搜索结果：deadly

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy with a very low survival rate. Asymptomatic disease progression, a complex tumour microenvironment (TME) and high resistance to current therapeutic methods, all contribute towards PDAC's dismal statistics. A key challenge towards better understanding of this deadly disease and its therapeutic response is the development of an in vitro disease model that is capable of mimicking the various complex and important features of the PDAC TME such as the biological/cellular, the biochemical as well as the biomechanical/biophysical complexity. We have previously developed a complex multicellular model of PDAC which is a spatially advanced multicellular scaffold that mimics the desmoplasia of PDAC. In this work, we have elucidated the importance/effect of interstitial fluid flow in the model. More specifically, we incorporated our multicellular PDAC model in a dynamic bioreactor for a flow rate of 3.5 ml/min. We exposed the model to flow either short-term (5 days) or long term (14 days). Thereafter we monitored the evolution of the cells under flow as well as their response to chemotherapy, as compared to non-dynamic (static) culture. Overall, fluid flow promoted the mesenchymal and reduced the epithelial cell population in our model, as compared to static conditions. Furthermore, the duration of the flow impacted the functionality of activated stellate cells, i.e., short-term flow promoted a more fibrotic/desmoplastic phenotype while long-term flow reduced the fibrosis, disrupted the deposition of collagen and increased the inflammatory levels. As a result, short-term flow exposure led to higher chemotherapy resistance as compared to long-term flow. This work highlights how dynamic flow can alter key features of in vitro models as well as the importance of flow consideration for increased in vitro biomimicry.

Meningitis is a significant global health threat, affecting millions and causing numerous deaths each year. Neisseria meningitides disproportionately affects resource-poor countries. Waterhouse-Friderichsen syndrome (WFS), a severe complication involving endotoxin-mediated adrenal damage, further worsens patient outcomes. A 35-year-old unvaccinated woman from Garbo, Somali, Ethiopia presented with a 24-hour history of fever, headache, and neck pain, progressing to altered mental status, right-sided weakness, and respiratory distress. Examination revealed confusion, respiratory distress, hypotension, tachycardia, and widespread non-blanching purpura, and right-sided weakness (3/5). Investigations showed leukocytosis, thrombocytopenia, and impaired renal function. The patient received supportive care with oxygen, fluid resuscitation, empiric antibiotics, epinephrine, and hydrocortisone. However, she continued to deteriorate and she ultimately expired with a presumed diagnosis of complicated Meningococcal meningitis with WFS. M. meningitis with suspected WFS is a medical emergency requiring prompt action. Resource-limited settings present challenges, leading to poor outcomes, as seen in this case. Meningococcal disease varies in severity, but its rapid progression is a key. Meningococcemia presents with fever, headache, and a non-blanching rash. WFS, a severe complication, involves shock, rash, and multiorgan failure. Diagnosing M. meningitis involves routine tests and definitive diagnosis relies on isolating the bacteria. Treatment includes prompt antibiotics and supportive treatment. M. meningitis, a deadly infection when complicated by WFS, demands urgent action. This case underscores the critical need for improved diagnostics, treatment protocols, and healthcare infrastructure in resource-limited settings to prevent fatalities and serves as a benchmark for addressing these challenges.

To develop the first public-facing dashboard that translates genomic sequencing data from wastewater into accessible and actionable community information concerning human pathogenic viruses, representing a shift to sequencing-based public health wastewater monitoring. We developed SeqBoard, a user-friendly dashboard that displays sequencing information from the total wastewater virome. The dashboard integrates diverse expertise and components, including data processing and analysis, visualization and management, security, and stakeholder engagement and feedback. We implemented a 3-tiered system for user interactions, customized to the general public, public health officials, and genomics experts. SeqBoard provides an intuitive interface for presenting genomic information as species-specific trend lines, level indicators, and all-site aggregates. It translates complex sequencing data into public health insights, including reporting on dozens of viruses of concern with modules for detections, variant information, and genomic context. The prevention of the next pandemic will require comprehensive pan-monitoring of deadly viruses and their evolution. Genomics-based dashboards will be essential for early detection of viral activity before significant clinical manifestation, thereby allowing public health systems to provide warnings, ready actions, and develop vaccines. SeqBoard shows that sequencing data can be translated into useful public health information, serving as a model for future sequencing-based pathogen dashboards. The dashboard is publicly available at https://tephi-ww.uth.edu/public-dashboard and represents the first publicly available dashboard providing pan viral genomic detection data for wastewater monitoring.

