATION IN FLUORESCENCE-GUIDED NEUROSURGERY

Abstract Maximal resection of malignant gliomas is hindered by difficulty in distinguishing tumor margins. Fluorescence-guided resection with 5-ALA assists in reaching this goal. Previously, we characterized five fluorophore emissions that accurately represent any spectrum measured from human brain tumor biopsies with a wide-field hyperspectral device. In this study, the effectiveness of these five spectra was explored for different tumor classification tasks in 891 hyperspectral widefield measurements of 184 patients harboring low- (n=30) and high-grade gliomas (n=115), non-glial primary brain tumors (n=19), radiation necrosis (n=2), miscellaneous (n=10) and metastases (n=8), which corresponds to up to 15000 spectra for a given test. The statistical differences in fluorophore abundances between classes were determined and visualized using dimensionality reduction techniques, including principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). Three machine-learning models were trained to classify tumor type (12 classes), grade (3 classes), and glioma margins (3 classes). Five algorithms were tested with varying hyperparameters for each classification task. We explored whether PCA projection onto five different axes than fluorophore abundances can provide more information for visualization and classification. The abundances of the five a priori fluorophore spectra matched or outperformed the five optimal PCA components for all classification tasks. These five axes capture 96-99% of the variance in the dataset. Using random forests and multilayer perceptrons, the classifiers achieved average test accuracies of 74-82%, 79%, and 81%, respectively. All five fluorophore abundances varied between tumor margin type as well as between grades (p &amp;lt; 0.01). For tissue type, at least four of five fluorophore abundances were found to be significantly different (p &amp;lt; 0.01) between all classes. These results demonstrate the differing contribution of fluorophores in different tissue classes tissue, as well as the five fluorophores value as potential optical biomarkers, opening new opportunities for intraoperative classification systems in fluorescence-guided neurosurgery.

Primary bud necrosis in vine propagation material

Abstract. The study was carried out in the period 2019-2021 in the vine nursery of the Institute of Viticulture and Enology, Pleven (43.42°N 24.62°E and 140 m altitude) with Muscat Plevenski and Bolgar varieties, grafted to Berlandieri x Riparia SO4 rootstock. The cuttings were rooted in two-row beds without mulching with polyethylene foil. The planting depth was 0.15 m, at 0.07-0.08 m intra-row distance and 0.5 m between the rows in the bed. The distance between the beds was 2 m. The experiment was conducted in four replicates The buds from the first to the fifth eye were examined twice – in the second half of October (15-20 October) and after the removal of the vines from the nursery (01-08 November). The proportion of necrotic buds was determined from samples of 10 shoots per replicate. The manifestations of primary bud necrosis in Muscat Plevenski and Bolgar were observed without exception during the three years of the experiment. Damage was found, regardless of the bud’s location along the examined length of the shoot, with no specific trend of a particular node being affected.

TRAIL and its receptors in cardiac diseases.

Cardiovascular disease is a leading cause of death worldwide. Loss of cardiomyocytes that occurs during many types of damage to the heart such as ischemic injury and stress caused by pressure overload, diminishes cardiac function due to their limited regenerative capacity and promotes remodeling, which further damages the heart. Cardiomyocyte death occurs through two primary mechanisms, necrosis and apoptosis. Apoptosis is a highly regulated form of cell death that can occur through intrinsic (mitochondrial) or extrinsic (receptor mediated) pathways. Extrinsic apoptosis occurs through a subset of Tumor Necrosis Receptor (TNF) family receptors termed "Death Receptors." While some ligands for death receptors have been extensively studied in the heart, such as TNF-α, others have been virtually unstudied. One poorly characterized cardiac TNF related ligand is TNF-Related Apoptosis Inducing Ligand (TRAIL). TRAIL binds to two apoptosis-inducing receptors, Death Receptor (DR) 4 and DR5. There are also three decoy TRAIL receptors, Decoy Receptor (DcR) 1, DcR2 and osteoprotegerin (OPG). While TRAIL has been extensively studied in the cancer field due to its ability to selectively induce apoptosis in transformed cell types, emerging clinical evidence points towards a role for TRAIL and its receptors in cardiac pathology. This article will highlight our current understanding of TRAIL and its receptors in normal and pathological conditions in the heart.

Integrated Transcriptome and Metabolome Analysis Revealed the Causal Agent of Primary Bud Necrosis in 'Summer Black' Grape.

Primary bud necrosis of grape buds is a physiological disorder that leads to decreased berry yield and has a catastrophic impact on the double cropping system in sub-tropical areas. The pathogenic mechanisms and potential solutions remain unknown. In this study, the progression and irreversibility patterns of primary bud necrosis in 'Summer Black' were examined via staining and transmission electron microscopy observation. Primary bud necrosis was initiated at 60 days after bud break and was characterized by plasmolysis, mitochondrial swelling, and severe damage to other organelles. To reveal the underlying regulatory networks, winter buds were collected during primary bud necrosis progression for integrated transcriptome and metabolome analysis. The accumulation of reactive oxygen species and subsequent signaling cascades disrupted the regulation systems for cellular protein quality. ROS cascade reactions were related to mitochondrial stress that can lead to mitochondrial dysfunction, lipid peroxidation causing damage to membrane structure, and endoplasmic reticulum stress leading to misfolded protein aggregates. All these factors ultimately resulted in primary bud necrosis. Visible tissue browning was associated with the oxidation and decreased levels of flavonoids during primary bud necrosis, while the products of polyunsaturated fatty acids and stilbenes exhibited an increasing trend, leading to a shift in carbon flow from flavonoids to stilbene. Increased ethylene may be closely related to primary bud necrosis, while auxin accelerated cell growth and alleviated necrosis by co-chaperone VvP23-regulated redistribution of auxin in meristem cells. Altogether, this study provides important clues for further study on primary bud necrosis.

