Poor Prognosis In Patients Research Articles

Impact of preoperative inflammatory and nutritional markers on the prognosis of patients with peritoneal metastasis of colorectal cancer.

Identifying patients with peritoneal metastasis (PMs) of colorectal cancer (CRC) who will benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is crucial before surgery. Inflammatory and nutritional indicators play essential roles in cancer development and metastasis. To investigate the association of preoperative inflammatory and nutritional markers with prognosis in patients with CRC-PM. We included 133 patients diagnosed with CRC-PM between July 2012 and July 2018. Patients' demographics, overall survival (OS), and preoperative inflammatory and nutritional markers were evaluated. The Kaplan-Meier method and log-rank test were used to estimate differences. Of the 133 patients, 94 (70.6%) had normal hemoglobin (Hb) and 54 (40.6%) had a high neutrophil-to-lymphocyte ratio (NLR). The median OS (mOS) was significantly lower for patients with high NLR (7.9 months) than for those with low NLR (25.4 months; P = 0.002). Similarly, patients with normal Hb had a longer mOS (18.5 months) than those with low Hb (6.3 months; P < 0.001). Multivariate analysis identified age, carbohydrate antigen 199 levels, NLR, Hb, and peritoneal cancer index as independent predictors of OS. Based on these findings, a nomogram was constructed, which demonstrated a good capacity for prediction, with a C-index of 0.715 (95% confidence interval: 0.684-0.740). Furthermore, the 1- and 2-year survival calibration plots showed good agreement between predicted and actual OS rates. The areas under the curve for the 1- and 2-year survival predictions of the nomogram were 0.6238 and 0.6234, respectively. High NLR and low Hb were identified as independent predictive risk factors for poor prognosis in patients with CRC-PM. The established nomogram demonstrated high accuracy in predicting OS for patients with CRC-PM, indicating its potential as a valuable prognostic tool for this patient population.

Abstract B023: Unravelling fibroinflammatory and immune signatures for pancreatic cancer early detection

Abstract Pancreatic cancer is associated with late-stage diagnosis and poor patient prognosis. The disease is characterised by chronic dysregulated immunity and inflammation. Moreover, chronic pancreatitis is linked with an increased risk of pancreatic cancer. Tissue remodelling during disease progression involves a complex network of cells and a crosstalk between cancer cells, stromal components and immune cells, but it remains poorly explored. Thus, to improve the outcome of patients, there is a need for better understanding of biological changes associated with the initiation and progression of pancreatic cancer at the molecular and spatial levels. Using samples obtained from our Accelerated Diagnosis of neuroEndocrine and Pancreatic TumourS (ADEPTS) biobank, we have evaluated blood samples for the discovery of non- invasive biomarkers to discriminate patients with pancreatic cancer from symptomatic patients without cancer. In this pilot study, the transcriptome of peripheral blood mononuclear cells (PBMCs), isolated using a ficoll gradient was explored to identify PDAC-associated mRNA signatures. Moreover, the Olink® Explore Inflammation and Oncology panels were performed in a cohort of 40 patients with early stage (I-II) PDAC, 40 chronic pancreatitis samples and 40 control patients with benign symptomatic upper GI diseases. To validate and enrich these results, a panel of inflammatory and immune markers including immunoglobulins, cytokines and chemokines was also run using multiplex techniques. Symptoms observed in our cohort were also analysed together with clinical (e.g diabetic status, biochemistry profile) and demographic data (age, sex, ethnicity, post code etc). We have identified mRNA transcriptome signatures and differentially expressed proteins associated with inflammatory and immunological processes in PDAC compared to benign symptomatic samples. Our results offer potential diagnostic utility for early-stage disease. Additionally, our unique cohort of patient samples comprising of those with confirmed PDAC and those presenting to clinic with benign disease and similar non-specific symptoms, allows for the development of non-invasive diagnostic tests with better translational applicability. Future work will involve the validation of these findings in a larger patient cohort and the use of NanoString GeoMx® Digital Spatial Profiler to perform whole transcriptome and proteome profiling in human chronic pancreatic and pancreatic cancer tissue samples. Citation Format: Kyra Fraser, Maria Rosado, Stephen P Pereira, Pilar Acedo. Unravelling fibroinflammatory and immune signatures for pancreatic cancer early detection [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B023.

