Lower Survival Rate In Patients Research Articles

PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression

Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).

A novel LINC02321 promotes cell proliferation and decreases cisplatin sensitivity in bladder cancer by regulating RUVBL2

Bladder cancer (BC) has a high incidence and is prone to recurrence. In most instances, the low 5-year survival rate of advanced BC patients results from postoperative recurrence and drug resistance. Long noncoding RNAs (lncRNAs) can participate in numerous biological functions by regulating the expression of genes to affect tumorigenesis. Our previous work had demonstrated that a novel lncRNA, LINC02321, was associated with BC prognosis. In this study, A high expression of LINC02321 was found in BC tissues, which was associated with poor prognosis in patients. LINC02321 promoted both proliferation and G1-G0 progression in BC cells, while also inhibited sensitivity to cisplatin. Mechanistically, LINC02321 can bind to RUVBL2 and regulate the expression levels of RUVBL2 protein by affecting its half-life. RUVBL2 is involved in the DNA damage response. The potential of DNA damage repair pathways to exert chemosensitization has been demonstrated in vivo. The rescue experiment demonstrated that RUVBL2 overexpression can markedly abolish the decreased cell proliferation and the increased sensitivity of BC cells to cisplatin caused by LINC02321 knockdown. The results indicate that LINC02321 functions as an oncogene in BC, and may serve as a novel potential target for controlling BC progression and addressing cisplatin resistance in BC therapy.

Glioblastoma mechanobiology at multiple length scales

Glioblastoma multiforme (GBM), a primary brain cancer, is one of the most aggressive forms of human cancer, with a very low patient survival rate. A characteristic feature of GBM is the diffuse infiltration of tumor cells into the surrounding brain extracellular matrix (ECM) that provide biophysical, topographical, and biochemical cues. In particular, ECM stiffness and composition is known to play a key role in controlling various GBM cell behaviors including proliferation, migration, invasion, as well as the stem-like state and response to chemotherapies. In this review, we discuss the mechanical characteristics of the GBM microenvironment at multiple length scales, and how biomaterial scaffolds such as polymeric hydrogels, and fibers, as well as microfluidic chip-based platforms have been employed as tissue mimetic models to study GBM mechanobiology. We also highlight how such tissue mimetic models can impact the field of GBM mechanobiology.

Potential value of expression of receptor accessory protein 4 for evaluating the prognosis of lower-grade glioma patients.

REEP4 is involved in the regulation of the biological process of mitosis. Lower grade glioma (LGG), as a malignant tumor, is accompanied by abnormalities in mitosis, but there have been no reports of REEP4 so far. We collected transcriptome data, DNA methylation data and the clinical characteristics of thousands of patients with LGG. Various big data analysis methods and molecular biology experiments were employed to reveal the impact of REEP4 on the pathological process of LGG. It was found that the expression of REEP4 was significantly elevated and negatively regulated by its methylation site. Therefore, both the high expression of REEP4 and low methylation state of cg16311504 showed that the patients are correlated with lower patient survival rate. In addition, high REEP4 expression participates in the regulation of various cancer-related cellular signaling pathways, such as the cell cycle, MAPK signaling pathway, NOD-like receptor signaling pathway, etc. More importantly, the level of immune cell infiltration significantly increased in the high expression group of REEP4 in the LGG tumor microenvironment and REEP4 has a high positive correlation with PD-L1 and other immune checkpoints. In brief, this study is the first to introduce REEP4 in malignant tumors, which can be used as an independent risk factor that participates in the malignant process of LGG. More importantly, REEP4 has the potential to become a new star in the field of anti-tumor treatment.

