Shorter Survival Time Research Articles

A Machine Learning Model to Predict Risk for Hepatocellular Carcinoma in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease

BACKGROUND & AIMSHepatocellular carcinoma (HCC) incidence is increasing and correlated with metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD), even in patients without advanced liver fibrosis who are more likely to be diagnosed with advanced disease stages and shorter survival time, and less likely to receive a liver transplant. Machine learning (ML) tools can characterize large datasets and help develop predictive models that can calculate individual HCC risk and guide selective screening and risk mitigation strategies. METHODSTableau and KNIME Analytics were used for descriptive analytics and machine learning tasks. ML models were developed using standard laboratory and clinical parameters. Sci-kit learn algorithms were used for model development. Data from UC Davis was used to develop and train a pilot predictive model, which was subsequently validated in an independent dataset from UC San Francisco (UCSF). MASLD and HCC patients were identified by ICD-9/10 codes. RESULTSOf the patients diagnosed with MASLD (n=1,561 training; n=686 validation), HCC developed in 14% (n=227) of the UC Davis training cohort and 25% (n=176) of the UCSF validation cohort. Liver fibrosis determined by the non-invasive FIB-4 score was the strongest single predictor for HCC in the model. Using the validation cohort, the model predicted HCC development at 92.06% accuracy with an AUC of 0.97, F1-score of 0.84, 98.34% specificity, and 74.41% sensitivity. CONCLUSIONSML models can aid physicians in providing early HCC risk assessment in patients with MASLD. Further validation will translate to cost-effective, personalized care of at-risk patients.

Effect of antibiotic drug use on outcome and therapy-related toxicity in patients with glioblastoma-A retrospective cohort study.

Glioblastoma (GB) is the most frequent malignant brain tumor and has a dismal prognosis. In other cancers, antibiotic use has been associated with severity of chemotherapy-induced toxicity and outcome. We investigated if these mechanisms are also involved in GB. We selected a cohort of 78 GB patients who received combined radiochemotherapy. We investigated if exposure to prediagnostic antibiotic use is associated with clinical side effects and laboratory changes during adjuvant therapy as well as overall survival (OS) and progression-free survival (PFS) using chi-square test, binary logistic regression, Kaplan-Meyer analysis, and multivariable Cox regression. Seventeen patients (21.8%) received at least one course of prediagnostic antibiotics and 61 (78.2%) received no antibiotics. We found a higher incidence of loss of appetite (23.5% vs. 4.9%; P = .018) and myelosuppression (41.2% vs. 18.0%; P = .045) in the antibiotic group. Multivariable logistic regression analysis revealed antibiotics to be a predictor for nausea (OR = 6.94, 95% CI: 1.09-44.30; P = .041) and myelosuppression (OR = 9.75, 95% CI: 1.55-61.18; P = .015). Furthermore, lymphocytopenia was more frequent in the antibiotic group (90.0% vs. 56.1%, P = .033). There were no significant differences in OS (P = .404) and PFS (P = .844). Multivariable Cox regression showed a trend toward shorter survival time (P = .089) in the antibiotic group. Our study suggests that antibiotic use affects symptoms and lab values in GB patients. Larger prospective studies are required to investigate if prediagnostic antibiotic use could be a prognostic factor in GB patients.

KIF20B Correlates with LUAD Progression and Is an Independent Risk Factor.

Kinesin family proteins (KIFs) play crucial roles in human tumorigenesis and progression. This study aimed to investigate the expression and association of Kinesin family member 20B (KIF20B) with lung adenocarcinoma (LUAD). RNA-seq data from LUAD patients (n = 535) were extracted from TCGA. KIF20B expression was compared between tumor tissues and controls, and between different stages of the disease. Survival and Cox regression analyses were performed, as well as in vitro cellular experiments on A549 cells. KIF20B is upregulated in LUAD tumor tissues compared with controls and is higher in advanced stages. Patients with high expression of KIF20B have shorter survival times. KIF20B is an independent risk factor for the prognosis of LUAD. High KIF20B expression samples were enriched in signaling pathways related to tumor progression. si-KIF20B transfection reduced migration and invasion of A549 cells and increased apoptosis. The expression of p53 and Bax proteins was upregulated by si-KIF20B, while Bcl-2 was down-regulated. This study reveals that high KIF20B expression is an independent risk factor for the poor prognosis of LUAD. The inhibition of KIF20B might be of great value for suppressing LUAD progression.

