Disease Poor Prognosis Research Articles

Trends and Disparities in Coronary Artery Disease and Obesity-Related Mortality in the United States From 1999-2022.

Almost half of the US adult population has obesity, which predisposes to atherosclerosis and can lead to poor prognosis in coronary artery disease (CAD). We aim to identify CAD and obesity-related mortality trends among adults in the United States stratified by age, sex, race and geographical location. The CDC-WONDER database was used to extract death certificate data for adults aged ≥ 25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were described by calculating annual percent change (APC) and the average APC (AAPC) in the rates using Joinpoint regression analysis. From 1999 to 2022, a total of 273,761 CAD and obesity-related deaths were recorded in the United States. The AAMR increased consistently from 1999 to 2018 (APC: 4.3, 95% confidence interval (CI): 3.4-4.9) and surged thereafter till 2022 (APC: 11.4; 95% CI: 7.7-19.1). During the COVID-19 pandemic (2020-2022), AAMR almost doubled that of the rest of the study period. Additionally, the AAMR for males was nearly twice that of females. Non-Hispanic (NH) Blacks or African Americans displayed the highest AAMR, followed by NH Whites, Hispanic or Latino, and other NH populations. AAMRs showed minimal variation by census regions. Rural areas exhibited a higher AAMR (AAMR: 5.9, 95% CI: 5.8-5.9) than urban areas (AAMR: 4.4, 95% CI: 4.4-4.5). We observed increasing trends in CAD and obesity-related deaths throughout the study period reaching a peak during the COVID-19 pandemic.

Decolonization strategies for ESBL-producing or carbapenem-resistant Enterobacterales carriage: a systematic review and meta-analysis

The prevalence of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) and carbapenem-resistant Enterobacterales (CRE) has become a global public health problem. ESBL-E/CRE colonization can increase the risk of infection in patients and lead to poor disease prognosis. We conducted a systematic review and meta-analysis to evaluate current decolonization strategies regarding ESBL-E/CRE and their efficacy. A literature search was conducted until August 2023 on the five databases to review decolonization strategies associated with ESBL-E/CRE. A meta-analysis was conducted using RevMan 5.4 to compare differences in the decolonization strategy with placebo controls. The primary outcome was decolonization rates, with secondary outcomes of attributable death and adverse events. Quality of identified studies was determined using the Newcastle–Ottawa scale and cochrane risk assessment tool. Random and fixed effects meta-analyses were performed to calculate pooled value. A total of 25 studies were included. In five randomized controlled trial (RCT) studies, the decolonization effect of selective digestive decontamination(SDD) on ESBL-E/CRE at the end of treatment was significantly better in the experimental group than the controls [risk radio (RR): 3.30; 95% CI 1.78–6.14]. In three n-RCT studies, the decolonization effect in the experimental group was still better than the controls one month after SDD therapy [odds ratio (OR): 4.01; 95% CI 1.88–8.56]. The combined decolonization rates reported by six single-arm trial studies of SDD therapy ranged from 53.8 to 68.0%. Additionally, TSA analysis confirmed the effectiveness of SDD therapy. In studies on Faecal microbiota transplantation (FMT) therapy, the decolonization effect of the experimental group was significantly better than the controls 1 month after treatment (OR: 2.57; 95% CI 1.07–6.16). In studies without a control group and with varying follow-up times, the decolonization rates varied widely but indicated the effectiveness trend of FMT therapy (61.3–81.2%). Currently, research on the decolonization effect of probiotic therapy on ESBL-E/CRE is insufficient, and only a systematic review was conducted. SDD and FMT strategies have short-term benefits for ESBL-E/CRE decolonization, but long-term effects are unclear. The effect of probiotic therapy on ESBL-E/CRE decolonization is an interesting topic that still requires further investigation.

MYC-dependent upregulation of the de novo serine and glycine synthesis pathway is a targetable metabolic vulnerability in group 3 medulloblastoma.

