Poor Prognosis In Patients Research Articles

Predictors of prognosis in stroke patients with tandem lesions who undergo emergent stenting.

The optimal endovascular approach for tandem lesions (extracranial internal carotid artery and intracranial large vessel occlusion) is not clear. Aims: The aim was to evaluate the follow-up results of stroke patients with tandem lesions who underwent emergent stenting of extracranial lesions with antithrombotic therapy combined with intracranial MT. Outcomes and predictors of poor prognosis and mortality compared with those of good prognosis at 90days, 1year, and 2years were assessed. A modified Rankin scale (mRS) score was used. Symptomatic intracranial hemorrhage (sICH), National Institutes of Health Stroke Scale (NIHSS) scores at admission and at 24h, successful recanalization, asymptomatic ICH, embolization, malignant infarction, decompression, in-stent restenosis and extracranial complications were also evaluated. The best age cutoff for predicting mortality was analyzed. A total of 71 subjects were included. Using patients with a good prognosis as a reference, the independent variables predicting a poor prognosis were a high 24-h NIHSS score and extracranial complications at all timepoints (3-month, 1-year, and 2-year follow-up). The most appropriate age cutoff for predicting 1-year mortality was 67years [AUC = 0.802 (95% CI = 0.684-0.920); p < .001]. The age cutoff determined for the first year was correlated with the prediction of mortality in the third month and the second year. No significant association was observed between sICH and the groups. In this study, the 24-h NIHSS score after reperfusion and age were predictors of poor prognosis and mortality in stroke patients with tandem lesions who underwent emergent stenting during thrombectomy.

Identification and validation of TSPAN13 as a novel temozolomide resistance-related gene prognostic biomarker in glioblastoma.

Glioblastoma (GBM) is the most lethal primary tumor of the central nervous system, with its resistance to treatment posing significant challenges. This study aims to develop a comprehensive prognostic model to identify biomarkers associated with temozolomide (TMZ) resistance. We employed a multifaceted approach, combining differential expression and univariate Cox regression analyses to screen for TMZ resistance-related differentially expressed genes (TMZR-RDEGs) in GBM. Using LASSO Cox analysis, we selected 12 TMZR-RDEGs to construct a risk score model, which was evaluated for performance through survival analysis, time-dependent ROC, and stratified analyses. Functional enrichment and mutation analyses were conducted to explore the underlying mechanisms of the risk score and its relationship with immune cell infiltration levels in GBM. The prognostic risk score model, based on the 12 TMZR-RDEGs, demonstrated high efficacy in predicting GBM patient outcomes and emerged as an independent predictive factor. Additionally, we focused on the molecule TSPAN13, whose role in GBM is not well understood. We assessed cell proliferation, migration, and invasion capabilities through in vitro assays (including CCK-8, Edu, wound healing, and transwell assays) and quantitatively analyzed TSPAN13 expression levels in clinical glioma samples using tissue microarray immunohistochemistry. The impact of TSPAN13 on TMZ resistance in GBM cells was validated through in vitro experiments and a mouse orthotopic xenograft model. Notably, TSPAN13 was upregulated in GBM and correlated with poorer patient prognosis. Knockdown of TSPAN13 inhibited GBM cell proliferation, migration, and invasion, and enhanced sensitivity to TMZ treatment. This study provides a valuable prognostic tool for GBM and identifies TSPAN13 as a critical target for therapeutic intervention.

CRIP1 inhibits cutaneous melanoma progression through TFAM-mediated mitochondrial biogenesis.