Protein tyrosine phosphatase non-receptor II: A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma.

The incidence of primary liver cancer is increasing year by year. In 2022 alone, more than 900000 people were diagnosed with liver cancer worldwide, with hepatocellular carcinoma (HCC) accounting for 75%-85% of cases. HCC is the most common primary liver cancer. China has the highest incidence and mortality rate of HCC in the world, and it is one of the malignant tumors that seriously threaten the health of Chinese people. The onset of liver cancer is occult, the early cases lack typical clinical symptoms, and most of the patients are already in the middle and late stage when diagnosed. Therefore, it is very important to find new markers for the early detection and diagnosis of liver cancer, improve the therapeutic effect, and improve the prognosis of patients. Protein tyrosine phosphatase non-receptor 2 (PTPN2) has been shown to be associated with colorectal cancer, triple-negative breast cancer, non-small cell lung cancer, and prostate cancer, but its biological role and function in tumors remain to be further studied. To combine the results of relevant data obtained from The Cancer Genome Atlas (TCGA) to provide the first in-depth analysis of the biological role of PTPN2 in HCC. The expression of PTPN2 in HCC was first analyzed based on the TCGA database, and the findings were then verified by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and immunoblotting. The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features. Finally, the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining. The results of immunohistochemical staining, qRT-PCR, and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways, including cancer-related pathways, the Notch signaling pathway, and the MAPK signaling pathway. Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways, such as the epithelial mesenchymal transition process. A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group. This study investigated PTPN2 from multiple biological perspectives, revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

Single-cell profiling uncovers proliferative cells as key determinants of survival outcomes in lower-grade glioma patients

Lower-grade gliomas (LGGs), despite their generally indolent clinical course, are characterized by invasive growth patterns and genetic heterogeneity, which can lead to malignant transformation, underscoring the need for improved prognostic markers and therapeutic strategies. This study utilized single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq to identify a novel cell type, referred to as "Prol," characterized by increased proliferation and linked to a poor prognosis in patients with LGG, particularly under the context of immunotherapy interventions. A signature, termed the Prol signature, was constructed based on marker genes specific to the Prol cell type, utilizing an artificial intelligence (AI) network that integrates traditional regression, machine learning, and deep learning algorithms. This signature demonstrated enhanced predictive accuracy for LGG prognosis compared to existing models and showed pan-cancer prognostic potential. The mRNA expression of the key gene PTTG1 from the Prol signature was further validated through quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings not only provide novel insights into the molecular and cellular mechanisms of LGG but also offer a promising avenue for the development of targeted biomarkers and therapeutic interventions.

Clinical significance of postoperative thrombocytosis after vats lobectomy for NSCLC

ObjectivesThrombocytosis is a clinical condition generally associated with poor prognosis in patients with cancer. Thrombocytosis may be present after lung cancer resection, but the clinical significance of thrombocytosis remains unclear. Herein, we evaluated whether postoperative thrombocytosis was a negative prognostic factor in patients undergoing thoracoscopic lobectomy for lung cancer.MethodsIt was a retrospective monocentric study including consecutive patients undergoing thoracoscopic lobectomy for lung cancer from January 2020 to January 2023. The outcome of patients with postoperative thrombocytosis (defined as platelet count ≥ 450 × 10^9/L at 24 h after the surgery and confirmed at postoperative day 7) was compared with a control group. Postoperative morbidity, mortality, and survival were compared between the two groups to define whether thrombocytosis negatively affected outcomes.ResultsOur study population included 183 patients; of these, 22 (12%) presented postoperative thrombocytosis: 9 (5%) mild thrombocytosis (451–700 × 10^9/L), 10 (5%) moderate thrombocytosis (701–900 × 10^9/L), and 3 (2%) severe thrombocytosis (901–1000 × 10^9/L). No significant differences were found regarding postoperative morbidity (p = 0.92), mortality (p = 0.53), overall survival (p = 0.45), and disease-free survival (p = 0.60) between the two study groups. Thrombocytosis was associated with higher rate of atelectasis (36% vs. 6%, p < 0.001) and residual pleural effusion (31% vs. 8%, p = 0.0008). Thrombocytosis group was administered low-dose acetylsalicylic acid for 10 days and no thrombotic events were observed. In all cases the platelet count returned to be within normal value at postoperative day 30.ConclusionsPostoperative thrombocytosis seems to be a transient condition due to an inflammatory state and it does not affect the surgical outcome and survival after thoracoscopic lobectomy.