Group 3 medulloblastoma (MBGRP3) represents around 25% of medulloblastomas and is strongly associated with c-MYC (MYC) amplification, which confers significantly worse patient survival. Although elevated MYC expression is a significant molecular feature in MBGRP3, direct targeting of MYC remains elusive, and alternative strategies are needed. The metabolic landscape of MYC-driven MBGRP3 is largely unexplored and may offer novel opportunities for therapies. To study MYC-induced metabolic alterations in MBGRP3, we depleted MYC in isogenic cell-based model systems, followed by 1H high-resolution magic-angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics, to assess changes in intracellular metabolites and pathway dynamics. Steady-state metabolic profiling revealed consistent MYC-dependent alterations in metabolites involved in one-carbon metabolism such as glycine. 13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC knockdown, which coincided with lower expression and activity of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in this pathway. Furthermore, MYC-overexpressing MBGRP3 cells were more vulnerable to pharmacological inhibition of PHGDH compared to those with low expression. Using in vivo tumor-bearing genetically engineered and xenograft mouse models, pharmacological inhibition of PHGDH increased survival, implicating the de novo serine/glycine synthesis pathway as a pro-survival mechanism sustaining tumor progression. Critically, in primary human medulloblastomas, increased PHGDH expression correlated strongly with both MYC amplification and poorer clinical outcomes. Our findings support a MYC-induced dependency on the serine/glycine pathway in MBGRP3 that represents a novel therapeutic treatment strategy for this poor prognosis disease group.

Flow Cytometry Analysis of CD4⁺ and CD8⁺ T Lymphocytes in COVID- 19 Patients

The clinical presentation of COVID-19 varies greatly from case to another, with host characteristics playing a pivotal role. The immune system is a pivotal function in establishing the course of SARS-COV-2 infection. Severe instances of COVID-19 and the resulting death are caused less by the virus itself than by the destructive unrestrained immune response. Among the host determinants for poor disease prognosis is probably genetic vulnerability to dysregulated immune response. The objective of this work is to examine some of the host genetic variables that are being studied in relation to the severity of COVID-19. The complex relationship between autoimmunity and the pathophysiology of COVID-19 was examined. Patients with COVID-19 were recruited from AL-Dewaniyah Teaching Hospital and AL-Hussain Teaching Hospital in Karbala city. All patients had been diagnosed with the virus using real-time polymerase chain reaction. A total of 70 blood samples (35 from the mild group, 35 from the severe group, and 35 from the controlled group) were obtained in EDTA tubes. Orderly to investigate the correlation between the progression of disease and variations in specific regions of host immunoassays had been used by flow cytometry. The results of the flow cytometry were reported as the average percentage of positive cells for CD4 and CD8 immunological markers. Cases with COVID-19 had a substantially lower mean CD4 concentration than the healthy patients. Furthermore, the mean concentration of CD8 was significantly lower in cases with COVID-19 than in healthy. In addition, there is significant (P 0.001) decline in both CD4 and CD8 mean levels between patients with severe and mild COVID-19.

Transfer learning approach in pre-treatment CT images to predict therapeutic response in advanced malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a poor-prognosis disease. Owing to the recent availability of new therapeutic options, there is a need to better assess prognosis. The initial clinical response could represent a useful parameter. We proposed a transfer learning approach to predict an initial treatment response starting from baseline CT scans of patients with advanced/unresectable MPM undergoing first-line systemic therapy. The therapeutic response has been assessed according to the mRECIST criteria by CT scan at baseline and after two to three treatment cycles. We used three slices of baseline CT scan as input to the pre-trained convolutional neural network as a radiomic feature extractor. We identified a feature subset through a double feature selection procedure to train a binary SVM classifier to discriminate responders (partial response) from non-responders (stable or disease progression). The performance of the prediction classifiers was evaluated with an 80:20 hold-out validation scheme. We have evaluated how the developed model was robust to variations in the slices selected by the radiologist. In our dataset, 25 patients showed an initial partial response, whereas 13 patients showed progressive or stable disease. On the independent test, the proposed model achieved a median AUC and accuracy of 86.67% and 87.50%, respectively. The proposed model has shown high performance even by varying the reference slices. Novel tools could help to improve the prognostic assessment of patients with MPM and to better identify subgroups of patients with different therapeutic responsiveness.

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer.