Metastasis is the leading cause of death in patients with cutaneous melanoma. CRIP1 (cysteine-rich protein 1) has been reported to be associated with malignant progression of several cancers. However, the biological function and underlying mechanisms of CRIP1 in melanoma progression are largely unknown. Bioinformatic prediction of CRIP1 expression in melanoma and its association with clinical parameters and prognosis of patients. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blots (WB) were used to detect stable overexpression and knockdown of CRIP1 in melanoma cells. The function of CRIP1 in cutaneous melanoma cells was determined by in vitro functional assays. WB, immunofluorescence, OCR detection, mitochondrial DNA assay, and cytosolic ATP assay were used to determine the relationship between CRIP1 and mitochondrial biogenesis, relationship between TFAM. The expression level of CRIP1 in melanoma tissues is lower than that in normal tissues and suggests a poor prognosis for melanoma patients. Functionally, CRIP1 inhibits the proliferation, migration, and invasion of melanoma cells in vitro. Mechanistic studies revealed that CRIP1 inhibited mitochondrial biogenesis in melanoma cells, which included suppression of relative mitochondrial content, mitochondrial DNA copy number, ATP production, respiratory capacity, and expression levels of oxidative phosphorylation-related proteins. Further studies revealed that CRIP1 inhibits mitochondrial biogenesis and malignant progression in melanoma cells by suppressing the protein levels of TFAM. Our results suggest that CRIP1 inhibits the proliferation and invasive ability of cutaneous melanoma cells by suppressing TFAM-mediated mitochondrial biogenesis. Therefore, CRIP1 may be a potential therapeutic target for melanoma.

COMMD3 Regulates Copper Metabolism via the ATOX1-ATP7A-LOX Axis to Promote Multiple Myeloma Progression

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells, with extramedullary myeloma (EMM) being an aggressive form involving malignant infiltration beyond the bone marrow. Copper metabolism is essential for tumor proliferation and metastasis, with copper metabolism MURR1 domain (COMMD) proteins regulating these processes and maintaining copper homeostasis. Dysregulated copper homeostasis contributes to cancer progression, including MM, with elevated copper levels linked to disease aggressiveness and poor prognosis. This study investigates the role of the COMMD3 in mediating MM cell progression, particularly its influence on copper metabolism. Methods: Comprehensive bioinformatics analyses were conducted on bone marrow and extramedullary samples to determine the expression of COMMD3, which was validated through in vitro and in vivo functional assays. The MM cell lines RPMI8226 and MM1S underwent lentiviral transfection for COMMD3 overexpression and knockdown. RNA sequencing was conducted on COMMD3 knockdown cells to identify differentially expressed genes. Functional assays measured cell proliferation, migration, apoptosis, and copper metabolism, with a non-obese diabetic severe combined immune-deficiency gamma (NSG) mouse xenograft model providing in vivo validation. Results: Elevated COMMD3 expression was correlated with extramedullary myeloma and poor prognosis in MM patients. COMMD3 promoted MM cell proliferation and migration, modulating intracellular copper levels, likely through the ATOX1-ATP7A-LOX copper-metabolism-related pathway. High ATOX1 expression was correlated with worse outcomes, and ATOX1 inhibition abolished COMMD3’s effects. Conclusions: This study highlights the pivotal role of COMMD3 in MM progression, particularly via the ATOX1-ATP7A-LOX axis. These findings provide insights into EMM mechanisms and position COMMD3 as a potential therapeutic target. Future research is needed to validate these findings in larger clinical cohorts and to unravel the precise molecular interactions between COMMD3 and copper metabolism proteins.

Systematic review and meta-analysis of the impact of abnormal expression of long non coding RNA on the prognosis of acute myeloid leukemia