Increased serum albumin corrected anion gap levels are associated with poor prognosis in septic patients with liver cirrhosis

The prognosis of septic patients with cirrhosis is worse compared to septic patients without cirrhosis. Early and accurate prognosis determination in patients with cirrhosis and sepsis is pivotal for guiding treatment decisions. The aim of this study was to investigate the association between albumin-corrected anion gap (ACAG) and clinical prognosis of patients with sepsis and cirrhosis. This study extracted data of patients with sepsis and cirrhosis from the Medical Information Mart for Intensive Care (MIMIC-IV) database. A total of 1340 patients (64.6% male) were enrolled. After confounders adjusting, elevated ACAG had a significant association with 28-day mortality (HR1.604; 95% CI 1.258–2.048; P < 0.001). Restricted cubic spline revealed that a linear relationship between ACAG and 28-day mortality (P-nonlinear = 0.089, P-overall = 0.001). According to the ROC curve analysis, the ACAG demonstrated a higher area under the curve (AUC) of 0.703 compared to AG (0.675). Kaplan–Meier analysis revealed higher 28-day mortality in high ACAG group (log-rank test, χ^2 = 175.638, P < 0.001). Furthermore, subgroup analysis showed a significant interaction between ACAG and etiology of cirrhosis (P for interaction = 0.014). Therefore, ACAG could provide clinicians with valuable insights for guiding interventions in this high-risk population.

Cut-off values of Geriatric Nutritional Risk Index for cardiovascular events in Japanese patients with acute myocardial infarction.

The Geriatric Nutritional Risk Index (GNRI) is a straightforward nutritional risk assessment tool with an established relationship with poor prognosis in patients with heart failure. However, the utility of the GNRI in patients with acute myocardial infarction (AMI) remains unclear given the time-dependent changes in the pathophysiology of AMI and the selected endpoints. Accordingly, we aimed to evaluate the optimal cut-off values of the GNRI for cardiovascular events in patients with AMI. We used time-dependent receiver operating characteristic analysis to identify the optimal cut-off values for two endpoints, all-cause death and major adverse cardiac events (MACE: all-cause death, non-fatal myocardial infarction, hospitalization for heart failure, and stroke), over 4years in 360 patients with AMI between 2012 and 2020. The cumulative incidence of MACE was 11.6%. The cut-off value of the GNRI for all-cause death was 82.7 (area under the curve [AUC], 0.834) at 3months and 90.3 (AUC 0.854) at 4years. The cut-off value of the GNRI for MACE was 83.0 (AUC 0.841) at 3months and 95.3 (AUC 0.821) at 4years. The GNRI demonstrated consistently high reliability relative to other indicators of AMI. Our findings indicated that the optimal cut-off value and reliability of the GNRI for cardiovascular events varied according to the endpoints and observation periods. GNRI emerges as a crucial predictor of prognosis for patients with AMI.

Bioinformatical and experimental validation on EFNA5 biomarker for pancreatic cancer