Psoas muscle area is associated with prognosis in elderly patients with hip fracture.

Sarcopenia is a key predictor of prognosis in patients with hip fractures. This study utilized computed tomography (CT) scan (1) to determine the association between psoas muscle cross-sectional area (CSA) and mortality, along with other muscles, and (2) to confirm the correlation between muscle CSA and appendicular lean mass (ALM) measured using DXA in elderly patients with hip fracture. Patients who were aged ≥ 50years and underwent surgical treatment for hip fracture were eligible for this study. After a series of exclusion criteria, 217 female patients were included. Patient data, including clinical characteristics, such as body mass index (BMI), CSA, and ALM, were retrospectively collected. The Kaplan-Meier survival method and Cox proportional hazards regression analysis were used for the statistical analyses. The correlation between CSA/BMI and ALM was also assessed. Patients in the lowest quartile of psoas muscle CSA/BMI had shorter survival times than those in the other quartiles. When the Cox proportional hazards regression analysis was adjusted for multiple variables, the lowest quartile of the CSA/BMI of the psoas was a risk factor for mortality. The CSA/BMI of the psoas showed the highest correlation coefficient. The CSA/BMI ratio of the other muscles showed a moderately positive correlation with ALM. The CSA of the psoas is associated with prognosis in elderly patients with hip fractures and shows a moderately positive correlation with ALM. Hence, the CSA of psoas is useful for predicting survival and muscle mass in elderly patients with hip fractures.

Double versus Single Primary Malignant Neoplasm of Breast and Colorectal Cancer: A Case-Control Study.

Breast cancer (BC) and colorectal cancer (CRC) are common in female. This study compared survival time between women affected with both cancers with ones with single BC or single CRC. Medical records of subjects with both BC & CRC (June 1, 2010, to June 30, 2021) were reviewed. Age-matched subjects who had BC or CRC alone were used as control. Survival analysis using Kaplan-Meier method was performed. There were 63 double cancers [40 BC first (DBC): 23 CRC first (DCRC), mean age±SD 60.5±9.9 and 60.9±12.2 years] and 76 subjects in single cancer group [53 SBC: 23 SCRC, mean age 57.4±11.3 and 61.1±12.5 years]. The 5-year survival rate of the double cancer group was 74.6% and the single cancer group was 63.2%. D-group had slightly longer survival time than S-group (116.5±4.0 vs. 101.3±5.5, p=0.055). In D-group, the occurrence of addition of other primary cancers were more common (p=0.015). The second cancer occurred 61.7±45.3 months later in DBC group, and 39.1±26.6 months later in DCRC group (p=0.016). SCRC had shorter survival time vs. DCRC group (p=0.031). SBC and DBC had no different in mean survival time. BC and CRC could occur as a part of multiple primary cancers. Detection of more than one cancer did not lead to decrease survival if the second cancer was early detected and treated. The occurrence of the second cancer might be beyond 5 years after the diagnosis of the first cancer. Thus, longer surveillance may be warranted. Awareness and provision of early screening should be offered to individuals diagnosed with either primary cancer. Detection of more than one cancer did not lead to shorter survival.

JAK2 Loss Arising From Tumor-Spread-Through-Air-Spaces (STAS) Promotes Tumor Progression by Suppressing CD8+ T Cells in Lung Adenocarcinoma: A Machine Learning Approach.

Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates. This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis. The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression. In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

MicroRNA let-7c-5p Alleviates in Hepatocellular Carcinoma by Targeting Enhancer of Zeste Homolog 2: A Study Intersecting Bioinformatic Analysis and Validated Experiments.