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

Significance of changes in cavity after treatment in Mycobacterium avium complex pulmonary disease

Cavities are characteristic radiological features related to increased mycobacterial burden and poor prognosis in Mycobacterium avium complex pulmonary disease (MAC-PD). However, cavity changes following treatment and their clinical implications remain unknown. We aimed to elucidate whether cavity obliteration or reduction in cavity size or wall thickness correlates with microbiological cure. In total, 136 adult patients with cavitary MAC-PD treated for ≥ 6 months between January 1st, 2009, and December 31st, 2021, in a tertiary referral centre in South Korea were enrolled. The cavity with the largest diameter at treatment initiation was tracked for size and thickness changes. Following median treatment of 20.0 months, 74 (54.4%) patients achieved microbiological cure. Cavity obliteration, achieved in 58 (42.6%) patients at treatment completion, was independently associated with microbiological cure. In patients with persistent cavities, size reduction of ≥ 10% was significantly associated with microbiological cure, whereas thickness reduction was not. Five-year mortality rates in patients with cavity obliteration, persistent but reduced cavity, and persistent cavity without shrinkage were 95.6%, 72.1%, and 65.3%, respectively (P < 0.001). In conclusion, cavity obliteration or shrinkage at treatment completion is associated with microbiological cure and reduced mortality in MAC-PD, suggesting that cavity changes could serve as a proxy indicator for treatment response.

PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages derived from peritoneal fluid macrophages and had a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. Furthermore, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in HGSC patients. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC.

Clinical Course, Therapy, and Long-Term Outcomes of Children With Moyamoya Disease and Posterior Cerebral Artery Involvement.

Posterior cerebral artery involvement (PCAi) has been identified as an important factor related to poor prognosis in moyamoya disease (MMD). This study summarized the characteristics of children with MMD and PCAi, clarified the clinical course, identified prognostic predictors, and investigated the long-term effect of encephaloduroarteriosynangiosis for posterior circulation (EDAS-p). We retrospectively reviewed all our pediatric MMD cases with follow-up angiograms from November 2003 to December 2016. PCAi was classified as early-onset at initial diagnosis and delayed-onset after anterior circulation revascularization. Multivariable data including clinical features, radiographic findings, and surgical outcomes were analyzed. Among 570 children with MMD, 246 (43.2%) had PCAi, with 176 (30.9%) classified as early-onset PCAi. During a median follow-up period of 10 years, 17.8% (70/394) of patients without initial PCAi developed delayed-onset PCAi. The median time to detection of a new PCA lesion was 15.5 (range 7-110) months from initial diagnosis, with a median age of 10.5 (3-22). Younger age at onset, familial occurrence, advanced Suzuki stages, and preoperative infarctions were predictors of delayed-onset PCAi. EDAS-p was performed on 294 hemispheres of 195 patients with PCAi. Stroke-free survival was significantly higher in the EDAS-p group than in the non-EDAS-p group (99.0% vs 90.2%; p < 0.001 [Breslow test]; p = 0.001 [log-rank test]; median follow-up: 101 months). PCAi is not uncommon in children with MMD, underscoring the need for long-term close clinical monitoring, especially in patients with high-risk factors for PCA progression. EDAS-p may be a safe and effective procedure for preventing subsequent stroke in children with MMD and PCAi.

Recommendations and quality criteria to improve the early diagnosis of primary biliary cholangitis

ObjectiveThe study aimed to establish recommendations and quality criteria to enhance the healthcare process of PBC. Patients and methodsIt was conducted using qualitative techniques, preceded by a literature review. A consensus conference involving five specialists in the field was held, followed by a Delphi process developed in two waves, in which 30 specialist physicians in family and community medicine, digestive system and internal medicine were invited to participate. ResultsSeven recommendations and 15 sets of quality criteria, indicators and standards were obtained. Those with the highest consensus were «Know the impact on the patient’s quality of life. Consider their point of view and agree on recommendations and care» and «Evaluate possible fibrosis at the time of diagnosis and during PBC follow-up, assessing the evolution of factors associated with poor disease prognosis: noninvasive fibrosis (elastography > 2.1 kPa/year), GGT, ALP and bilirubin annually», respectively. ConclusionsThe implementation of the consensus recommendations and criteria would provide better patient care. The need for multidisciplinary follow-up and an increased role of primary care is emphasized.

Single-cell transcriptome analysis deciphers the CD74-mediated immune evasion and tumour growth in lung squamous cell carcinoma with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune-inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single-cell level. We performed single-cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co-culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single-cell analyses. LSCC with COPD showed increased proportions of tumour-associated macrophages (TAMs) and higher levels of CD8+ T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74+ tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-programmed cell death-1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion. Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy. Our results demonstrated higher proportions of tumour-associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8+ T cells in the microenvironment of LSCC with COPD. CD74+tumour cells were associated with poor disease prognosis. Migration inhibitory factor (MIF)-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-PD-L1 signalling pathway, facilitating immune evasion.