Pancreatic cancer is one of the most aggressive malignancies in the digestive system, characterized by vague early symptoms and rapid disease progression. Currently, treatment options for pancreatic cancer are limited, with unsatisfactory outcomes and poor prognosis, as the overall 5-year survival rate is less than 10%. Therefore, it is crucial to identify new biomarkers for pancreatic cancer.We analyzed the differential expression of EFNA5 at the mRNA level using data from the TCGA, GTEX, and GEO databases, followed by validation of EFNA5 protein expression differences through immunohistochemistry. Kaplan-Meier survival analysis and Cox regression analysis were used to explore the prognostic value of EFNA5. KEGG, GO enrichment analyses, and GSEA were employed to predict the biological functions of EFNA5. Bioinformatics algorithms were utilized to analyze the impact of EFNA5 on drug sensitivity, immune cell infiltration, and tumor mutational burden. Finally, we conducted cell phenotype experiments to investigate the effects of EFNA5 on the proliferation, migration, and invasion of pancreatic cancer cells. Bioinformatics data showed that the mRNA level of EFNA5 was higher in pancreatic cancer tissues compared to normal tissues. Immunohistochemistry experiments confirmed that the protein expression level of EFNA5 was significantly higher in pancreatic cancer tissues (n = 19) than in adjacent normal tissues (n = 19). Survival analysis indicated that the overall survival (OS) and progression-free survival (PFS) were worse in the high EFNA5 expression group compared to the low expression group. Univariate and multivariate Cox regression analyses demonstrated that EFNA5 is a risk factor affecting the prognosis of pancreatic cancer patients. KEGG pathway enrichment analysis revealed that differentially expressed genes (DEGs) between high and low EFNA5 expression groups were primarily enriched in pathways such as PI3K/Akt, axon guidance, and focal adhesion. GO enrichment analysis showed that DEGs were mainly associated with functions like epidermis development, cell adhesion, and intercellular junctions. Immune cell infiltration analysis found that EFNA5 expression was correlated with the infiltration levels of various immune cells. The tumor mutational burden was higher in the high EFNA5 expression group compared to the low expression group. Drug sensitivity analysis indicated that the high EFNA5 expression group had lower sensitivity to several commonly used chemotherapy drugs for pancreatic cancer. Cellular experiments demonstrated that knocking down EFNA5 inhibited the proliferation, invasion, and migration of pancreatic cancer cells. EFNA5 is overexpressed in pancreatic cancer tissues, and its high expression is associated with poor prognosis in pancreatic cancer patients. Downregulation of EFNA5 reduces the proliferation, migration, and invasion capabilities of the pancreatic cancer cell line BxPC-3. EFNA5 is closely related to the occurrence, development, prognosis, immune infiltration, and drug sensitivity of pancreatic cancer. Our study suggests that EFNA5 is a potential biomarker and therapeutic target.

The red blood cell distribution width to albumin ratio was a potential prognostic biomarker for acute respiratory failure: a retrospective study

BackgroundThe association between red blood cell distribution width (RDW) to albumin ratio (RAR) and prognosis in patients with acute respiratory failure (ARF) admitted to the Intensive Care Unit (ICU) remains unclear. This retrospective cohort study aims to investigate this association.MethodsClinical information of ARF patients was collected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) version 2.0 database. The primary outcome was, in-hospital mortality and secondary outcomes included 28-day mortality, 60-day mortality, length of hospital stay, and length of ICU stay. Cox regression models and subgroup analyses were conducted to explore the relationship between RAR and mortality.ResultsA total of 4547 patients with acute respiratory failure were enrolled, with 2277 in the low ratio group (RAR < 4.83) and 2270 in the high ratio group (RAR > = 4.83). Kaplan-Meier survival analysis demonstrated a significant difference in survival probability between the two groups. After adjusting for confounding factors, the Cox regression analysis showed that the high RAR ratio had a higher hazard ratio (HR) for in-hospital mortality (HR 1.22, 95% CI 1.07–1.40; P = 0.003), as well as for 28-day mortality and 60-day mortality. Propensity score-matched (PSM) analysis further supported the finding that high RAR was an independent risk factor for ARF.ConclusionThis study reveals that RAR is an independent risk factor for poor clinical prognosis in patients with ARF admitted to the ICU. Higher RAR levels were associated with increased in-hospital, 28-day and 60-day mortality rates.

Cardiac effects of COVID-19 infection in children.