Enhancer of zeste homolog 2 (EZH2)gene has a prognostic role in hepatocellular carcinoma (HCC). This study aimed to identify the role of microRNAs (miRNAs) let-7c-5p by targeting EZH2 in HCC. We downloaded gene and miRNA RNA-seq data from The Cancer Genome Atlas (TCGA) database. Differences in EZH2 expression between different groups were analyzed and the association of EZH2 expression with HCC prognosis was detected using Cox regression analysis. The miRNA-EZH2-pathway network was constructed. Dual-luciferase reporter assay was performed to detect the hsa-let-7c-5p-EZH2. Cell proliferation, migration, invasion, and apoptosis were detected by CCK-8, Wound healing, Transwell, and Flow cytometry, respectively. RT-qPCR and Western blot were used to detect the expression of let-7c-5p and EZH2. EZH2 was upregulated in HCC tumors (P < 0.0001). Cox regression analysis showed that TCGA HCC patients with high EZH2 expression levels showed a short survival time [hazard ratio (HR) = 1.677, 95% confidence interval (CI) 1.316-2.137; P < 0.0001]. Seven miRNAs were negatively correlated with EZH2 expression and were significantly downregulated in HCC tumor samples (P < 0.0001), in which hsa-let-7c-5p was associated with prognosis in HCC (HR = 0.849 95% CI 0.739-0.975; P = 0.021). We identified 14 immune cells that showed significant differences in EZH2 high- and low-expression groups. Additionally, let-7c-5p inhibited HCC cell proliferation, migration, and invasion and reversed the promoted effects of EZH2 on HCC cell malignant characteristics. hsa-let-7c-5p-EZH2 significantly suppressed HCC malignant characteristics, which can be used for HCC prognosis.

KRT80 expression works as a biomarker and a target for differentiation in gastric cancer.

Keratin 80 (KRT80) is a filament protein that participates in cell differentiation and the integrity of the epithelial barrier. Here, KRT80 expression was higher in gastric cancer compared with normal mucosa at both mRNA and protein levels by bioinformatic analysis, qRT-PCR and Western blot (p<0.05), however, the methylation of KRT80 was lower than in normal mucosa (p<0.05). There was a negative relationship between promoter methylation and expression level of KRT80 gene in gastric cancer (p<0.05). KRT80 mRNA and protein expression was positively correlated with the differentiation of gastric cancer (p<0.05), while KRT80 methylation was negatively associated with gastric cancer differentiation and p53 mutation (p<0.05). The expression of KRT80 mRNA was positively linked to the short survival time of gastric cancers (p<0.05). The differential genes of KRT80 mRNA were involved in ligand-receptor interaction, estrogen signal pathway, peptidase, filament and cytoskeleton, keratinocyte differentiation, vitamin D receptor, muscle contraction, and B cell-mediated immunity (p<0.05). KRT80-related genes were classified into cell adhesion and junction, cadherin binding, skin and epidermis development, and so forth (p<0.05). KRT80 knockdown suppressed proliferation, anti-apoptosis, anti-pyroptosis, migration, invasion and epithelial-mesenchymal transition in gastric cancer cells (p<0.05). These findings indicated that up-regulated expression of KRT80 played a crucial part in gastric carcinogenesis, and might be considered as a biological marker for aggressive behaviors and poor prognosis. Its silencing might be used as an approach of target therapy for gastric cancer patients.

Bioinformatic Analysis and Computer-Aided Study to Investigate the Potential Application of a Bioflavonoid Compound Bilobetin in Liver Cancer Treatment.

Hepatocellular carcinoma (HCC/LIHC) is the most common type of primary liver cancer, which is a leading cause of cancer death worldwide. Patients with HCC have a short survival time after diagnosis. Unfortunately, there are no effective treatments for advanced or aggressive HCC. Thus, the rapid development of new therapeutic drugs or treatment methods for HCC is urgently needed. Bioinformatic tools and computer-aided predictions advance the processes of drug development. In this study, we incorporated bioinformatic analyses and computer-aided drug development processes to investigate the potential application of bilobetin, a bioactive compound of bioflavonoid, as a therapeutic agent for HCC treatment. Our results revealed that 4 out of 20 predicted hub target genes of bilobetin displayed functional importance in cancer-related signaling pathways in different cancers, including HCC. Importantly, the mRNA expression levels of these four key hub genes (VEGFA, SRC, MMP9, and CDK1) were significantly different between normal and HCC tumor samples. Their expression levels were significantly associated with the clinical survival outcomes of HCC patients, as well as the immune cell infiltration levels in the HCC tumor microenvironment. In addition, these four genes showed significant co-expression correlated with immune checkpoint genes, including CD274, PDCD1, CTLA4, and CD47. Furthermore, we used computer-aided approaches to investigate the binding affinity and potential binding mechanisms between bilobetin and target proteins encoded by four key hub genes. In conclusion, our study shed light on the potential application of the bioactive bioflavonoid molecule bilobetin in LIHC treatment by regulating four key hub genes.