Optimisation Studies of Mesoporous Silica Nanoparticle as a Drug Carrier for Gemcitabine: Enhancing Therapeutic Effectiveness in Pancreatic Cancer

Pancreatic cancer, often referred to as “the silent killer”, presents with minimal or no symptoms in its early stages, leading to late detection when surgical resection is no longer the optimal treatment option. Gemcitabine (GEM), one of the leading chemotherapeutic drug for advanced stages of cancer, is a crucial treatment for pancreatic cancer. However, the low 5-year survival rate of pancreatic cancer patients highlight the limited effectiveness of current treatments. In recent years, mesoporous silica nanoparticles (MSNP) have garnered significant attention in both scholarly and pharmaceutical fields due to their unique combination of properties including stable porous structure and high loading capacities. This research aims to investigate the potential of MSNP as a carrier for anticancer drugs, specifically GEM. MSNP was successfully synthesized in the laboratory using sol-gel method with tetraethyl orthosilicate (TEOS) as silica source and cetyltrimethylammonium bromide (CTAB) as surfactant template. Comprehensive morphological and physical characterizations of the MSNP product were performed through transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX) spectroscopy, element mapping, X-ray diffractometry (XRD), and accelerated surface area porosimetry (ASAP). The results demonstrate that MSNP exhibits desirable properties for drug loading, including a stable mesoporous structure with pore size of ~ 4.94 nm, a high surface area of about 278.32 m²/g, and average particle diameter of approximately 85 nm. The effects of incubation time and initial GEM concentrations were studied to determine the optimal drug loading parameters for the MSNP vehicle. The successful loading of up to 24 µg of GEM in 1 mg of MSNP achieved in an optimized incubation time of 2 hour, validates the tremendous potential of MSNP as a potential anticancer drug carrier in pancreatic cancer treatment. These findings provide a valuable reference for future research and investigations in this promising field.

The Prognostic Role of Genetic Aberrations in Mantle Cell Lymphoma: A Literature Review and Clinical Experience

Mantle cell lymphoma (MCL) is a type of peripheral B-cell non-Hodgkin’s lymphoma characterized by constitutive cyclin D1 overexpression leading to cell-cycle dysregulation and disruption of DNA damage repair. Apart from the typical translocation t(11;14)(q13;q32) and more rare variants, such as t(2;11)(p11;q13) and t(11;22)(q13;q11), a considerable number of patients quite often show secondary molecular and chromosomal aberrations underlying heterogeneity of the clinical course of MCL. Among a wide range of molecular genetic abnormalities, particular attention during the last years has been concentrated on studying the so-called double-hit MCL within a subgroup of patients with translocations involving CCND1 and MYC genes. Double-hit MCL is distinguished with rapid progression and tumor generalization at the time of diagnosis. Poor prognosis and low survival rates in most MCL patients call for the fastest possible diagnosis. Morphological and immunohistochemical as well as genetic methods (standard cytogenetic technique and fluorescence in situ hybridization) contribute to improving the quality of evidence-based diagnosis. The results of comprehensive diagnostic studies optimize prognosis assessment and treatment decision making in clinic.

An Accelerated Failure Time Model to Predict Cause-Specific Survival and Prognostic Factors of Lung and Bronchus Cancer Patients with at Least Bone or Brain Metastases: Development and Internal Validation Using a SEER-Based Study