ObjectiveLong non-coding RNA (lncRNA) is aberrantly expressed in a variety of tumor diseases. To date, its specific role in acute myeloid leukemia (AML) has not been fully elucidated. This study aims to evaluate the association between aberrant lncRNA expression and poor prognosis in AML patients, and to systematically assess the relationship between aberrant lncRNA expression and AML prognosis.MethodsWe conducted a comprehensive literature search in PubMed, Embase, Cochrane Library, CNKI (China National Knowledge Infrastructure), WanFang (China Wanfang Database), VIP (China VIP Database), and Sinomed (China Biomedical Literature Database) to identify relevant Chinese and English articles. The search period covered from the inception of these databases to 4 August 2024. Articles were screened according to predefined inclusion and exclusion criteria, and meta-analysis was performed using Stata.ResultsA total of 25 articles were included in the analysis. Aberrant lncRNA expression was significantly associated with reduced overall survival (univariate HR = 2.46, 95%CI 2.11–2.88, P &amp;lt; 0.001; multivariate HR = 2.46, 95%CI 2.11–2.88, P &amp;lt; 0.001), event-free survival (HR = 1.51, 95%CI 1.19–1.90, P = 0.001), recurrence-free survival (HR = 2.82, 95%CI 2.03–3.91, P &amp;lt; 0.001), and disease-free survival (HR = 2.390, 95%CI 1.037–5.507, P = 0.041). These findings were statistically significant. The 25 articles collectively identified 22 lncRNAs whose aberrant expression was associated with AML prognosis. Notably, multiple studies highlighted the aberrant expression of lncRNA CRNDE, ZEB2-AS1, and TUG1 as being particularly relevant to AML prognosis. Our meta-analysis revealed that high expression of lncRNA CRNDE and TUG1 was associated with reduced overall survival, while high expression of lncRNA ZEB2-AS1 was linked to decreased disease-free survival, both with statistically significant differences.ConclusionThe expression levels of lncRNAs are closely associated with the prognosis of AML patients and may serve as important indicators for monitoring prognosis in the future. However, further high-quality studies are needed to validate these findings.

Biomineralized Nanocomposite-Integrated Microneedle Patch for Combined Brachytherapy and Photothermal Therapy in Postoperative Melanoma Recurrence and Infectious Wound Healing.

In the surgical management of malignant melanoma, incomplete tumor resection and large-area cutaneous defects are major contributors to high locoregional recurrence and uncontrolled wound infections, resulting in poor prognosis and prolonged recovery times for patients. Herein, a versatile nanocomposite microneedle patch (referred to as GM-Ag2S/Ca32P) is designed to simultaneously eliminate residual tumor post-surgery and promote the healing of infectious wounds. This microneedle patch effectively penetrates subcutaneous tissues, delivering therapeutic payloads to infiltrating tumor cells and bacteria. The Ag2S/Ca32P nanocomposites encapsulated within the microneedle patch decompose in the acidic microenvironment of tumors and bacterial biofilms, releasing radioactive 32P and Ag2S nanodots, which enhance tumor eradication and bacteria killing through synergistic brachytherapy and photothermal therapy (PTT). Moreover, the nanocomposite microneedle patch promotes scar-free wound healing by reducing inflammation, and promoting granulation tissue formation, collagen deposition, and angiogenesis, thanks to localized hyperthermia, radiation, and the swelling and biodegradation of the microneedle matrices. This microneedle patch-based postoperative adjuvant therapy offers a comprehensive strategy for addressing melanoma recurrence and infectious wound healing, with promising potential for clinical application in postsurgical management.

Novel prognostic score for colorectal necrosis requiring emergency surgery.

Colorectal necrosis is a serious condition associated with high morbidity and mortality. We investigated the clinical features and prognostic factors of patients who underwent emergency surgery for colorectal necrosis. Data from 40 patients who underwent surgery for colorectal necrosis were reviewed retrospectively to assess the various clinical and operative factors and risk factors for hospital mortality. The Kaplan-Meier method showed that total colectomy, a platelet count < 100,000/μL, a prothrombin time-international normalized ratio ≥ 1.5, creatine kinase ≥ 566 U/L, lactate ≥ 22.8mg/dL, base excess < -12mmol/L, platelet-lymphocyte ratio < 321, and C-reactive protein/albumin ratio < 1.0 were significantly associated with poor prognosis. Multivariate analyses identified that a platelet count < 100,000/μL (hazard ratio = 7.101, p = 0.0070) and base excess < -12mmol/L (hazard ratio = 3.663, p = 0.0464) were independent predictive factors for hospital mortality in patients with colorectal necrosis. We established a novel prognostic score based on platelet count, creatine kinase, and base excess. Patients with a novel prognostic score ≥ 4 had significantly poorer survival rates than patients with a score ≤ 3 (0.0% vs. 73.4%, p < 0.001). A platelet count < 100,000/μL and base excess < -12mmol/L are associated with a poor prognosis for patients with colorectal necrosis. This novel prognostic score may be a more accurate prognostic factor for patients with colorectal necrosis.