L3MBTL3 Is a Potential Prognostic Biomarker and Correlates with Immune Infiltrations in Gastric Cancer.

Recent research has linked lethal (3) malignant brain tumor-like 3 (L3MBTL3) to cancer aggressiveness and a dismal prognosis, but its function in gastric cancer (GC) is unclear. This research investigated the association between L3MBTL3 expression and clinicopathological characteristics of GC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that L3MBTL3 expression was upregulated in malignant GC tissues, which was associated with a shortened survival time and poor clinicopathological characteristics, including TNM staging. A functional enrichment analysis including GO/KEGG and GSEA illustrated the enrichment of different L3MBTL3-associated pathways involved in carcinogenesis and immune response. In addition, the correlations between L3MBTL3 and tumor-infiltrating immune cells were determined based on the TIMER database; the results showed that L3MBTL3 was associated with the immune infiltration of macrophages and their polarization from M1 to M2. Furthermore, our findings suggested a possible function for L3MBTL3 in the regulation of the tumor immune microenvironment of GC. In summary, L3MBTL3 has diagnostic potential, and it also offers new insights into the development of aggressiveness and prognosis in GC.

Novel approach for enhancing skin allograft survival by bioadhesive nanoparticles loaded with rapamycin

Skin graft rejection is a significant challenge in skin allografts for skin defects, particularly in extensive burn injury patients when autografts are insufficient. Enhancing the survival duration of allogeneic skin grafts can improve the success rate of subsequent autologous skin grafting, thereby promoting the therapeutic efficacy for wound healing. Rapamycin (Rapa), a potent immunosuppressant with favorable efficacy in organ transplantation, is limited by its systemic administration-associated toxicity and side effects. Therefore, addressing the short survival time of allogeneic skin grafts and minimizing the toxicity related to systemic application of immunosuppressive agents is an urgent requirement. Here, we present a topical formulation based on bioadhesive poly (lactic acid)-hyperbranched polyglycerol nanoparticles (BNPs) with surface-modified encapsulation of Rapamycin (Rapa/BNPs), applied for local immunosuppression in a murine model of allogeneic skin grafts. Our Rapa/BNPs significantly prolong nanoparticle retention, reduce infiltration of T lymphocytes and macrophages, decrease the level of pro-inflammatory cytokines and ultimately extend skin allograft survival with little systemic toxicity compared to free Rapa or Rapamycin-loaded non-bioadhesive nanoparticles (Rapa/NNPs) administration. In conclusion, Rapa/BNPs effectively deliver local immunosuppression and demonstrate potential for enhancing skin allograft survival while minimizing localized inflammation, thus potentially increasing patient survival rates for various types of skin defects.

Prognostic and immunological values of SKA3 for overall survival in lung adenocarcinoma and its RNA binding protein involved mechanisms

This article aimed to investigate the correlations among SKA3 expression and prognosis, clinical relevance, tumor immunity, and RNA-binding protein (RBP)-involved mechanisms for overall survival (OS) in lung adenocarcinoma (LUAD). To explore the SKA3 expression level in LUAD by analyzing the genomic data as well as related clinical characteristics from the database of TCGA. Nomogram and gene set enrichment analysis (GSEA) were applied, respectively, to evaluate the performance of SKA3 in LUAD. Correlations between SKA3 and immunity and RBP-involved mechanisms were also performed. SKA3 had a higher expression level in LUAD samples than in adjacent normal lung samples, with shorter survival times in the high-SKA3-expressed LUAD subgroup (P < 0.05). qRT-PCR results remained consistent (P < 0.05). Uni-/multivariate Cox analyses revealed that SKA3 could have independent prognostic ability for LUAD (both P < 0.05). The nomogram model constructed with clinical pathological parameters and SKA3 expression levels predicted OS rates for LUAD and GSEA revealed SKA3-related pathways. In aspects of tumor immunity, SKA3 was significantly involved with tumor neoantigen burden, tumor mutational burden, immune cell pathways, and immune checkpoint inhibitor (ICI) molecules (all P < 0.05). The CellMiner database also found significant correlations between SKA3 and the antitumor drug sensitivity of chemotherapy, fenretinide, and PX-316. Besides, a total of nine LncRNA/RBP/SKA3 networks were revealed in LUAD for their RBP-involved mechanisms. SKA3 could serve as a potential biomarker for OS prognosis and immunotherapy in LUAD. LncRNA/RBP/SKA3 networks were identified in LUAD for their RBP-involved mechanisms, paving the way for further experimental verifications.