It is known established that the cardiac effects of COVID-19 infection are associated with poor prognosis and high mortality rates in infected patients. The aim of this study was to evaluate the cardiac effects of COVID-19 infection in paediatric patients and identify the correlations between clinical and laboratory data and the degree of cardiac involvement. A retrospective data analysis was conducted on 64 paediatric patients at Gazi University Department of Pediatrics who were treated as inpatients with a diagnosis of COVID-19. Patients were classified as "COVID-19-related cardiac involvement cases" if their electrocardiogram and echocardiogram results indicated a pathology and/or if their laboratory data indicated increased cardiac enzymes. All patients were divided into subgroups based on whether they had cardiac involvement and whether they were diagnosed with multisystem inflammatory syndrome in children. In comparison to patients who did not have cardiac involvement, those with cardiac involvement had significantly higher levels of hs-Troponin T, Pro-BNP, and D-dimer. Patients with multisystem inflammatory syndrome in children had significantly longer PR intervals than those without multisystem inflammatory syndrome in children (p = 0.0001). Patients with multisystem inflammatory syndrome in children had a significantly higher rate of pathological valve insufficiencies (68.1%) than those without multisystem inflammatory syndrome in children (14.2%) (p = 0.001). In our study, the strongest predictive biomarker of cardiac involvement in paediatric patients with COVID-19 infection was determined to be hs-Troponin T. It was observed that pathologic electrocardiogram changes could reflect cardiac involvement in the absence of any other signs. Patients with multisystem inflammatory syndrome in children exhibited significantly greater rates of pathologic echocardiogram findings and myocardial dysfunction than those without multisystem inflammatory syndrome in children. In all patients, pathologic electrocardiogram and echocardiogram findings were found to be strongly associated with the severity of inflammation.

Increased PRIM2 expression associated with poor-prognosis in patients with pancreatic ductal adenocarcinoma.

To explore the association between PRIM2 expression and prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) from multi clinic centers. Samples from PDAC patients were collected and processed to tissue microarray (TMA). PRIM2 expression was detected by immunohistochemistry (IHC) of in 127 enrolled PDAC patients, which underwent surgical resection from January 2012 to December 2018, with complete follow-up, were enrolled and grouped by PRIM2 stain level into two groups. The expression differences, the association to clinicopathologic features and the survival were evaluated by the groups. Data of RNA/protein expression and clinical features from public databases were used for validation. PRIM2 was highly expressed in PDAC patients and associated with poor-prognosis in patients with PDAC. Association was found between increased PRIM2 levels and pathology grade (p = 0.050). Moreover, in multivariate analysis of survival, the highly expression of PRIM2 was identified as an independent risk factor for poor survival (HR1.78, p = 0.031). Analysis on public databases validated above results. High expression of PRIM2 associated with poor prognosis in PDAC patients, PRIM2 could be used as an independent risk indicator.

PLXDC1 serves as a potential prognostic marker and involves in malignant progression and macrophage polarization in colon cancer.

The malignant behavior and immune escape ability of cancer cells lead to therapeutic failure and poor prognosis for patients with various cancers, including colon cancer. Plexin domain containing 1 (PLXDC1) was initially identified to exert key roles in tumor by regulating angiogenesis and has recently proved to be involved in cell proliferation and migration of glioblastoma and gastric cancer cells. However, its roles in colon cancer remain unclear. In this study, the online bioinformatics databases confirmed high expression of PLXDC1 in colon cancer specimens, which was associated with cancer stages and nodal metastasis. Similarly, the increased expression of PLXDC1 was also validated in our collected samples and colon cancer cells. Moreover, patients with high expression of PLXDC1 had shorter survival, indicating that PLXDC1 might be a potential prognostic predictor for colon cancer patients. Notably, targeting PLXDC1 inhibited cancer cell viability and invasion, and enhanced cell apoptosis. Intriguingly, Tumor Immune Estimation Resource database confirmed that PLXDC1 expression was related to various tumor-infiltrating immune cells in colon adenocarcinoma including macrophages, and its expression was also correlated with M2-like macrophage markers. In vitro, colon cancer cells with PLXDC1 downregulation had a reduced ability to recruit and polarize macrophage towards M2 phenotype by decreasing the percentage of CD206+ cells and M2-like markers (CD206, CD163, arginase1, and interleukin 10 [IL-10]). Moreover, PLXDC1 knockdown attenuated M2 macrophage-mediated promotion in cancer cell viability and invasion. Mechanically, inhibition of PLXDC1 suppressed activation of the IL-6/Signal transducer and activator of transcription 3 (STAT3) signaling. Reactivating the above pathway by transfection with IL-6 plasmids reversed the suppressive effects of PLXDC1 knockdown on cancer cell malignant behaviors, macrophage recruitment and M2-like polarization. Thus, PLXDC1 downregulation may inhibit the malignancy of colon cancer cells and their ability to recruit and polarize macrophages towards M2 phenotype by blocking the IL-6/STAT3 pathway. Together, targeting PLXDC1 may attenuate the progression of colon cancer by direct roles in cancer cells and indirect roles in macrophage polarization, representing a promising therapeutic target for colon cancer patients.