Necrotizing enterocolitis (NEC) is the most deadly gastrointestinal disease in preterm neonates, with up to 50% mortality. There is no cure for NEC. Enhancing our understanding of intestinal epithelial cell (IEC) responses to NEC will provide novel therapeutic targets. The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) plays roles in intestinal development and repair. Notably, roles for IMP1 in NEC are unknown. Intestinal goblet cells produce protective mucus, and their function depends on the transcription factor Spdef. Evidence suggests that goblet cell mucus glycosylation affects barrier function and inflammation. We aimed to define the role of IMP1 in NEC damage response using neonatal human enteroids and a NEC-like intestinal injury model. At post-natal day 3, wild-type mice or littermates with IEC-specific Imp1 overexpression (Imp1IEC-OE) or loss (Imp1∆IEC) were assigned to control or NEC groups. NEC was induced with stress, formula feeding, bacterial exposure, and hypoxia. Imp1 effects on NEC response were assessed using RNA sequencing, western blotting, immunostaining, and a cytokine array. We found that pro-inflammatory bacteria induced IMP1 expression in neonatal human enteroids. During NEC, Imp1IEC-OE mice exhibit more severe intestinal damage and priming for lytic cell death. Elevated Imp1 levels were linked to a Spdef transcriptional signature and in silico analysis predicted Imp1 binding to Spdef and mucus glycosylation mediator mRNAs. Functionally, Imp1 increased fucosylation in the intestinal epithelium. Collectively, results suggest that Imp1 primes the intestine for lytic death and promotes the production of fucosylated mucus, changes which could alter the damage response.