A Cost-Effectiveness Analysis of Adjuvant Nivolumab for Patients with Resected Esophageal Cancer or Gastroesophageal Junction Cancer in France.

Esophageal and gastroesophageal junction cancer (EC/GEJC) is a poor prognosis disease with a high risk of recurrence even in patients curatively resected. Adjuvant nivolumab is currently used for patients with completely resected (R0) EC/GEJC who have residual pathologic disease following prior neoadjuvant chemoradiotherapy. This study aimed to determine the cost effectiveness of nivolumab in this indication in France according to the collective perspective excluding indirect costs. A simplified four-health-state semi-Markov model was developed to model EC/GEJC patients who have residual disease after neoadjuvant chemoradiotherapy followed by R0 over a 15-year time horizon, comparing adjuvant nivolumab versus surveillance, which was the recommended French clinical practice before immunotherapy arrival. Time-to-recurrence (TTR) from CheckMate 577 was used to inform transition from disease-free to post-recurrence health state; patients who recurred were split according to the distribution of type of recurrence observed during the trial. Post-recurrence survival (PRS) according to the type of recurrence was derived from a real-world registry. Adjuvant treatment with nivolumab led to an incremental survival gain of 1.19 years (+34%), mostly in the disease-free state, an incremental cost of €48,634 and QALY of 0.98 resulting in an incremental cost-utility ratio (ICUR) of €49,572/QALY with limited uncertainty. 'Cure assumption' at 5years had an important impact on the results (€41,115/QALY; -17%), as that tends to increase life-years and QALYs while costs remain the same. Probabilistic sensitivity analyses confirmed reference ICUR (€52,542/QALY) with 80% probability of nivolumab being cost effective at a willingness-to-pay threshold of €75,000/QALY. Our analysis suggests that adjuvant nivolumab is cost effective in the treatment of EC/GEJC patients who have residual disease after neoadjuvant CRT followed by R0 resection. Compared with previously evaluated cost-effectiveness analyses for other immune-checkpoint inhibitors indicated in metastatic settings, ICUR appears particularly low in this early setting thanks to the important impact on health outcomes and capped treatment duration.

Early-onset pancreatic cancer and associated metabolic risk factors in the Middle East and North Africa: A 20-year analysis of the Global Burden of Disease Study.

Early-onset pancreatic cancer (EOPC) is associated with poor prognosis and high disease burden. Metabolic risk factors such as diabetes and obesity are considered risk factors of EOPC. Recently, there has been an increasing number of EOPCs worldwide. However, the analysis of EOPC, including its metabolic risk factors, in the Middle East and North Africa (MENA) region has not been fully addressed. Data from the Global Burden of Disease Study between 2000 and 2019 was used to analyze the prevalence, incidence, deaths and disability-adjusted life years (DALYs) associated with EOPC and its metabolic risk factors. The analysis further categorized the data based on countries, income status and sex and examined the annual percentage change (APC). Approximately 2800 cases, 2400 deaths and 114,000 DALYs were attributable to EOPC in the MENA region. The incidence (APC + 3.42%), death (APC + 0.73%) and DALYs (APC + 3.23%) rates of EOPC increased. In addition, the death and DALY rates of EOPC attributable to obesity and diabetes increased. High and upper-middle-income countries exhibited a higher burden of EOPC than lower-income countries. Over the past two decades, the burden of EOPC and its associated metabolic risk factors has increased. There is an urgent need for region-wide policy development, including screening methods and risk factor reduction, to mitigate the high and rising burden of EOPC in the MENA region.

CDK1 Acts as a Prognostic Biomarker Associated with Immune Infiltration in Pan-Cancer, Especially in Gastrointestinal Tumors.