Upregulation of EFCAB7 after radiofrequency ablation promoting hepatocellular carcinoma metastasis and survival by regulating PARK7.

Radiofrequency ablation (RFA) is an established treatment for unresectable and early-stage hepatocellular carcinoma (HCC). However, in some cases, residual tumor cells undergo malignant transformation following RFA. The molecular mechanisms underlying this phenomenon remain poorly understood. EFCAB7, a member of the EF-hand structure family, is of particular interest due to its association with oncogenesis. Nevertheless, the role of EFCAB7 in oncogenesis remains unclear. Gene expression level of EFCAB7 in HCC tissues before and after RFA was measured, while in vitro and in vivo experiments were proposed for exploring the roles of EFCAB7 in tumor cell proliferation and metastasis. Mass spectrometry and CO-IP were adopted to validate the interaction between PARK7 and EFCAB7. Finally, PARK7 in EFCAB7 silencing cells was overexpressed and different functions were measured in vitro to determine regulation between two genes. EFCAB7 showed increased expression after RFA in patient samples and EFCAB7 expression correlated with poor prognosis in HCC patients from the TCGA database. Then, EFCAB7 promoted HCC tumor cell proliferation and metastasis while inhibiting apoptosis. Furthermore, Mass spectrometry and Co-IP experiments revealed a direct interaction between EFCAB7 and PARK7. Finally, when we overexpressed PARK7 in EFCAB7 knockdown tumor cells, it rescued proliferation and metastasis, indicating a functional relationship between these two genes. EFCAB7 might be a core contributor to HCC cells' malignant transformation after RFA and could be a potential novel target to provide a therapeutic strategy for the prevention of recurrence after RFA in HCC.

GATA factor TRPS1, a new DNA repair protein, cooperates with reversible PARylation to promote chemoresistance in patients with breast cancer

Resistance to DNA-damaging agents is a major unsolved challenge for breast cancer patients undergoing chemotherapy. Here, we show that elevated expression of transcriptional repressor GATA binding 1 (TRPS1) is associated with lower drug sensitivity, reduced response rate, and poor prognosis in chemotherapy-treated breast cancer patients. Mechanistically, elevated TRPS1 expression promotes hyperactivity of DNA damage repair (DDR) in breast cancer cells. We provide evidence that TRPS1 dynamically localizes to DNA breaks in a Ku70- and Ku80-dependent manner, and that TRPS1 is a new member of the DDR protein family. We also discover that the dynamics of TRPS1 assembly at DNA breaks is regulated by its reversible PARylation in the DDR, and that mutations of the PARylation sites on TRPS1 lead to increased sensitivity to chemotherapeutic drugs. Taken together, our findings provide new mechanistic insights into the DDR and chemoresistance in breast cancer patients and identify TRPS1 as a critical DDR protein. TRPS1 may also be considered as a target to improve chemo-sensitization strategies and, consequently, clinical outcomes for breast cancer patients.

The NRF2-CARM1 axis links glucose sensing to transcriptional and epigenetic regulation of the pentose phosphate pathway in gastric cancer

Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment.