Anorexia nervosa (AN) is a deadly psychiatric disorder with relapse rates approaching 50% after weight restoration. Disrupted gastrointestinal interoception may underlie persistent symptoms and relapse vulnerability. To examine behavioral, computational, neural, and physiological markers of gastrointestinal interoception in weight-restored individuals with AN and test their association with relapse. This crossover trial was a single-blind, within-participant, randomized (block-order) trial conducted at the Laureate Institute for Brain Research between August 2021 and February 2025. Participants were females with weight-restored restrictive AN and age- and sex-matched healthy comparators (HCs). All participants ingested a vibrating capsule that delivered counterbalanced blocks of normal- and enhanced-intensity gut stimulation. Behavioral detection performance, electroencephalography, peripheral physiology, and computational modeling were used to assess interoception. Experimental-session measures included interoceptive accuracy, prior beliefs, interoceptive precision, learning rates, gastric-evoked potentials (GEPs), and hunger. Main clinical outcomes at 6 months included relapse status and symptom severity. The cohort included 62 female participants with weight-restored restrictive AN (mean [SD] age, 18.9 [4.5] years) and 57 age- and sex-matched healthy comparators (HCs; mean [SD] age, 20.7 [5.3] years). Six-month follow-up data were collected for 54 participants with AN. Compared with HCs, participants with AN showed lower perceptual accuracy (Cohen d&#x2009;=&#x2009;-0.98; 95% CI, -1.51 to -0.44; P&#x2009;=&#x2009;.001) and higher miss rates (Cohen d&#x2009;=&#x2009;1.02; 95% CI, 0.55 to 1.48; P&#x2009;<&#x2009;.001). Computational modeling revealed in the AN group stronger prior expectations that capsule vibrations would not be present (Cohen d&#x2009;=&#x2009;-0.31; 95% CI, -0.67 to 0.05; P&#x2009;=&#x2009;.05), greater shifts in interoceptive precision between blocks (Cohen d&#x2009;=&#x2009;0.38; 95% CI, 0.02 to 0.75; P&#x2009;=&#x2009;.01), and learning asymmetries (vibration: Cohen d&#x2009;=&#x2009;-0.40; 95% CI, -0.77 to -0.04; P&#x2009;=&#x2009;.007; no-vibration: Cohen d&#x2009;=&#x2009;0.35; 95% CI, -0.02 to 0.71; P&#x2009;=&#x2009;.01). GEP amplitudes did not differ by group but were correlated with accuracy and learning in AN. Capsule stimulation induced greater hunger increases in AN (interaction: &#x3b7;2p&#x2009;=&#x2009;0.04, P&#x2009;=&#x2009;.04; AN: Cohen d&#x2009;=&#x2009;0.94; 95% CI, 0.57 to 1.30; HCs: Cohen d&#x2009;=&#x2009;0.40; 95% CI, 0.03 to 0.77). At follow-up, relapse was predicted by initial priors (odds ratio [OR], 3.82; 95% CI, 1.02 to 15.91; P&#x2009;=&#x2009;.05), response bias (OR, 5.37; 95% CI, 1.15 to 32.04; P&#x2009;=&#x2009;.04), and stomach unpleasantness (OR, 5.73; 95% CI, 1.38 to 33.5; P&#x2009;=&#x2009;.03), while eating disorder symptom severity was predicted by miss rate (&#x3b2;&#x2009;=&#x2009;1.05; R2&#x2009;=&#x2009;0.08; P&#x2009;=&#x2009;.05), difference in interoceptive precision (&#x3b2;&#x2009;=&#x2009;5.84; R2&#x2009;=&#x2009;0.16; P&#x2009;=&#x2009;.004), and initial priors (&#x3b2;&#x2009;=&#x2009;-2.99; R2&#x2009;=&#x2009;0.09; P&#x2009;=&#x2009;.05). In this study of weight-restored females with AN, gastrointestinal interoception was disrupted across multiple domains, including reduced accuracy detecting gut signals, maladaptive priors, rigid learning, and abnormal hunger rating. Several interoceptive markers predicted relapse and symptom severity at follow-up. These findings support the use of ingestible mechanosensory probes and computational modeling as scalable tools to monitor treatment response and guide relapse prevention in eating disorders. ClinicalTrials.gov Identifier: NCT05111977.

Reye's syndrome, an uncommon and potentially deadly childhood disease, is characterized by sudden noninflammatory brain dysfunction combined with hepatic dysfunction caused by the accumulation of fat. It was initially identified by Australian pathologist R.D.K. Reye in 1963. National monitoring of Reye's syndrome commenced in the United States in the early 1970s, resulting in strict cautions about the use of aspirin in children. MicroRNA (miRNA), small (~&#x2009;22 nt) non-coding RNA that regulate gene expression by reducing mRNA levels, plays a critical role in the onset and advancement of Reye's syndrome. It can affect numerous target proteins, significantly contributing to the substantial abnormalities in the syndrome's cause and development. The review thoroughly explores the influence of miRNAs on liver enzyme metabolism, emphasizing their involvement in the disruption of these enzymes and in cerebral edema as well as hepatomegaly where they contribute to the occurrence of Reye's syndrome. A comprehensive understanding of the role of miRNAs in hepatic metabolism and cerebral edema is essential for developing effective treatments aimed at diseases resulting from disrupted mitochondrial and enzymatic metabolism.