Targeting Methionine Addiction of Osteosarcoma with Methionine Restriction to Overcome Drug Resistance: A New Paradigm for a Recalcitrant Disease

Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Cancer cells need larger amounts of exogenous methionine in order to grow compared to normal cells, despite their ability to synthesize normal or greater amounts of methionine from homocysteine, due to increased transmethylation reactions in cancer cells. Methionine restriction therapy, including recombinant methioninase (rMETase), arrests cancer cells in the late-S/G2 phase of the cell cycle by targeting methionine addiction. First-line chemotherapy for osteosarcoma, including methotrexate (MTX), doxorubicin (DOX), and cisplatinum (CDDP), targets cells in the S/G2-phase, where cancer cells are also inhibited by methionine restriction, resulting in the synergy of methionine restriction to overcome drug resistance. In the present review, we describe the synergistic efficacy of conventional chemotherapy and methionine restriction therapy, including rMETase, in overcoming the drug resistance of osteosarcoma. The clinical potential of this new paradigm to overcome the drug resistance of osteosarcoma is discussed.

A new prognostic model based on serum apolipoprotein AI in patients with HBV-ACLF and acutely decompensated liver cirrhosis

Background/AimTo investigate the prognostic value of circulating apolipoprotein AI (apoAI) levels and develop a new prognostic model in individuals with acute-on-chronic liver failure (ACLF) and acute decompensation (AD) of liver cirrhosis caused by hepatitis B virus (HBV) infection.MethodsBaseline levels of serum lipids were measured, and data concerning the presence of complications were collected from 561 HBV-ACLF and AD patients. Survival analysis was conducted by log-rank test. Proportional hazards model was used to perform multivariate analysis. The dynamics of serum apoAI levels were also explored in 37 HBV-ACLF patients.ResultsIn the cohort, the negatively correlation was found between the Model for End-Stage Liver Disease (MELD) score and serum apoAI levels (r = -0.7946, P < 0.001). Circulating apoAI concentration was an independent risk factor for 90-day survival according to Cox multivariate analysis. A new prognostic score-integrated serum lipid profile for ACLF patients (Lip-ACLF score = 0.86×International Normalized Ratio (INR) + 0.0034×total bilirubin (TBIL) (µmol/L) + 0.99× hepatorenal syndrome (HRS) (HRS: no/1; with/2) + 0.50×hepatic encephalopathy (HE) (grade/ponint: no/1; 1–2/2; 3–4/3) − 2.97×apoAI (g/L) + 5.2) was subsequently designed for the derivation cohort. Compared to MELD score, Child-Turcotte-Pugh (CTP) score or apoAI, Lip-ACLFs was superior for the prediction of 90-day outcomes (receiver operating characteristic curve (ROC): 0.930 vs. 0.885, 0.833 or 0.856, all P < 0.01), as was the validation cohort (ROC 0.906 vs. 0.839, 0.857 or 0.837, all P < 0.05). In Kaplan‒Meier survival analysis, low apoAI levels (< 0.42 g/L) at baseline indicated poor prognosis in ACLF and AD patients. Among the 37 patients, the deceased individuals were characterised with significantly decreased serum apoAI levels during the follow-up test compared with those at baseline (P < 0.05), whereas in patients with a good prognosis, the serum apoAI levels remained stable during the follow-up.ConclusionIn HBV-ACLF and AD patients, lower serum apoAI levels suggest greater disease severity and 90-day mortality risk. For predicting the short-term prognosis of these patients, the new Lip-ACLF score might serve as a potential model.

β-Elemene inhibits epithelial-mesenchymal transformation in non-small cell lung cancer by targeting ALDH3B2/RPSA axis.