Multimodal radiomics-based methods using deep learning for prediction of brain metastasis in non-small cell lung cancer with 18F-FDG PET/CT images

Objective. Approximately 57% of non-small cell lung cancer (NSCLC) patients face a 20% risk of brain metastases (BMs). The delivery of drugs to the central nervous system is challenging because of the blood–brain barrier, leading to a relatively poor prognosis for patients with BMs. Therefore, early detection and treatment of BMs are highly important for improving patient prognosis. This study aimed to investigate the feasibility of a multimodal radiomics-based method using 3D neural networks trained on 18F-FDG PET/CT images to predict BMs in NSCLC patients. Approach. We included 226 NSCLC patients who underwent 18F-FDG PET/CT scans of areas, including the lung and brain, prior to EGFR-TKI therapy. Moreover, clinical data (age, sex, stage, etc) were collected and analyzed. Shallow lung features and deep lung-brain features were extracted using PyRadiomics and 3D neural networks, respectively. A support vector machine (SVM) was used to predict BMs. The receiver operating characteristic (ROC) curve and F1 score were used to assess BM prediction performance. Main result. The combination of shallow lung and shallow-deep lung-brain features demonstrated superior predictive performance (AUC = 0.96 ± 0.01). Shallow-deep lung-brain features exhibited strong significance (P < 0.001) and potential predictive performance (coefficient > 0.8). Moreover, BM prediction by age was significant (P < 0.05). Significance. Our approach enables the quantitative assessment of medical images and a deeper understanding of both superficial and deep tumor characteristics. This noninvasive method has the potential to identify BM-related features with statistical significance, thereby aiding in the development of targeted treatment plans for NSCLC patients.

Poor Survival of Patients With Very Small But Locally Advanced (T4) Oropharyngeal Cancer.

Objective : The size of T4 tumor could vary in oropharyngeal squamous cell carcinoma (OPSCC). Using the Surveillance, Epidemiology, and End Results (SEER) database, this study aimed to investigate the role of tumor size in the prognosis of patients with T4 OPSCC. Study Design: Retrospective cross-sectional. Setting: SEER-Medicare-linked database. Methods: This study enrolled 1153 patients diagnosed with T4 OPSCC from the SEER registry between 2010 and 2016. The primary study variables were tumor size, human papillomavirus (HPV) infection, and disease-specific survival (DSS). Primary tumor size and clinicopathological variables according to HPV status were analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression. Results: The 5-year DSS of patients with HPV-negative T4 OPSCC tumors ≤1 cm was worse than that of patients with tumors >1 cm (P < .001). The results were consistent even after propensity score matching (P = .002). Tumors ≤1 cm had a hazard ratio (HR) as high as that of distant metastasis (HR 2.8 vs HR 2.6, P = .006). A decreased DSS of ≤ 1 cm tumors was observed in HPV-negative T4 OPSCC, but not in HPV-positive T4 OPSCC (P < .001 vs P = .96). Conclusion: A tumor diameter ≤1 cm was associated with poor prognosis in patients with HPV-negative T4 OPSCC. Tumor diameter ≤1 cm could be a predictive factor for poor outcomes in HPV-negative T4 OPSCC.

TCEB2/HIF1A signaling axis promotes chemoresistance in ovarian cancer cells by enhancing glycolysis and angiogenesis

Ovarian cancer is an extremely malignant gynaecological tumour with a poor patient prognosis and is often associated with chemoresistance. Thus, exploring new therapeutic approaches to improving tumour chemosensitivity is important. The expression of transcription elongation factor B polypeptide 2 (TCEB2) gene is reportedly upregulated in ovarian cancer tumour tissues with acquired resistance, but the specific mechanism involved in tumour resistance remains unclear. In this study, we found that TCEB2 was abnormally highly expressed in cisplatin-resistant tumour tissues and cells. TCEB2 silencing also inhibited the growth and glycolysis of SKOV-3/cisplatin (DDP) and A2780/DDP cells. We further incubated human umbilical vein endothelial cells (HUVECs) with culture supernatants from cisplatin-resistant cells having TCEB2 knockdown. Results revealed that the migration, invasion, and angiogenesis of HUVECs were significantly inhibited. Online bioinformatics analysis revealed that the hypoxia-inducible factor-1A (HIF-1A) protein may bind to TCEB2, and TCEB2 silencing inhibited SKOV-3/DDP cell growth and glycolysis by downregulating HIF1A expression. Similarly, TCEB2 promoted HUVEC migration, invasion, and angiogenesis by upregulating HIF1A expression. In vivo experiments showed that TCEB2 silencing enhanced the sensitivity of ovarian cancer nude mice to cisplatin and that TCEB2 knockdown inhibited the glycolysis and angiogenesis of tumour cells. Our findings can serve as a reference for treating chemoresistant ovarian cancer.