A large number of deadly heat waves have been observed over the last few decades. They have important consequences on public health. To protect populations, a variety of heat-health warning systems (HHWS) has been developed. Conventional HHWS are based on a single threshold. Tiered HHWS was established on the basis of more than one threshold for a given indicator. Despite their usefulness, there are limited studies regarding the development and application of tiered HHWS.&#xa0;The objective of this study is to conduct a scoping review regarding tiered HHWSs. A scoping review of existing literature was performed based on best practices. Studies from all countries, in French or English languages published after 2000 have been considered.&#xa0;Ten studies covering seventeen tiered systems in different regions around the world have been included. Among them, only three studies are peer reviewed. In addition, significant variation is found in the determination of alert thresholds with no universal tiered system.&#xa0;This scoping review can be seen as a starting point towards encouraging the development of tiered HHWSs in regions without such systems or to improve existing ones. To standardize tiered system methodologies, a common approach is required that integrates the advantages and relevant variables of these systems.

Mesenteric ischemia is a potentially deadly condition that occurs due to the lack of blood supply to the intestine. There is also emerging evidence that the mesenteric circulation may result in vascular dysfunction and ischemic damage caused by environmental contaminants especially heavy metals such as lead and mercury. Persistent exposure leads to endothelial dysfunction through the generation of oxidative stress, nitric oxide depletion, mitochondrial dysfunction and inflammatory signaling pathways. This hypothesis-generating narrative review integrates toxicological and vascular evidence to propose that chronic low-level exposure to these metals could represent an underrecognized etiological factor in mesenteric ischemia. The main molecular mechanisms, including oxidative stress, endothelial dysfunction, mitochondrial dysfunction, and vascular remodeling, are discussed, and the potential synergistic toxicity of the combined exposure to metals is considered. Additionally, several crucial diagnostic biomarkers are mentioned, such as intestinal fatty acid-binding protein (I-FABP), alpha-glutathione S-transferase (&#x3b1;-GST), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and malondialdehyde (MDA). A knowledge of the connection between mesenteric vascular injury and exposure to heavy metals may aid in the development of improved methods of diagnosis and treatment.

Lung cancer remains one of the most prevalent and deadly malignant neoplasms worldwide, with smoking being a primary risk factor. Among the numerous carcinogens in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent. The carcinogenic effects of NNK are believed to be mediated through its metabolic activation by CYP2A13 in the lungs, leading to DNA adduct formation and subsequently lung cancer development. However, whether NNK exerts its carcinogenic effects by upregulating CYP2A13 expression and the mechanisms by which NNK upregulates CYP2A13 remain unclear. In this study, we demonstrated that CYP2A13 was overexpressed in human lung adenocarcinoma and NNK exposure significantly upregulated the expression of CYP2A13 in bronchial epithelial cells. Mechanistically, NNK exposure enhanced both transcription and stabilization of CYP2A13 mRNA. Further exploration showed that elevated transcription of CYP2A13 was mediated by the activation of the p-PP2A-C/p-JNK/p-c-Jun signaling axis, while CYP2A13 mRNA stability was driven through the S6/TRIM25/Dicer/miR-7108-3p axis. These findings not only provide critical insights into the mechanisms underlying NNK-induced lung carcinogenesis, but also identify potential therapeutic targets, including PP2A, TRIM25, and miR-7108-3p, for further exploration.