Background: This study addresses the significant challenge of low survival rates in patients with cause-specific lung cancer accompanied by bone or brain metastases. Recognizing the critical need for an effective predictive model, the research aims to establish survival prediction models using both parametric and non-parametric approaches. Methods: Clinical data from lung cancer patients with at least one bone or brain metastasis between 2000 and 2020 from the SEER database were utilized. Four models were constructed: Cox proportional hazard, Weibull accelerated failure time (AFT), log-normal AFT, and Zografos–Balakrishnan log-normal (ZBLN). Independent prognostic factors for cause-specific survival were identified, and model fit was evaluated using Akaike’s and Bayesian information criteria. Internal validation assessed predictive accuracy and discriminability through the Harriel Concordance Index (C-index) and calibration plots. Results: A total of 20,412 patients were included, with 14,290 (70%) as the training cohort and 6122 (30%) validation. Independent prognostic factors selected for the study were age, race, sex, primary tumor site, disease grade, total malignant tumor in situ, metastases, treatment modality, and histology. Among the accelerated failure time (AFT) models considered, the ZBLN distribution exhibited the most robust model fit for the 3- and 5-year survival, as evidenced by the lowest values of Akaike’s information criterion of 6322 and 79,396, and the Bayesian information criterion of 63,495 and 79,396, respectively. This outperformed other AFT and Cox models (AIC = [156,891, 211,125]; BIC = [158,848, 211,287]). Regarding predictive accuracy, the ZBLN AFT model achieved the highest concordance C-index (0.682, 0.667), a better performance than the Cox model (0.669, 0.643). The calibration curves of the ZBLN AFT model demonstrated a high degree of concordance between actual and predicted values. All variables considered in this study demonstrated significance at the 0.05 level for the ZBLN AFT model. However, differences emerged in the significant variations in survival times between subgroups. The study revealed that patients with only bone metastases have a higher chance of survival compared to only brain and those with bone and brain metastases. Conclusions: The study highlights the underutilized but accurate nature of the accelerated failure time model in predicting lung cancer survival and identifying prognostic factors. These findings have implications for individualized clinical decisions, indicating the potential for screening and professional care of lung cancer patients with at least one bone or brain metastasis in the future.

Absence of July effect on trauma outcomes at the start of the academic medical calendar

Purpose The “July effect” refers to the phenomenon of a higher complication incidence and lower survival rate for patients treated at academic institutions during the beginning of the academic medical calendar. To date, no multi-center study has examined the presence of a “July effect” in a large cohort of trauma patients. We sought to determine if there is a by-month effect on survival and length of stay (LOS) for trauma patients in large academic centers. Methods We performed a multicenter, retrospective cohort study between 2010 and 2020 from five high-volume academic trauma centers in the United States. We included all adult motor vehicle collision (MVC) traumas evaluated at all centers in the study population (age >16 years, mechanism of injury classified as “motor vehicle collision”). Data included date and time of injury, injury severity score (ISS), LOS, and mortality. Each injury was classified as minor (ISS 1–8), moderate (9–15), severe (16–24), and very severe (>25). The mortality and LOS for each range over the entire epoch was calculated by month for each ISS classification. Results We analyzed 39,668 MVC traumas (mean age 41.83, range 39.9–43.3 among sites, 58.9% male and range 56.1–60.4%, 67.4% white range 42.3–84.7%). Survival for the “very severe” traumas ranged from 86.7–90.3%. Across the five sites, there was no significant change in survival (either increased or decreased mortality) or LOS for MVC patients in July or August for any injury classification level. Both age and ISS had a significant effect on survival (OR 0.02 for ISS >25, 0.22 for patients >65 years-old, both p < 0.05). Conclusions In five high-volume centers, there was no significant effect of the July transition on survival or LOS of MVC trauma patients.

PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2.

TPS585 Background: SEER data report that US patients with advanced gastrointestinal (GI) cancers have a poor prognosis as indicated by low 5-year survival rates in patients with colorectal (15.6%), liver (3.5%), and other GI cancers, highlighting the need for more efficacious treatments. Dysregulation of the mTOR pathway contributes to tumor growth and disease progression in many cancers, including GI cancers. The tumor suppressor genes TSC1 and TSC2 are critical negative regulators of mTOR activity whose inactivation can lead to tumor cell growth. Inactivating TSC1 and TSC2 alterations have been observed in GI cancers with a combined frequency of up to 6.5% in hepatocellular carcinoma, 1.7% in colorectal adenocarcinoma and gastrointestinal stromal tumors, and 1.6% in cholangiocarcinoma. nab-Sirolimus, approved in the US for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had a confirmed response. Most treatment-related adverse events were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION 1 trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers harboring TSC1 or TSC2 inactivating alterations. The trial is open to patients with GI cancers with inactivating alterations in TSC1 or TSC2. Methods: In PRECISION 1 (NCT05103358), eligible patients are ≥12 years old and mTORi-naïve, have advanced malignant solid tumors harboring TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) of tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began in March 2022. Collaboration with leading NGS vendors is expediting the identification of patients with qualifying TSC1 and TSC2 alterations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Clinical trial information: NCT05103358 .