Prognostic factors associated with acute retinal necrosis treated non-surgically.

To analyse the prognostic factors for visual acuity in acute retinal necrosis (ARN) patients treated non-surgically. The clinical data of ARN patients who visited our hospital from January 2010 to January 2023 were retrospectively analysed. Twenty-four patients (29 eyes) were included. Aqueous humour samples were collected from 20 out of 29 eyes, and PCR confirmed that 85% (17/20) of the eyes had VZV infection, 10% (2/20) had CMV infection, and 5% (1/20) had HSV infection. All patients were treated with intravenous antiviral agents. Intravitreal ganciclovir and oral corticosteroids were given according to the patients' wishes. A comparison of visual acuity at the time of first identification of inactive ARN with that at the first visit revealed that 16 (55.2%) eyes improved and 13 (44.8%) did not improve. Logistic regression analysis revealed that risk factors for failure to improve vision after treatment included retinal detachment (odds ratio [OR],33.75; 95% CI, 3.245-351.067; P = 0.003), necrotising retinitis involving the posterior pole (odds ratio [OR],8.167; 95% CI, 1.297-51.403, P = 0.025), and arteritis involving the large retinal arteries (odds ratio [OR],9.167; 95% CI, 1.493-56.297; P = 0.017). The VZV viral load in the aqueous humour at initial presentation was significantly associated with visual prognosis (r = 0.688, P = 0.013), retinal detachment (τ = 0.597, P = 0.021) and the extent of retinal necrosis (τ = 0.57, P = 0.027). The neutrophil to lymphocyte ratio (NLR) of VZV-infected patients at first presentation was significantly correlated with the prognosis of visual acuity (r = 0.616, P = 0.033) and retinal detachment (τ = 0.728, P = 0.004). High NLR and viral DNA copy number in the aqueous humour at the initial presentation, as well as subsequent retinal detachment, necrotising retinitis involving the posterior pole, and arteritis involving the large retinal arteries were risk factors for poor visual prognosis in VZV-infected ARN patients.

NUAKs promote mTOR/c-Myc-induced glucose and glutamine reprogramming for cell growth and metastasis in breast cancer cells

Breast cancer progression and metastasis are closely connected to changes in glucose and glutamine metabolism. While Novel (nua) kinase family 1 (NUAK1) and Novel (nua) kinase family 2 (NUAK2), which are two members of the AMPK-related kinases, have been associated with breast tumorigenesis, their role in the metabolic reprogramming that occurs during breast cancer progression remains unclear. Our research uncovers that NUAKs expression is significantly higher in breast cancer tissues and cell lines, and it is positively related to glycolysis, the pentose phosphate pathway (PPP), glutamine metabolism, and a poor prognosis for breast cancer patients. We show that NUAKs significantly increase metabolic reprogramming, including aerobic glycolysis, PPP, and glutamine metabolism in triple negative breast cancer subtypes but only induce aerobic glycolysis and PPP in luminal breast cancer subtypes to meet the anabolic demands of rapidly dividing breast cancer cells. In contrast, the depletion of NUAKs has the opposite effect. Mechanistic insights reveal that NUAKs activate mammalian target of rapamycin (mTOR) signaling, which in turn upregulates the c-Myc transcription factor, a crucial regulator of glucose and glutamine metabolic gene expression. Moreover, we demonstrate that NUAKs enhance mTOR/c-Myc signaling pathways, leading to increased glucose and glutamine reprogramming, which supports rapid cell proliferation and metastatic potential in breast cancer cells. Importantly, pretreating breast cancer cells with mTOR inhibitors blocked the metabolic reprogramming and tumor-promoting effect of NUAK1/2. Therefore, targeting NUAKs may represent a novel therapeutic strategy for the treatment of breast cancer.