Pathological effects due to metacercariae of Clinostomum piscidium migration in snakeskin gourami (Trichopodus pectoralis) in Thailand.

Clinostomum spp. is a fish-borne pathogen and a digenetic trematode with a global range. Despite its zoonotic relevance, the pathogenic impact of the parasite in Thai aquaculture is currently unclear. The present study deals with the pathogenic changes that fluke causes in their host, Trichopodus pectoralis, and the molecular confirmation of the Clinostomum piscidium by targeting 18 s rDNA and ITS gene. The metacercariae of C. piscidium were discovered in the body cavity of infected fish. The gross pathological examination revealed a few white migratory tracks on the surface of the liver and spleen. The migratory track showed histologically as a primary hemorrhage and necrosis of hepatic cells surrounded by a layer of macrophages and epithelioid cells, inflammatory cells, and eosinophilic granular cells in the cytoplasm of liver cells and close to the epithelial cells of the intestine. Also, the migratory track in the spleen appeared as a marked decrease of Red Blood Cell (RBC) count and changes in the necrotic tissue. Infection with this metacercaria produced hepatic tissue injury, which disrupted hepatic metabolism and decreased body weight in the fish hosts. The findings of the study suggest that the pathological effect of C. piscidium on farm T. pectoralis can cause significant economic loss by stunting fish development and predisposing fish to opportunistic pathogens in the environment. Hence, the treatment and control of C. piscidium infections are crucial for the viability of the aquaculture sector since this parasite has been found to cause pathological damage to the vital organs of fish.

Methods to increase the effectiveness of cytoreductive surgical interventions in patients with complicated disseminated tumors of the abdominal cavity and pelvis

The expediency of performing two-stage cytoreductive interventions in patients with complicated disseminated tumors of the abdominal cavity and pelvis is presented. Ninety-two patients with complicated disseminated tumors of the abdominal cavity and pelvis were examined into two groups. The main group consisted of 33 patients who received surgical treatment by two-stage cytoreductive surgery. The control group included 59 patients who underwent single-stage cytoreductive operations. In both groups, life-threatening complications were dominated by primary tumor necrosis (main group, n = 15; control group, n = 31) and impaired intestinal patency (main group, n = 12; control group, n = 16, respectively). The average Charlson comorbidity index was 7.85 1.37 and 7.53 1.5 points, respectively. Anesthetic risk of grades IIIIV according to the classification of the American Society of Anesthesiologists was detected in 23 (69.7%) and 45 (76.27%) patients of the main and control groups, respectively. Functional status of 23 points on the Eastern Cooperative Oncological Group was established in 23 (69.7%) and 46 (77.9%) patients of the main and control groups, respectively. The peritoneal carcinomatosis index was significantly higher in the main group (13.1 6 vs 9.9 4.8 points) than in the control group (p = 0.012). A comparative analysis of the results obtained in the treatment of the main and control groups demonstrated that the two-stage cytoreductive surgical interventions can reduce the frequency of postoperative complications, primarily ClavienDindo grades IIIIV from 40.7 to 18.2% (p = 0.049) and mortality from 16.9% to 9.1% (p = 0.468) and increase the frequency of achieving complete cytoreduction from 49.1% to 90.9% (p = 0.002) and the frequency of intraperitoneal hyperthermic chemoperfusion from 40.7 to 93.9% (p 0.001). Thus, two-stage cytoreductive surgical interventions are a safe and effective technique in the surgical treatment of complicated disseminated tumors of the abdominal cavity and pelvis.

Nationwide Multicenter Survey on Primary Tracheobronchial Necrosis after Esophagectomy

Nationwide Multicenter Survey on Primary Tracheobronchial Necrosis after Esophagectomy

TMIC-16. INTRATUMORAL THROMBOSIS INITIATES HYPOXIA AND NECROSIS TO DRIVE TUMOR PROGRESSION THROUGH DRAMATIC TUMOR MICROENVIRONMENTAL ALTERATION