Abstract C083: SMNDC1 alters the splicing of ERK to potentiate its activity in pancreatic cancer

Abstract While oncogenic KRAS is believed to drive pancreatic cancer by maintaining active ERK signaling, our studies suggest that ERK signaling can be also regulated in a KRAS-independent manner. We found that survival motor neuron domain containing 1 (SMNDC1), a poorly studied splicing factor is amplified or upregulated in 30% of pancreatic ductal adenocarcinomas (PDACs) and associated with lower survival rates in patients. To determine the role of SMNDC1 in PDACs, we conducted loss- and gain-of-function studies and found that this splicing factor drives tumor growth by promoting the retention of A/C-rich cassette exons, which otherwise are excluded or retained at a lower rate after RNA splicing in normal cells. Importantly, across tumors, SMNDC1 promoted the inclusion of the cassette exon 4 (E4) of MAPK3 (ERK1), which encodes the kinase-activating phosphorylation sites (Thr202/Tyr204). Forced exclusion of MAPK3-E4 using antisense oligonucleotide morpholino (ASO), inhibited tumor establishment, ERK1 phosphorylation, and expression of ERK-targets. We then tested if retention of E4 in MAPK3 by SMNDC1 is a mechanism to resist chemical inhibition of the KRAS-MEK-ERK pathway. We found that PDAC cells acutely treated with selective MEK inhibitors (MEKi), trametinib, or selumetinib increased SMNDC1 and MAPK3 E4 retention expression. In addition, PDAC cells deficient for SMNDC1 were 25-fold more sensitive to trametinib than isogenic cells expressing SMNDC1. To demonstrate that increased E4 retention drives MEKi resistance, we concomitantly treated SMNDC1 proficient PDAC cells with trametinib and E4 ASO, which led to an 8-fold increase in sensitivity compared to cells treated with trametinib and control ASO. Also, we found that resistance to standard-of-care chemotherapeutic agents to treat PDAC, Gemcitabine (GEM) and 5-fluorouracil (5-FU), was also associated with increased expression of SMNDC1 and retention of E4 in MAPK3 in multiple PDAC cells lines. To determine the biochemical mechanism that leads to E4 inclusion by SMNDC1, we performed high-throughput RNA Bind-n-Seq (RBNS) and e-CLIP of SMNDC1 in PDAC cells which revealed specific RNA-binding preference for C-rich polypyrimidine tract upstream of retained MAPK3-E4. To validate these findings, we constructed a dual-fluorescent reporter mini-gene of MAPK3-E4 splicing, with either wild-type sequences in E4 and polypyrimidine tract, or different point mutations at the predicted cis-elements. We found that retention of the E4 of MAPK3 is dependent on SMNDC1-binding to C-rich sequences at distant 3’ splice sites of PDAC cells. These data support that PDAC cells exploit a “splicing switch” to promote ERK kinase activity and resistance to therapies, independent of activating mutations in the EGFR/RAS/MAPK pathway and offer a druggable alternative to block oncogenic signaling and altered RNA splicing in PDAC. Citation Format: Md Afjalus Siraj, Yushan Zhang, Prabir Chakraborty, Robert Tseng, Li-Ting Ku, Grant Goda, Gilbert Giri, Deanne Yugawa, Mathew Wang, Shamik Das, Anindya Dey, Shailendra Dhar Dwivedi, Geeta Rao, Min Zhang, Da Yang, Md Nazir Hossen, Wei-Qun Ding, Kar-Ming Fung, Daniel Dominguez, Resham Bhattacharya, Luisa Escobar-Hoyos, Priyabrata Mukherjee. SMNDC1 alters the splicing of ERK to potentiate its activity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C083.