The pharmacological mechanism of β-elemene in non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we identified aldehyde dehydrogenase 3B2 (ALDH3B2) as a pivotal target for β-elemene's anti-tumor effects in NSCLC by bioinformatic analysis. The overexpression of ALDH3B2 is specifically associated with the malignancy of NSCLC and the poor prognosis in patients with lung adenocarcinoma. Furthermore, we observed a positive correlation between ALDH3B2 levels and the sensitivity of cells to β-elemene. Additionally, we confirmed that β-elemene suppresses ALDH3B2 expression in PC-9 and NCI-H1373 cell lines. Notably, ALDH3B2 overexpression in NCI-H1373 cells resulted in enhanced migration, invasion, and a prominent epithelial-mesenchymal transition (EMT), which could be attenuated by β-elemene via inhibition of ALDH3B2 expression. Subsequent investigations demonstrated that ALDH3B2 overexpression upregulated ribosomal protein SA (RPSA) expression. β-elemene counteracted the upregulation of RPSA by suppressing ALDH3B2. Furthermore, knocking down of ALDH3B2 and β-elemene treatment significantly reduced the activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways via suppression of RPSA. In summary, our research uncovers that in NSCLC, ALDH3B2 functions as an oncogenic protein, promoting tumor progression. Meanwhile, β-elemene inhibits EMT of NSCLC by inhibition of ALDH3B2/RPSA axis and subsequently downregulating AKT and ERK signaling pathways. Our study highlights the significant role of ALDH3B2 in the progression of NSCLC, signifying it as a potential pharmacodynamic biomarker for β-elemene. These findings enrich the understanding of anti-tumor pharmacological mechanism of β-elemene, and provides new theoretical and experimental foundations for its potential application in the treatment of NSCLC.

Prognostic study of intracranial branch atheromatous disease in the blood-supplying areas of the lenticulostriate and paramedian pontine arteries.

Branch atheromatous disease (BAD) is prone to early neurological deterioration (END), leading to a poor prognosis. The most common arteries causing END are the lenticulostriate arteries (LSA) and the paramedian pontine arteries (PPA). To gain insight into the characteristics of symptomatic plaques and their association with poor prognosis in patients with BAD, we conducted a prospective study using high-resolution magnetic resonance imaging (HRMRI). A total of 75 patients with BAD in the vascular range of LSA or PPA were recruited for this study. The vascular and plaque features of the carrier middle cerebral artery (MCA) and basilar artery (BA) were evaluated through the application of HRMRI, and the local cerebral blood flow (CBF) of the lesion was assessed through pseudo-continuous arterial spin-labeling (pCASL), and the number and location of cerebral microbleeds (CMBs) were documented by susceptibility-weighted imaging (SWI). Univariable and multivariable logistic regression analyses were performed to analyze the factors that affected the prognosis. A poor prognosis was observed in 24 patients (32%) with BAD. A total of 28 patients (37%) developed END. Multifactorial analysis showed statistically significant differences in the dorsal plaque of BA (OR: 19.15, 95% CI 1.72-385.37, p=0.028), male (OR: 26.22, 95% CI 3.18-406.31, p=0.007), and NIHSS at 7 days of onset (OR: 2.24, 95% CI 1.4-4.45, p=0.004). In patients with BAD in LSA and PPA areas, the dorsal plaque of BA, male, and NIHSS at 7 days of onset were independent risk factors for poor prognosis.

High-adhesion ovarian cancer cell resistance to ferroptosis: The activation of NRF2/FSP1 pathway by junctional adhesion molecule JAM3.

Ovarian cancer remains a significant challenge due to the lack of effective treatment and the resistance to conventional therapies. Ferroptosis, a form of regulated cell death characterized by iron-depend and lipid peroxidation, has emerged as a potential therapeutic target in cancer. Ovarian cancer has been reported to exert an "iron addiction" phenotype which makes it is susceptible to ferroptosis inducers. However, we found here that high-adhesion ovarian cancer cells were resistant to ferroptosis. Mechanistically, by PCR array, we identified junctional adhesion molecule 3 (JAM3) as a key mediator of ferroptosis resistance in high-adhesion ovarian cancer cells. Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis. Furthermore, we demonstrated that JAM3 promoted ferroptosis resistance through NRF2-induced upregulation of FSP1, a critical suppressor of lipid peroxidation. Inhibition of the NRF2/FSP1 pathway eliminated high-adhesion, JAM3 overexpressed ovarian cancer cells resistance to ferroptosis, and decreased cancer cells resistance to cisplatin. Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer.