Clinical-epidemiological profile and outcome of old people hospitalized for COVID-19

Objective: to describe the clinical-epidemiological profile and outcome of old people hospitalized for COVID-19 at the University Hospital of Piauí. Methods: An observational, cross-sectional study was carried out with secondary data involving 137 medical records of old patients hospitalized for COVID-19 in the UH during the period from April to December 2020. Data were collected in August and September 2021. A form consisting of questions equivalent to the sociodemographic and epidemiological data of old patients was used. Data were analyzed using SPSS statistical software version 25. Results: It was observed that the "use of mechanical ventilation" (Odds Ratio: 35.96 [10.23-126.47]) and "type of hospitalization bed" (Odds Ratio: 9.40 [2.69-32.82]) were the variables that best explain the deaths being independent predictors for this outcome. There was a statistically significant association between the number of comorbidities (p=0.007), the presence of clinical manifestations (p=0.003), the number of clinical manifestations (p=0.003) and death. The shorter survival time was associated with ICU admission and use of mechanical ventilation (p=0.000). Conclusion: The results of the study show that the presence of risk factors for COVID-19, clinical manifestations of the disease, to be admitted to ICU beds, using MV and those who were older had worse outcomes.

Evaluation of survival time in people hospitalized for COVID-19 in Brazil

This study aimed to evaluate the time between hospitalization and death of patients affected by COVID-19, and to investigate which factors are associated with this survival time. The data were obtained from the Influenza Epidemiological Surveillance Information System, which contains all cases of hospitalization for Severe Acute Respiratory Syndrome in Brazil. Initially, survival time was evaluated descriptively using the Kaplan-Meier estimator, which allows you to calculate the median survival time and the probability that a patient will survive certain periods of hospitalization. Next, a parametric regression model was constructed to investigate the relationship between the survival time and several factors jointly and the results were interpreted in terms of median survival time. Among the possible associated factors, the registration variables (gender, age, region, race and education), comorbidities and symptoms presented were considered. The results showed that the probability of a patient surviving the first day of hospitalization is 97.9%, dropping to 87.5% on the seventh day and reaching 33.5% on the thirtieth day. Half of the deaths occurred within 21 days of hospitalization and only 25% of the patients survived for more than 38 days, showing that, over time, the mortality rate decreases. Evaluating the associated factors, the results showed that elderly patients with low education have a shorter survival time and, consequently, a higher risk of death. With regard to comorbidities, neurological and liver diseases are the main risk factors. On the other hand, we do not have enough evidence to state that survival time is influenced by puerperal variables, down syndrome and abdominal pain.

RSRC2 Expression Inhibits Malignant Progression of Triple-Negative Breast Cancer by Transcriptionally Regulating SCIN Expression.

Triple-negative breast cancer (TNBC) has a shorter survival time and higher mortality rate than other molecular subtypes. RSRC2 is a newly discovered tumor suppressor gene. However, the potential functional mechanism of RSRC2 in TNBC remains unknown so far. Multiple bioinformatics databases were used. A Human Transcriptome Array 2.0 analysis, ChIP-seq analysis, ChIP-qPCR, RT-qPCR, Western blot, cell function assays in vitro and a metastatic mouse model in vivo were performed to demonstrate the role of RSRC2 in TNBC. Through the analysis of various databases, RSRC2 expression was the lowest in TNBC tissues compared to other molecular subtypes. The low expression of RSRC2 was associated with a worse prognosis for patients with breast cancer. The transcriptome array, ChIP-seq and bioinformatics analysis identified that GRHL2 and SCIN might have a close relationship with RSRC2. The functional bioinformatics enrichment analysis and functional cell experiments showed that RSRC2 was involved in cell adhesion, cell proliferation, cell migration and invasion. Furthermore, RSRC2 expression suppressed SCIN expression but not GRHL2 expression. SCIN re-expression in the RSRC2 overexpression cells or SCIN knockdown in the RSRC2 knockdown cells reversed the cellular function caused by RSRC2. Mechanistically, RSRC2 transcriptionally inhibited SCIN expression. In summary, our study reveals that RSRC2 acts as a tumor suppressor in TNBC development and progression through negatively regulating SCIN-mediated cell function, thus providing a potential target for TNBC treatment.