A SERS-assisted 3D organotypic microfluidic chip for in-situ visualization and monitoring breast cancer extravasation process

Extravasation, as one of the key steps in cancer metastasis, refers to the process where tumor cells escape the bloodstream by crossing the vascular endothelium and invade the targeted tissue, which accounts for the low five-year survival rate of cancer patients. Understanding the mechanism of cancer metastasis and inhibiting extravasation are crucial to improve patient prognosis. Here, a 3D organotypic microfluidic chip combined with SERS-based protein imprinted nanomaterials (SPINs) was proposed to study the extravasation process in vitro. The chip consists of a collagen gel channel and a vascular channel where human vein endothelial cells (HUVECs) and breast cancer cells are injected sequentially to induce extravasation. By comparing two subtypes of breast cancer cells (MCF-7 and MDA-MB-231), we successfully observed the difference in extravasation capabilities between two kinds of cells through fluorescence imaging. Meanwhile, thanks to the high specificity of molecular imprinting technology and the high sensitivity of surface enhanced Raman scattering (SERS), SPINs were utilized to analyze the concentration of several cancer secretions (interleukin-6 and interleukin-8) in complex biological fluid in real-time. Further, our model showed that downregulation of secretions by therapeutic drugs can inhibit the extravasation of breast cancers. This microfluidic model may pave the way for the fundamental research of the cancer metastasis and evaluating the therapeutic efficacy of potential drugs.

Impact of sarcopenia on outcomes in surgical patients: a systematic review and meta-analysis.

Surgeons have historically used age as a preoperative predictor of postoperative outcomes. Sarcopenia, the loss of skeletal muscle mass due to disease or biological age, has been proposed as a more accurate risk predictor. The prognostic value of sarcopenia assessment in surgical patients remains poorly understood. Therefore, the authors aimed to synthesize the available literature and investigate the impact of sarcopenia on perioperative and postoperative outcomes across all surgical specialties. The authors systematically assessed the prognostic value of sarcopenia on postoperative outcomes by conducting a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching the PubMed/MEDLINE and EMBASE databases from inception to 1st October 2022. Their primary outcomes were complication occurrence, mortality, length of operation and hospital stay, discharge to home, and postdischarge survival rate at 1, 3, and 5 years. Subgroup analysis was performed by stratifying complications according to the Clavien-Dindo classification system. Sensitivity analysis was performed by focusing on studies with an oncological, cardiovascular, emergency, or transplant surgery population and on those of higher quality or prospective study design. A total of 294 studies comprising 97643 patients, of which 33070 had sarcopenia, were included in our analysis. Sarcopenia was associated with significantly poorer postoperative outcomes, including greater mortality, complication occurrence, length of hospital stay, and lower rates of discharge to home (all P <0.00001). A significantly lower survival rate in patients with sarcopenia was noted at 1, 3, and 5 years (all P <0.00001) after surgery. Subgroup analysis confirmed higher rates of complications and mortality in oncological (both P <0.00001), cardiovascular (both P <0.00001), and emergency ( P =0.03 and P =0.04, respectively) patients with sarcopenia. In the transplant surgery cohort, mortality was significantly higher in patients with sarcopenia ( P <0.00001). Among all patients undergoing surgery for inflammatory bowel disease, the frequency of complications was significantly increased among sarcopenic patients ( P =0.007). Sensitivity analysis based on higher quality studies and prospective studies showed that sarcopenia remained a significant predictor of mortality and complication occurrence (all P <0.00001). Sarcopenia is a significant predictor of poorer outcomes in surgical patients. Preoperative assessment of sarcopenia can help surgeons identify patients at risk, critically balance eligibility, and refine perioperative management. Large-scale studies are required to further validate the importance of sarcopenia as a prognostic indicator of perioperative risk, especially in surgical subspecialties.