Cyclin-dependent kinase 1 (CDK1) regulates the cell cycle and is highly expressed in most tumors. CDK1 expression has been associated with poor disease prognosis. This study aimed to identify the prognostic value of CDK1 in pan-cancer and investigate the association between CDK1 expression and immune cell infiltration. CDK1 expression and its correlation with prognosis in pan-cancer were analyzed using online databases. Immune infiltration was assessed by ESTIMATE and CIBERSORT algorithms. We then evaluated the relationship between CDK1 expression and tumor mutational burden (TMB), microsatellite instability (MSI), or tumor-infiltrating immune cells. In addition, we performed the co-expression analysis of immune-related genes and GO analysis with CDK1 expression in pan-cancer. Finally, we compared the CDK1 expression profile with the immune-related genes in 30 pairs of clinical gastrointestinal tumor samples. Our analysis demonstrated overexpression of CDK1 in most tumor tissues, especially in gastrointestinal tumors. The high expression of CDK1 was associated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), and sarcoma (SARC). Besides, CDK1 expression was significantly associated with TMB in 22 cancer types and MSI in 8 cancer types as well as greater frequencies of MSI-high (MSI-H) status and high tumor mutational burden (TMB-H) in uterine corpus endometrial carcinoma (UCEC), stomach adenocarcinoma (STAD), sarcoma (SARC), rectum adenocarcinoma (READ), mesothelioma (MESO), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD). In addition, CDK1 expression correlated with immune cell infiltrating levels, such as M0, M1, or M2 macrophages, memory CD4 T cells, T follicular helper cells, and naive B cells. Our data showed that CDK1 was remarkably correlated with 47 immune-related and immune checkpoint genes in many cancer types. Furthermore, CDK1 was up-regulated in gastrointestinal tumor samples, especially in gastric cancer and intestinal cancer. CDK1 was positively correlated with IDO1 in gastric cancer and PD-1 in intestinal cancer. Taken together, our data demonstrated the roles of CDK1 in oncogenesis and metastasis in pan-cancer. Thus, CDK1 is a potential prognostic biomarker and a target for tumor immunotherapy.

Stress-Induced Hypercoagulability: Insights from Epidemiological and Mechanistic Studies, and Clinical Integration.

By integrating findings from comprehensive reviews, meta-analyses, and cutting-edge genetic studies, this article illuminates the significance of stress-induced hypercoagulability in clinical medicine. In particular, the findings from numerous prospective cohort studies indicate that stress and hemostatic factors of a hypercoagulable state are associated with increased incident risk and poor prognosis for atherosclerotic cardiovascular disease and venous thromboembolism. Mendelian randomization studies suggest that these associations are partially causal. The review synthesizes extensive research on the link between acute and chronic stress and hypercoagulability, outlining a potential pathway from stress to thrombosis risk. Consistent with the allostatic load concept, acute stress-induced hypercoagulability, initially adaptive, can turn maladaptive under chronic stress or excessive acute stress, leading to arterial or venous thrombotic events. Individuals with predisposing factors, including atherosclerosis, thrombophilia, or immobilization, may exhibit an increased risk of thrombotic disease during stress. Contextual sociodemographic characteristics, the stress experience, and coping resources additionally modulate the extent of stress-induced hypercoagulability. Research into the neuroendocrine, cellular, and molecular bases reveals how stress influences platelet activation coagulation and fibrinolysis. The activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, along with vagal withdrawal, and the effects of catecholamines, cortisol, and vasopressin, are the central mechanisms involved. Hemoconcentration, inflammation, endothelial dysfunction, and thrombopoiesis additionally contribute to stress-induced hypercoagulability. Further research is needed to prove a causal link between chronic stress and hypercoagulability. This includes exploring its implications for the prevention and management of thrombotic diseases in stressed individuals, with a focus on developing effective psychosocial and pharmacological interventions.

Clinical Characteristics and Prognosis of Older Patients with Coronavirus Disease 2019 Requiring Mechanical Ventilation.

An older age is associated with severe progression and poor prognosis in coronavirus disease 2019 (COVID-19), and mechanical ventilation is often required. The specific characteristics of older patients undergoing mechanical ventilation and their prognostic factors are largely unknown. We aimed to identify potential prognostic factors in this group to inform treatment decisions. This retrospective cohort study collected data from patients with COVID-19 at 22 medical centers. Univariate and multivariate Cox regression analyses were performed to assess factors that influence mortality. We allocated 434 patients in geriatric (≥80 years) and elderly (65-79 years) groups. The former group scored significantly higher than the elderly group in the clinical frailty scale and sequential organ failure assessment, indicating more severe organ dysfunction. Significantly lower administration rates of tocilizumab and extracorporeal membrane oxygenation and higher intensive care unit (ICU) and in-hospital mortality were noted in the geriatric group. The factors associated with ICU and in-hospital mortality included high creatinine levels, the use of continuous renal replacement therapy, prone positioning, and the administration of life-sustaining treatments. These results highlight significant age-related differences in the management and prognosis of critically ill older patients with COVID-19. Increased mortality rates and organ dysfunction in geriatric patients undergoing mechanical ventilation necessitate age-appropriate treatment strategies to improve their prognoses.