Determinants of late-stage cervical cancer presentation in Ethiopia: a systematic review and meta-analysis

IntroductionBehind breast, colorectal, and lung cancers, cervical cancer is the fourth most common cancer affecting females. Despite, it is a preventable form of cancer both the incidence and mortality figures reflect it as a major reproductive health problem. Late-stage cervical cancer diagnosis is associated with complicated clinical presentation which can result in short survival time and increased mortality. Several factors contribute to the late-stage presentation of cervical cancer patients. In Ethiopia nationally summarized evidence on the level and the factors contributing to late-stage cervical cancer diagnosis is scarce. Therefore, this systematic review and meta-analysis aimed to assess the pooled prevalence of late-stage cervical cancer diagnosis and its determinants in Ethiopia.MethodA systematic review and meta-analysis were conducted using PRISMA guidelines. Comprehensive literature was searched in PubMed, Embase, Google Scholar, and African Online Journal to retrieve eligible articles. A weighted inverse variance random effect model was used to estimate pooled prevalence. Cochrane Q-test and I2 statistics were computed to assess heterogeneity among studies. Funnel plot and Egger’s regression test were done to assess publication bias.ResultOverall, 726 articles were retrieved and finally 10 articles were included in this review. The pooled prevalence of late-stage cervical cancer diagnosis in Ethiopia was 60.45% (95%CI; 53.04%-67.85%). Poor awareness about cervical cancer and its treatment (AOR = 1.55, 95% CI: (1.03 – 2.33, longer delay to seek care (AOR = 1.02, 95% CI: (1.01 – 1.03)) and rural residence (AOR = 2.07, 95% CI:( 1.56 – 2.75)) were significantly associated to late-stage diagnosis.ConclusionIn Ethiopia, six in every ten cervical cancer cases are diagnosed at the late stage of the disease. Poor awareness about cervical cancer and its treatment, long patient delay to seek care, and rural residence were positively associated with late–stage diagnosis. Therefore intervention efforts should be made to improve public awareness about cervical cancer, minimize patient delay to seek care, and expand screening services specifically in the rural residing segment of the population to detect the disease early and improve survival.

Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model.

The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice. After biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry. In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time. 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.

Frailty and long-term survival among patients in Australian intensive care units with metastatic cancer (FRAIL-CANCER study): a retrospective registry-based cohort study

Recent advances in cancer therapeutics have improved outcomes, resulting in increasing candidacy of patients with metastatic cancer being admitted to intensive care units (ICUs). A large proportion of patients also have frailty, predisposing them to poor outcomes, yet the literature reporting on this is scarce. We aimed to assess the impact of frailty on survival in patients with metastatic cancer admitted to the ICU. In this retrospective registry-based cohort study, we used data from the Australia and New Zealand Intensive Care Society Adult Patient (age ≥16 years) database to identify patients with advanced (solid and haematological cancer) and a documented Clinical Frailty scale (CFS) admitted to 166 Australian ICUs. Patients without metastatic cancer were excluded. We analysed the effect of frailty (CFS 5-8) on long-term survival, and how this effect changed in specific subgroups (cancer subtypes, age [<65 years or ≥65 years], and those who survived hospitalisation). Because estimates tend to cluster within centres and vary between them, we used Cox proportional hazards regression models with robust sandwich variance estimators to assess the effect of frailty on survival time up to 4 years after ICU admission between groups. Between Jan 1, 2018, and March 31, 2022, 30 026 patients were eligible, and after exclusions 21 174 patients were included in the analysis; of these, 6806 (32·1%) had frailty, and 11 662 (55·1%) were male, 9489 (44·8%) were female, and 23 (0·1%) were intersex or self-reported indeterminate sex. The overall survival was lower for patients with frailty at 4 years compared with patients without frailty (29·5% vs 10·9%; p<0·0001). Frailty was associated with shorter 4-year survival times (adjusted hazard ratio 1·52 [95% CI 1·43-1·60]), and this effect was seen across all cancer subtypes. Frailty was associated with shorter survival times in patients younger than 65 years (1·66 [1·51-1·83]) and aged 65 years or older (1·40 [1·38-1·56]), but its effects were larger in patients younger than 65 years (pinteraction<0·0001). Frailty was also associated with shorter survival times in patients who survived hospitalisation (1·49 [1·40-1·59]). In patients with metastatic cancer admitted to the ICU, frailty was associated with poorer long-term survival. Patients with frailty might benefit from a goal-concordant time-limited trial in the ICU and will need suitable post-intensive care supportive management. None.