Co-culture device for in vitro high throughput analysis of cancer associated fibroblast and cancer cell interactions.

Introduction Cancers in general, and specifically lung cancer, continue to have low patient survival rates when the patient is at an advanced stage when diagnosed. It appears that the local environment, especially fibroblasts and their signaling molecules, tends to induce metastasis, increase cancer cell resistance to treatment, and aid in tumor growth rates. Since 3-D models quickly become too complex and/or expensive, and therefore rarely leave the lab they are developed in, it is interesting to develop a 2-D model that more closely mimics the clustered tumor formation and bulk interaction with a surrounding fibroblast environment. Methods In the present study, we utilize an off-the-shelf stereolithography 3-D printer, standard use well plates, magnets, and metallic beads to create a customizable 2-D co-culture system capable of being analyzed quantitatively with staining and qualitatively with standard fluorescent/brightfield microscopy to determine cancer-fibroblast interactions while also being able to test chemotherapeutic drugs in a high-throughput manner with standard 96-well plates. Results Comparisons from monoculture and co-culture growth rates shows that the presence of fibroblasts allows for significantly increased growth rates for H460 cancer. Additionally, viability of cancer cells can be quantified with simple cell staining methods and morphology and cell-cell interactions can be observed and studied. Discussion The high throughput model demonstrates that boundary condition changes can be observed between cancer cells and fibroblasts based upon the different chemotherapeutics that have been administered.

Prognostic impact of diabetes mellitus on in-hospital mortality in patients with acute myocardial infarction complicating renal dysfunction according to age and sex

BackgroundPatients with acute myocardial infarction (AMI) complicating renal dysfunction (RD) are recognized as being at high risk. Although diabetes mellitus (DM) is a major cause of RD, the prognostic impact of coexisting DM on mortality in patients with AMI complicating RD is ill-defined. This study compared the prognostic impact of coexisting DM in patients with AMI complicating RD according to both age and sex. MethodsA multicenter retrospective study was conducted on 2988 consecutive patients with AMI complicating RD (estimated glomerular filtration rate <60 mL/min per 1.73 m2). Multivariable Cox regression analysis was performed to investigate the effects of DM on in-hospital mortality. ResultsStatistically significant interactions between age and DM and between sex and DM for in-hospital mortality were revealed in the entire cohort. Coexisting DM was identified as an independent risk factor for in-hospital mortality (hazard ratio [HR], 2.543) in young (aged <65 years), but not old (aged ≥65 years), patients. DM was identified as an independent risk factor (HR, 1.469) in male, but not female, patients. Kaplan–Meier survival curves showed that DM correlated with significantly low survival rates in patients that were young or male as compared to those who were old or female. ConclusionsThere were significant differences in the prognostic impact of DM on in-hospital mortality between young and old as well as male and female patients with AMI complicating RD. These results have implications for future research and the management of patients with DM, RD, and AMI comorbidities.

Low Serum Creatinine as Well as High Serum Creatinine Is Associated with Prognosis of Patients with Cancer in End-of-Life.

The prognosis of end-of-life patients is challenging, and clinicians have attempted to predict survival more accurately. High serum creatinine (sCr) levels are associated with lower survival rates in patients with various cancers; however, low sCr levels are commonly expected in patients with terminal cancer because of muscle wasting and malnutrition. Therefore, we investigated the prevalence of low and high sCr levels and their association with survival duration in patients with terminal cancer in a palliative care unit. We analyzed the medical records of 280 patients admitted to a palliative care unit. Patients were divided into low (<0.5 mg/dL), normal (0.5-1.2 mg/dL), and high (>1.2 mg/dL) sCr groups. Kaplan-Meier survival curves using sCr levels were plotted and compared using the log-rank test. Using stepwise selection, a multivariable Cox proportional hazards model was used to identify the significant prognostic factors. The median survival durations in the high-, low-, and normal-sCr groups were 9.57 days, 22.26 days, and 27.51 days, respectively. Multivariable Cox proportional hazard model identified that males (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.16-2.85), poor performance status (HR, 3.43; 95% CI, 1.12-10.54), total parenteral nutrition use (HR, 1.84; 95% CI, 1.09-3.1), high sCr (HR, 2.74; 95% CI, 1.52-4.94), and low sCr (HR, 1.22; 95% CI, 1.07-1.43) were significantly associated with a shorter survival time. Low and high serum creatinine levels were significantly associated with poor survival in patients with cancer at the end-of-life stage. Therefore, readily available and simple biomarkers may help plan advanced care in palliative care settings.