Andes orthohantavirus (ANDV) is a deadly pathogen that causes hantavirus cardiopulmonary syndrome (HCPS), which is a severe disease characterized by respiratory failure and high mortality rates (~30-40%). While previous studies have shown that neutralizing antibodies have a critical role in survival, the contribution of the Fc-mediated effector functions remains unexplored. We performed a serological profiling of acute HCPS patients and survivors, analyzing antibody types, subtypes, and neutralization capacity targeting ANDV glycoproteins (Gn and GnGc). Fc-mediated effector functions, which are key to defining antibody-mediated correlates of protection, were analyzed using Fc&#x3b3;R reporter signaling assays, antibody-dependent NK cell activation, and antibody-dependent complement deposition (ADCD). Acute HCPS patients who developed moderate disease exhibited significantly higher IgG levels against the Gn glycoprotein and stronger Fc-mediated effector functions, including antibody-dependent NK cell activation and ADCD against glycoproteins, compared to the more severe cases. Surviving acute patients showed elevated IgG and IgM responses against Gn. In survivors, polyfunctional non-neutralizing IgG activities persisted for years after infection and were more pronounced against the GnGc complex than Gn alone. In summary, our study reveals the existence of functional diversity in the humoral immune response to ANDV glycoprotein during HCPS, which can be associated with protective responses and may contribute to a long-lasting immune response to restrict ANDV infection. These findings identify Fc effector functions as important correlates of protection and provide valuable insights for the design of next-generation vaccines and therapeutics against hantaviruses.

Ovarian cancer (OC) is the deadliest gynecological disease in women, with high-grade serous ovarian cancer (HGSC) being its most common and lethal subtype. This disease accounts for 75% of OC cases and has a five-year survival rate of only 32%, mainly due to diagnoses at an advanced stage. Inheriting a pathogenic BRCA1 or 2 mutation significantly increases the risk of developing HGSC. However, the early molecular processes that lead to this deadly subtype remain poorly understood. The ovarian hormone progesterone (P4) has been shown to induce metastatic HGSC in Dicer1-Pten double-knockout (DKO) mice, an animal model that develops this specific type of OC with molecular, histological, and clinical features similar to those of BRCA1/2 mutation carriers. To explore P4-induced metabolic changes before and after the onset of HGSC, we analyzed serum samples from DKO mice treated with P4 or mifepristone, an inhibitor of P4 signaling, at premalignant and early tumor stages. These samples underwent both targeted and non-targeted metabolomic analysis using ultra-high performance liquid chromatography-mass spectrometry. The non-targeted data revealed significant trends among various phospholipid classes, phosphatidylcholines, sphingomyelins, and triacylglycerols, in early-stage HGSC. Additionally, two metabolites previously linked to OC, lysophosphatidylethanolamine (18:1) and tetrahydrocortisone, were significantly elevated at the premalignant stage of HGSC development. Conversely, at this same stage, the targeted dataset showed notable increases in estrogens and glucocorticoids, while higher corticosterone levels were detected as HGSC began to develop. Overall, this study highlights the disruption of specific metabolites, phospholipid classes, and steroid hormones, in relation to HGSC tumor development under P4 treatment, suggesting their potential roles in OC development.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a dismal 5-year survival rate at 12%. The fibrotic PDAC desmoplasia is a major contributor to chemoresistance and metastasis that drive this poor prognosis. Cancer-associated fibroblasts (CAFs) generate PDAC tumour fibrosis and have been identified as therapeutic targets to remodel the stroma to a more drug-permissive microenvironment. We assessed the therapeutic potential of inhibiting the collagen chaperone, heat shock protein 47 (HSP47) in PDAC cells and CAFs. Collagen is a key component of PDAC fibrosis and requires the activity of HSP47 to ensure correct maturation and secretion. Herein, we show that HSP47 knockdown inhibits both PDAC cells and CAF proliferation in vitro. In vivo, therapeutic HSP47 knockdown in orthotopic PDAC tumours significantly reduced intratumoural fibrosis and opened intratumoural blood vessels, while stable HSP47 knockdown specifically in CAFs additionally reduced PDAC tumour growth. We observed that HSP47 is highly expressed in the stroma of >80% of patients in a PDAC cohort (Australian Pancreatic Cancer Genome Initiative), but that it was only prognostic of poorer overall survival in the tumour compartment. Functional relevance in the tumour compartment was further validated in 3D human PDAC explants. Our work demonstrates that HSP47 is a potential therapeutic target in both PDAC cells and CAFs and represents a robust target to interfere with tumour collagen deposition.