Abstract All GBM molecular subsets share the common trait of accelerated progression following necrosis which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. We suggest that development of necrosis is much more than a passive phenomenon related to rapid growth but rather is a driving force behind TME restructuring responsible for sustaining accelerated expansion. Current tumor models fail to adequately mimic the magnitude of post-necrotic restructuring within the microenvironment and remain overly reliant on post-mortem analyses, obligating researchers to extrapolate causal relationships between necrosis and progression phenomena during tumor evolution. In GBM (WHO grade 4), the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. Mechanisms enabling selective fitness within a hypoxic/anoxic GBM setting remain poorly understood. Nanostring GeoMX spatial profiling demonstrates M1-like TAM enrichment in non-necrotic human samples and M2-like TAMs in perinecrotic regions. Our immunocompetent RCAS/tv-a model aptly captures events seen in human gliomas, exposing dynamic temporal and spatial changes that facilitate GBM progression, incorporating unique microenvironmental stressors typically absent from GBM animal models, specifically emerging central necrosis. Simultaneously, our in vitro models scrutinize how hypoxia-dependent signaling between GBM cells, microglia and monocytes alter TAM accumulation and function in the TME. TAMs increase dramatically with the onset of necrosis, with a preferential localization to the hypoxic zone in the perinecrotic niche, which supports their survival. Flow cytometry on digested pre- and post-necrotic GBMs, showed increased TAM accumulation at 6 weeks vs. 2 weeks (necrosis emerges in week 4-5). Our in vivo data along with in silico analysis of Ivy GAP and TCGA datasets suggests GBM cells within the peri-necrotic niche attract and polarize TAMs through MIF secretion, necrotic DAMP (adenosine, S100B) release, and arginase secretion to suppress T cells.

Effects of cane- and spur-retained node numbers on the pre-flowering vegetative growth of cane-pruned Sauvignon blanc

In established vineyards, node number retention at winter pruning is the first step to achieving and maintaining vine balance. Balanced vines exhibit timely and quasi-uniform 100 percent budburst. To understand how vine capacity and balance are expressed before flowering, mature Sauvignon blanc vines were pruned according to a 5 [total node numbers on canes: 10, 20, 30, 40, 50] x 3 [total node numbers on spurs: 1, 2, 3] factorial design in one site, and in two other sites according to a 5 [total node numbers on canes: 10, 20, 30, 40, 50] x 2 [total node numbers on spurs: 1, 2] factorial design. Two spurs of one, two or three nodes each were retained on either side of the vine. The number of canes laid down per vine was one, two, three and four canes each of 10 nodes for the 10-, 20-, 30- and 40-node treatments, and four canes averaging 12.5 nodes for the 50-node treatment. The budburst percentage was calculated on the whole vine, canes, and spurs. Blind nodes, count shoots, non-count shoots and double shoots were counted and mapped along canes and spurs. Many non-count shoots were measured on the vine head of 10-node vines (29.5 ± 3.0 shoots, p &lt; 0.001), compared to 50-node vines (2.8 ± 1.9 shoots, p &lt; 0.001). 50-node vines had an overall budburst of 100 %, despite having the highest number of blind nodes (7.6 ± 0.3 nodes, p &lt; 0.001). These were mainly located at the canes’ proximal sections relative to the vine head and were likely caused by correlative inhibition and primary bud necrosis. Cane budburst provided a more accurate assessment of the vine response to node loading than vine budburst. The number of double shoots was not associated with the vine node load, as they appeared on both low-node and high-node vines. Three-node spurs developed more blind nodes than one-node and two-node spurs (p &lt; 0.001). Based on the findings of this research, we recommend a composite metric (cane percent budburst, cane blind node count and head shoot count) to assess vine capacity and balance between budburst and flowering, and the practice of retaining one- or two-node spurs at cane pruning is also justified.

Primary tracheobronchial necrosis after esophagectomy: A nationwide multicenter retrospective study in Japan.

The clinical features of postoperative primary tracheobronchial necrosis (P-TBN; the necrosis without anastomotic leakage or other cervical and mediastinal abscess) remains unclear. This nationwide multicenter retrospective study first investigated the clinical features of P-TBN after esophagectomy for upper aerodigestive tract cancer with a large cohort. As a study of the Japan Broncho-Esophagological Society, a nationwide questionnaire survey was conducted in 67 institutions. The clinical data of 6370 patients who underwent esophagectomy for laryngeal, pharyngeal, and esophageal cancer between 2010 and 2019 were collected. Grades of P-TBN were defined as follows: Grade 1, mucosal necrosis; Grade 2, transmural bronchial wall necrosis without fistula or perforation; Grade 3, transmural bronchial wall necrosis with fistula or perforation. P-TBN was observed in 48 (0.75%) of 6370 patients. The incidences of P-TBN for pharyngo-laryngo-cervical esophagectomy (PLCE; n=1650), total pharyngo-laryngo-esophagectomy (TPLE; n=205), and subtotal esophagectomy (SE; n=4515) were 2.0%, 5.4%, and 0.1%, respectively. The upper mediastinal LN dissection (P=0.016) and the higher level of the tracheal resection (P=0.039) were significantly associated with a higher grade of necrosis in PLCE and TPLE. Overall survival rates were significantly lower in patients with Grade 2 (P=0.009) and Grade 3 (P=0.004) than in those with Grade 1. The incidence of TBN restricted to P-TBN was lower than previously reported. Maintaining the tracheal blood flow is essential to prevent worsening P-TBN, especially in PLCE and TPLE. Our new P-TBN severity grade may predict the outcome of patients with P-TBN.