Integrated analysis of single-cell and bulk RNA-sequencing reveals the poor prognostic value of ABCA1 in gastric adenocarcinoma

PurposeATP-binding cassette A1 (ABCA1) is a potential prognostic marker for various tumor types. However, the biological effects and prognostic value of ABCA1 in gastric adenocarcinoma (GAC) remain unknown.MethodsGAC-associated single-cell RNA and bulk RNA-sequencing (bulk-seq) data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. The differential expression of ABCA1 between GAC and normal gastric tissues was analyzed based on the bulk-seq data. Additionally, the relationship between ABCA1 expression and various clinicopathological features was explored. Furthermore, Kaplan–Meier survival and Cox regression analyses were performed to establish the prognostic value of ABCA1. The relationships between ABCA1 expression and anti-tumor drug sensitivity and immune checkpoints were also explored. Finally, the biological functions of ABCA1 were evaluated at the single-cell level, and in vitro studies were performed to assess the effects of ABCA1 on GAC cell proliferation and invasion.ResultsABCA1 expression is significantly elevated in GAC samples compared with that in normal gastric tissues. Clinical features and survival analysis revealed that high ABCA1 expression is associated with poor clinical phenotypes and prognosis, whereas Cox analysis identified ABCA1 as an independent risk factor for patients with GAC. Furthermore, high ABCA1 expression suppresses sensitivity to various chemotherapeutic drugs, including cisplatin and mitomycin, while upregulating immune checkpoints. ABCA1-overexpressing macrophages are associated with adverse clinical phenotypes in GAC and express unique ligand–receptor pairs that drive GAC progression. In vitro, ABCA1-knockdown GAC cells exhibit significantly inhibited proliferative and invasive properties.ConclusionHigh ABCA1 expression promotes an adverse immune microenvironment and low survival rates in patients with GAC. Furthermore, ABCA1 and ABCA1-producing macrophages may serve as novel molecular targets in GAC treatment.

Association between a four-parameter inflammatory index and all-cause mortality in critical ill patients with non-traumatic subarachnoid hemorrhage: a retrospective analysis of the MIMIC-IV database (2012-2019).