Negative Impact of High FOXP3 Status in Lymph Nodes of Esophageal Squamous Cell Carcinoma Patients.

Available data on the immune profiles of regional lymph nodes in individuals with esophageal squamous cell carcinoma (ESCC) are limited. This study investigated the immune profiles of proximal regional lymph nodes (PLNs) and evaluated the association between PLNs and the outcomes of patients with ESCC. This study included 39 patients with ESCC who underwent subtotal esophagectomy with three-field lymph node dissection. The immune profiles of tumor-infiltrating lymphocytes and PLNs were evaluated through immunohistochemistry. Furthermore, the impact of this immune profile on long-term outcomes was analyzed. Cox proportional-hazards analysis for overall survival revealed that ypT ≥3 [hazard ratio (HR)=8.91; 95% confidence interval (CI)=1.59-49.8] and high FOXP3 status in PLNs (HR=4.29; 95%CI=1.06-17.4) are significant independent prognostic factors. Meanwhile, analysis of disease-free survival (DFS) revealed that ypT ≥3 (HR=5.52; 95%CI=1.15-26.6) and ypN ≥1 (HR=7.74; 95%CI=1.58-37.9) are independent prognostic factors. Furthermore, high FOXP3 status in PLNs was associated with low DFS rate, although the association was not statistically significant (HR=1.70; 95%CI=0.58-5.02). High FOXP3 status in PLNs is associated with poor prognosis in patients with ESCC.

Stress hyperglycemia ratio is associated with delayed cerebrovascular ischemia and poor prognosis in patients with aneurysmal subarachnoid hemorrhage undergoing neurointerventional therapy

Stress hyperglycemia ratio is associated with delayed cerebrovascular ischemia and poor prognosis in patients with aneurysmal subarachnoid hemorrhage undergoing neurointerventional therapy

A practical distribution pattern of α-SMA-positive carcinoma associated fibroblasts indicates poor prognosis of patients with pancreatic ductal adenocarcinoma.

Purpose The present study aimed to clarify the distribution pattern of carcinoma associated fibroblasts (CAFs) across pancreatic ductal adenocarcinoma (PDAC) and its prognostic prediction value. Methods Data of two cohorts were retrospectively collected from consecutive patients who underwent primary pancreatic resection from January 2015 to December 2017. We used tumor specimens to screen out the most suitable markers for the spatial distribution analysis for CAFs subpopulations. We utilized a tissue microarray to assess the spatial intensity of α-SMA expression within the tumor microenvironment. Specifically, we classified CAFs into two types based on their α-SMA spatial expression. Type II CAFs were designated as those located in the juxtatumoural stroma with α-SMA expression that was moderate or higher, and those in the peripheral stroma with α-SMA expression that was less than moderate. All other cases, where the α-SMA expression did not meet these criteria, were categorized as Type I CAFs. Multivariable Cox proportional hazards regression was used to assess risk factors associated with patient outcomes. RNA sequencing data were obtained from bulk tumor samples and isolated CAFs from patients to reveal the distinct pattern and elucidated their fundamental characteristics. Results The α-SMA spatial intensity was the most suitable variable for representative of CAFs spatial characteristics. Patients with Type Ⅰ CAFs were more likely to be allocated into N1 or N2 of the N stage and Ⅱ and Ⅲ of the TNM stage. The spatial distribution pattern of CAFs (Type Ⅰ v.s. Type Ⅱ: HR, 1.568; 95 % CI, 1.053-2.334; P = 0.027) was an independent prognostic factor in the discovery cohort, so as in the validation (Type Ⅰ vs. Type Ⅱ: HR, 2.197; 95 % CI, 1.410-3.422; P = 0.001). RNA sequencing analysis revealed that the differentially expressed genes (DEGs) in Type I CAFs are closely associated with those in corresponding tumor tissues, highlighting the enhanced biological significance of immune-related and oncogenic invasive pathways. Conclusions Our findings that two types of α-SMA-positive CAFs with different spatial patterns present heterogeneously across tissues of PDACs and correlated with patients' outcomes. The spatial location of CAFs may facilitate patients' selection in precision medicine of PDACs.