Spleen-Derived CCL9 Recruits MDSC to Facilitate Tumor Growth in Orthotopic Hepatoma Mice.

Objectives Spleen is involved in multiple diseases, the role of the spleen and spleen-derived factors in hepatocellular carcinoma (HCC) is still not clarified. Methods In the current study, a murine H22 orthotopic hepatoma model was established. Three groups were divided: normal mice, tumor-bearing mice with spleen-preserving, and tumor-bearing mice with splenectomy. Spleen and tumor weights were recorded by weeks 1 and 2. The proportion of myeloid-derived suppressor cell (MDSC) in peripheral blood and tumor tissue was detected using flow cytometry. Protein chip assay was used to compare the differential cytokines between normal liver supernatant and tumor supernatant. The common upregulated cytokines both in spleen and tumor were focused and analyzed using gene expression profiling interactive analysis (GEPIA) database. Enzyme-linked immunosorbent assay was performed to verify the chip result, and to examine CCL9 expression before and after splenectomy. Spleen MDSC was sorted using flow cytometry, and chemotaxis assay was performed to demonstrate whether CCL9 attracted spleen MDSC. Results The spleen enlarged during tumor progression, and compared with splenectomy group, there were faster tumor growth, shorter survival time, and higher proportions of MDSC in spleen-preserving group. Protein chip assay and GEPIA database revealed CCL9 was the most promising chemokine involved in HCC upregulated both in spleen and tumor tissue. CCL9 attracted MDSC in vitro, the level of CCL9 in tumor tissue was downregulated, and the percentage of MDSC was decreased after splenectomy. Conclusion The results demonstrate that CCL9 may be derived from spleen; it facilitated HCC growth via the chemotaxis of MDSC, targeting CCL9 may be a promising strategy in HCC treatment.

Interleukin-8 Rs4073 Genotypes as Prognostic Predictors for Childhood Acute Lymphocytic Leukemia.

Interleukin 8 (IL-8) is highly expressed in refractory acute lymphocytic leukemia (ALL) cells. This study aimed to investigate the contribution of IL-8 polymorphisms to the risk of childhood ALL. The genotypes of IL-8 rs4073, rs2227306, rs2227543, and rs1126647 were determined in 266 childhood ALL cases and 266 controls using the PCR-RFLP method. Additionally, we assessed whether the interactions of these genotypes with age and sex contributed to childhood ALL risk. The distributions of genotypic and allelic frequencies of IL-8 rs4073, rs2227306, rs2227543, and rs1126647 were not significantly different between childhood ALL cases and controls (all p>0.05). However, carriers of the variant AA genotype at IL-8 rs4073 had a significantly higher risk of childhood ALL among those aged ≤3.5 years and among girls (OR=2.39 and 3.32, 95%CI=1.21-4.73 and 1.51-7.30, p=0.0182 and 0.0042, respectively). In the stratification analysis, IL-8 rs4073 AT and AA genotypes were associated with higher childhood ALL risk classification and shorter survival time (OR=2.21 and 4.13, 95%CI=1.29-3.78 and 1.87-9.10, p=0.0054 and 0.0002, respectively). There was no positive association for rs2227306, rs2227543, or rs1126647 (all p>0.05). The A allele of IL-8 rs4073 can serve as a diagnostic predictor for childhood ALL, but only in girls and patients younger than or equal to 3.5 years old. More importantly, it can serve as a prognostic marker for high-risk classification and shorter survival time. Further validation studies can help extend the use of this prognostic predictor in clinical practice.