MDB-74. SERINE/GLYCINE METABOLISM REPRESENTS A NOVEL TARGETABLE THERAPEUTIC VULNERABILITY IN MYC-AMPLIFIED MEDULLOBLASTOMA

Abstract BACKGROUND Medulloblastoma is the most frequent malignant brain tumour of childhood. Whilst advances in risk-stratification and upfront multimodal therapy have led to five-year survival rates around 70%, a subset of tumours remain refractory to current therapies. Group 3 medulloblastomas (MBGRP3) are enriched for amplification or overexpression of the proto-oncogene MYC which conveys a dismal prognosis (&amp;lt;10% survival), highlighting the urgent need for novel therapeutic strategies. Recent advances have revealed a role for metabolic reprogramming in MYC-amplified MBGRP3 tumorigenesis, providing novel opportunities for selective therapeutic targeting. METHODS &amp; RESULTS To investigate MYC-dependent metabolic alterations in MBGRP3, we generated three independent isogenic MBGRP3 cell-based models with regulable MYC expression (iMBGRP3-MYC) using a doxycycline-inducible shRNA system. Using 1H high-resolution magic angle spectroscopy and stable isotope-resolved metabolomics, we identified upregulation of the de novo serine/glycine biosynthesis pathway (SGP), attributable to elevated expression of the rate-limiting enzyme PHGDH, as a novel therapeutic target. Genetic and pharmacological (NCT-503) inhibition of PHGDH induced greater cell death in MYC-expressing cells compared to MYC knockdown cells and increased survival across two independent MYC-amplified MBGRP3 mouse models. The decrease in tumour growth observed was moderate; we therefore hypothesised that a compensatory reliance on exogenous serine/glycine may play a role in sustaining tumour progression under therapy. To explore this, we investigated the impact of exogenous serine/glycine starvation on MBGRP3-MYC tumour development. Starvation resulted in a marked MYC-dependent reduction in cell viability in vitro across independent iMBGRP3-MYC models. Notably, dietary serine/glycine starvation was well-tolerated, delayed tumour progression, and increased survival (by 50%) in an MBGRP3-MYC mouse model (p=0.005), highlighting the metabolic plasticity of MYC-amplified tumours to utilise both de novo and exogenous serine/glycine sources to survive and proliferate. CONCLUSIONS These findings identify serine/glycine metabolism as a targetable therapeutic vulnerability within MYC-amplified MBGroup3 and a novel therapeutic strategy to treat this poor-prognosis disease group.

Development of Traceable Mouse Models of Advanced and Metastatic Bladder Cancer.

Bladder cancer (BC) is the fourth most common cancer in men, with a poor patient prognosis for advanced disease. The poor survival of patients with muscle-invasive bladder cancer (MIBC) and metastatic status emphasizes the urgent need to develop new therapies. Lacking in the field of BC is the availability of relevant advanced BC mouse models, especially metastatic ones, that accurately recapitulate the complexities of human pathology to test and study new therapeutic strategies. Addressing this need, we developed a traceable mouse model of BC that expresses tumor-associated antigens within the context of advanced muscle-invasive BC. This novel system was achieved through the deletion of the tp53 and pten genes, alongside the incorporation of the fusion construct of Firefly luciferase (Luc) and the SIYRYYGL (SIY) T-cell antigen. We validate that the presence of the transgene did not impact on the development of the tumors while allowing us to measure tumor progression by bioluminescence. We show that the transgene did not influence the composition of the immune tumor microenvironment. More importantly, we report that this model was unresponsive to anti-PD-1 treatment, as in the majority of patients with BC. We also develop a new model based on the orthotopic injection of BC clonal cell lines derived from our first model. We demonstrate that this new model invades the muscle layer and has a metastasis development rate of 83%. The advantage of this model is that we can visualize tumor growth and metastasis development in vivo. These mouse models' characteristics, displaying many similarities with the human pathology, provide a valuable tool for tracking tumor progression, metastasis spread in vivo, and treatment resistance, as well as exploring fundamental and translational aspects of BC biology. This work contributes to the improvement in the landscape of mouse models of advanced BC for testing new therapeutic strategies.