Multifaceted functions of the Wilms tumor 1 protein: From its expression in various malignancies to targeted therapy.

Wilms tumor 1 (WT1) is a multifaceted protein with dual functions, acting both as a tumor suppressor and as a transcriptional activator of oncogenes. WT1 is highly expressed in various types of solid tumors and leukemia, and its elevated expression is associated with a poor prognosis for patients. High WT1 expression also indicates a greater risk of refractory disease or relapse. Consequently, targeting WT1 is an effective strategy for disease prevention and relapse mitigation. Substantial information is available on the pathogenesis of WT1 in various diseases, and several WT1-targeted therapies, including chemical drugs, natural products, and targeted vaccines, are available. We provide a comprehensive review of the mechanisms by which WT1 influences malignancies and summarize the resulting therapeutic approaches thoroughly. This article provides information on the roles of WT1 in the pathogenesis of different cancers and provides insights into drugs and immunotherapies targeting WT1. The goal of this work is to provide a systematic understanding of the current research landscape and of future directions for WT1-related studies.

Integrative pan-cancer genomic analysis highlights mitochondrial protein p32 as a potential therapeutic target in Myc-driven tumorigenesis.

Tumor metabolic reprogramming, particularly involving mitochondrial metabolism, is a hallmark of malignancy. The mitochondrial protein p32 (C1QBP) has emerged as a critical regulator in various cancers, frequently associated with poor patient prognosis. However, the role of p32 across different cancer types remains largely unexplored. Our bioinformatics analysis demonstrates that p32 is significantly overexpressed in several malignancies and is closely involved in multiple oncogenic pathways related to tumor progression and metabolic reprogramming. Moreover, p32 expression positively correlates with genomic heterogeneity and drug sensitivity. We identified a strong association between p32 and c-Myc in both normal and cancerous tissues. We confirmed that p32 is a direct transcriptional target of c-Myc, which upregulates p32 by binding to its promoter. Functional experiments established that p32 is crucial for MYC-driven tumorigenesis, with its knockdown or knockout inhibiting tumor proliferation and extending survival. Targeting p32 may inhibit MYC-driven tumorigenesis, highlighting its potential as a therapeutic target in MYC-driven cancers.

FAM49B drives colorectal cancer progression by stabilizing c-Myc through NEK9 phosphorylation.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is the second leading cause of cancer mortality. FAM49B, a member of the FAM49 gene family, is a recently identified, evolutionarily conserved gene. Emerging studies indicate that FAM49B plays a role in various cancers, though its specific mechanism in CRC remains largely unexplored. In this study, we observed that FAM49B was abnormally expressed in CRC tissues and cell lines, with elevated expression correlating with poor patient prognosis. FAM49B knockdown markedly suppressed CRC cell proliferation by arresting the cell cycle and reducing cell migration and invasion. Single-cell RNA-seq (ScRNA-seq) analysis revealed that high FAM49B expression in malignant epithelial cell clusters was strongly linked to c-Myc oncogene activation. Further, FAM49B knockdown significantly reduced c-Myc expression by enhancing its K48 ubiquitination. We identified NEK9 as a direct interacting partner of FAM49B, with FAM49B knockdown inhibiting NEK9-Thr210 phosphorylation. Similarly, high NEK9 expression was linked to unfavorable prognosis in CRC. In FAM49B-overexpressing CRC cells, NEK9 knockdown significantly suppressed c-Myc expression, c-Myc-ser62 phosphorylation, and reduced cell proliferation, migration, and invasion. Thus, directly targeting the FAM49B/NEK9/c-Myc pathway presents a promising therapeutic approach for c-Myc positive CRC patients.

Abstract TP140: The Blood Proteome Profiling Identifies Biomarkers Associated With Ischemic Stroke Prognosis

Blackground: Due to the narrow therapeutic time window and strict indications, there are still a large number of patients unable to receive thrombolysis and endovascular therapy, resulting in a poor long-term functional prognosis. Moreover, it is unclear what effective therapeutic targets as well as molecular systemic changes in stroke in the chronic phase. Therefore, to provide useful insights into its pathogenesis, identification of therapeutic targets and biomarker discovery, we analyze the proteomic profile of blood in ischemic stroke patients in order to gain insights into the disease. Method: We use proteomics technologies to examine serum at baseline and use the modified Rankin Scale (mRS) to evaluate neurological function at baseline and 3-month follow-up after ischemic stroke. Based on data-independent acquisition mass spectrometry and parallel reaction monitoring (PRM) technology, we implement a staged discovery-confirmatory pipeline in serum samples from better prognosis patients(n=48) and poor prognosis patients(n=50) according to mRS to comprehensively identify and validate more accurate biomarker performance characteristics of candidate proteins. Results: In this proteomic study, we characterize 4,740 circulating proteins and 324 differentially expressed proteins in 98 patients. We identify circulating proteomic signatures for ischemic stroke prognosis, and correlate these with clinical data to develop a proteomic profile of 14 markers. Based on machine learning algorithms such as LASSO regression and exhaustive feature selection (EFS), we finally identify some biomarkers (IQGAP2, LYZ, PDGFD, EHD3, CETP, FYB1) are validated as contributors to the ischemic stroke prognosis model through verification of an additional 58 serum samples. (AUC range:0.65-0.99). Conclusion: We identify potential biomarkers and therapeutic targets and offer an opportunity for more precise prognosis and treatment in ischemic stroke.

Systematic literature review (SLR) of prognostic factors (PFs) in locally advanced rectal cancer (LARC) and mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer (RC).

303 Background: Innovative immunotherapies arebeing developed to improve clinical outcomes in patients (pts) withdMMR/MSI-H LARC who respond poorly to the current standard of care. A comprehensive overview of PFs in dMMR/MSI-H LARC may provide insight into the natural history of this disease to inform clinical study design and pt risk stratification. Methods: Systematic searches of bibliographic databases (EMBASE, MEDLINE, Cochrane; 2013–2023) and congress websites (2021–2023) were conducted to identify PFs for tumor response and survival outcomes in adult pts with LARC (SLR1) and dMMR/MSI-H RC (SLR2). Given the expected high volume of evidence, SLR1 was limited to large observational studies (≥1000 pts) and clinical trials (≥100 pts); SLR2 had no such limits. Results: 95 of 2307 publications met the inclusion criteria for SLR1. Of the PFs reported in ≥20 studies, older age, more lymph node involvement or fewer nodes assessed, higher T-stage or larger tumor size, higher histologic grade, and more comorbidities were most frequently significantly associated with poorer patient prognosis (Table). 3 of 289 publications met the inclusion criteria for SLR2. Neoadjuvant chemoradiation therapy (CRT) compared to chemotherapy (CT) was associated with statistically significant worse disease-free survival (DFS) and distant metastasis-free survival (DMFS), while T- or N-stage, age, and sex did not significantly impact these outcomes. Low vs middle tumor localization was also associated with worse DMFS. Stage III and IV disease were associated with worse RC-specific survival, while surgical procedure (segmental vs extended) showed no difference in overall survival (OS). The addition of neoadjuvant CRT or adjuvant CRT/CT to surgery alone had no impact on OS but was associated with worse DFS. Conclusions: Evidence regarding PFs in dMMR/MSI-H RC is scarce and may limit its interpretability, highlighting the need for further research that may be informed by the PFs identified from SLR1. The results from these SLRs may be helpful for optimizing patient management and treatment decision making, and to further contextualize RC clinical trials. PFs reported in ≥20 studies with ≥75% of studies reporting significant results in pts with LARC. PF Studies reporting PF (n) Studies reporting significant* impact of PF on prognosis (%) Poorer prognosis group Top 2 most frequently reported outcomes Age 59 81.4 Older OS, DFS Lymph node involvement/assessment 55 78.2 Yes or higher N stage OS, DFS T-stage or tumor size 53 79.2 Higher or larger OS, DFS Histologic grade 37 75.7 Higher OS, pathological complete response (pCR) Comorbidities 23 87.0 More OS, pCR *p-value &lt;0.05 was considered significant as reported in the identified studies.