Combined effects of matrix stiffness and obesity-associated signaling directs progressive phenotype in PANC-1 pancreatic cancer cells in vitro.

Obesity is a leading risk factor of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor disease prognosis and outcomes. Retrospective studies have identified this link, but interactions surrounding obesity and PDAC are still unclear. Research has shifted to contributions of fibrosis (desmoplasia) on malignancy, which involves increased deposition of collagens and other extracellular matrix (ECM) molecules and increased ECM crosslinking, all of which contribute to increased tissue stiffening. However, fibrotic stiffening is underrepresented as a model feature in current PDAC models. Fibrosis is shared between PDAC and obesity, and can be leveraged for in vitro model design, as current animal obesity models of PDAC are limited in their ability to isolate individual components of fibrosis to study cell behavior. In the current study, methacrylated type I collagen (PhotoCol®) was photo-crosslinked to pathological stiffness levels to recapitulate fibrotic ECM stiffening. PANC-1 cells were encapsulated within PhotoCol®, and the tumor-tissue constructs were prepared to represent normal (healthy) (∼600 Pa) and pathological (∼2000 Pa) tissues. Separately, human mesenchymal stem cells were differentiated into adipocytes representing lean (2D differentiation) and obese fat tissue (3D collagen matrix differentiation), and conditioned media was applied to PANC-1 tumor-tissue constructs. Conditioned media from obese adipocytes showed increased vimentin expression, a hallmark of invasiveness and progression, that was not seen after exposure to media from lean adipocytes or control media. Characterization of the obese adipocyte secretome suggested that some PANC-1 differences may arise from increased interleukin-8 and -10 compared to lean adipocytes. Additionally, high matrix stiffness associated induced an amoeboid morphology in PANC-1 cells that was not present at low stiffness. Amoeboid morphology is an accessory to epithelial-to-mesenchymal transition and is used to navigate complex ECM environments. This plasticity has greater implications for treatment efficacy of metastatic cancers. Overall, this work 1) highlights the importance of investigating PDAC-obesity interactions to study the effects on disease progression and persistence, 2) establishes PhotoCol® as a matrix material that can be leveraged to study amoeboid morphology and invasion in PDAC, and 3) emphasizes the importance of integrating both biophysical and biochemical interactions associated within both pathologies for in vitro PDAC models.

Cost-effectiveness of brentuximab vedotin compared with conventional chemotherapy for relapsed or refractory classic Hodgkin lymphoma in China

BackgroundRelapsed or refractory classic Hodgkin lymphoma (RRcHL) associates with poor prognosis and heavy disease burden to patients. This study evaluated the cost-effectiveness of brentuximab vedotin (BV) in comparison to conventional chemotherapy in patients with RRcHL, from a Chinese healthcare perspective.MethodsThe lifetime cost and quality adjusted life years (QALYs) were estimated through a partitioned survival model with three health states (progression free, post progression, and death). Two cohorts for each BV arm and chemotherapy arm were built, representing patients with and without transplant after BV or chemotherapy, respectively. Clinical parameters were retrieved from BV trials and the literature. Resource utilization data were mainly collected from local expert surveys and cost parameters were reflecting local unit prices. Utility values were sourced from the literature. A discount rate of 5% was employed according to the Chinese guideline. A series of deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness and uncertainty associated with the model.ResultsResults of the base case analysis showed that the incremental cost-effectiveness ratio (ICER) for BV versus chemotherapy was $2,867 (¥19,774). The main model driver was the superior progression-free and overall survival benefits of BV. The ICERs were relatively robust in a series of sensitivity analyses, all under a conventional decision threshold (1 time of Chinese per capita GDP). With this conventional threshold, the probability of BV being cost-effective was 100%.ConclusionsBrentuximab vedotin can be considered a cost-effective treatment versus conventional chemotherapy in treating relapsed or refractory classic Hodgkin lymphoma in China.