Non-traumatic subarachnoid hemorrhage (SAH), primarily due to the rupture of intracranial aneurysms, contributes significantly to the global stroke population. A novel biomarker, pan-immune-inflammation value (PIV) or called the aggregate index of systemic inflammation (AISI), linked to progression-free survival and overall survival in non-small-cell lung cancer and mortality in Coronavirus Disease 2019 (COVID-19) patients, has surfaced recently. Its role in non-traumatic SAH patients, however, remains under-researched. This study aims to determine the relationship between PIV and all-cause mortality in non-traumatic SAH patients. A retrospective analysis was conducted using data from the Medical Information Mart for Intensive Care (MIMIC-IV) database to examine the association between PIV and all-cause mortality in critically ill patients with non-traumatic SAH. PIV measurements were collected at Intensive Care Unit (ICU) admission, and several mortality measures were examined. To control for potential confounding effects, a 1:1 propensity score matching (PSM) method was applied. The optimal PIV cutoff value was identified as 1362.45 using X-tile software that is often used to calculate the optimal cut-off values in survival analysis and continuous data of medical or epidemiological research. The relationship between PIV and short- and long-term all-cause mortality was analyzed using a multivariate Cox proportional hazard regression model and Kaplan-Meier (K-M) survival curve analysis. Interaction and subgroup analyses were also carried out. The study included 774 non-traumatic SAH patients. After PSM, 241 pairs of score-matched patients were generated. The Cox proportional hazard model, adjusted for potential confounders, found a high PIV (≥ 1362.45) independently associated with 90-day all-cause mortality both pre- (hazard ratio [HR]: 1.67; 95% confidence intervals (CI): 1.05-2.65; P = 0.030) and post-PSM (HR: 1.58; 95% CI: 1.14-2.67; P = 0.042). K-M survival curves revealed lower 90-day survival rates in patients with PIV ≥ 1362.45 before (31.1% vs. 16.1%%, P < 0.001) and after PSM (68.9% vs. 80.9%, P < 0.001). Similarly, elevated PIV were associated with increased risk of ICU (pre-PSM: HR: 2.10; 95% CI: 1.12-3.95; P = 0.02; post-PSM: HR: 2.33; 95% CI: 1.11-4.91; P = 0.016), in-hospital (pre-PSM: HR: 1.91; 95% CI: 1.12-3.26; P = 0.018; post-PSM: 2.06; 95% CI: 1.10-3.84; P = 0.034), 30-day (pre-PSM: HR: 1.69; 95% CI: 1.01-2.82; P = 0.045; post-PSM: 1.66; 95% CI: 1.11-2.97; P = 0.047), and 1-year (pre-PSM: HR: 1.58; 95% CI: 1.04-2.40; P = 0.032; post-PSM: 1.56; 95% CI: 1.10-2.53; P = 0.044) all-cause mortality. The K-M survival curves confirmed lower survival rates in patients with higher PIV both pre- and post PSM for ICU (pre-PSM: 18.3% vs. 8.4%, P < 0.001; post-PSM:81.7 vs. 91.3%, P < 0.001), in-hospital (pre-PSM: 25.3% vs. 12.8%, P < 0.001; post-PSM: 75.1 vs. 88.0%, P < 0.001), 30-day (pre-PSM: 24.9% vs. 11.4%, P < 0.001; post-PSM:74.7 vs. 86.3%, P < 0.001), and 1-year (pre-PSM: 36.9% vs. 20.8%, P < 0.001; P = 0.02; post-PSM: 63.1 vs. 75.1%, P < 0.001) all-cause mortality. Stratified analyses indicated that the relationship between PIV and all-cause mortality varied across different subgroups. In critically ill patients suffering from non-traumatic SAH, an elevated PIV upon admission correlated with a rise in all-cause mortality at various stages, including ICU, in-hospital, the 30-day, 90-day, and 1-year mortality, solidifying its position as an independent mortality risk determinant. This study represents an attempt to bridge the current knowledge gap and to provide a more nuanced understanding of the role of inflammation-based biomarkers in non-traumatic SAH. Nevertheless, to endorse the predictive value of PIV for prognosticating outcomes in non-traumatic SAH patients, additional prospective case-control studies are deemed necessary.

Tumor-Derived Membrane Vesicles Restrain Migration in Gliomas By Altering Collective Polarization.

Mechanobiology is a cornerstone in physiology. However, its role in biomedical applications remains considerably undermined. In this study, we employed cell membrane vesicles (CMVs), which are currently being used as nanodrug carriers, as tactile cues for mechano-regulation of collective cell behaviors. Gliomas, which are among the most resilient brain tumors and have a low patient survival rate, were used as the cell model. We observed that mechanical responses due to the application of glioma- or microglia-derived CMVs resulted in the doubling of the traction stress of glioma cell collectives with a 10-fold increase in the CMV concentration. Glioma-CMVs constrained cell protrusions and hindered their collective migration, with the migration speed of such cells declining by almost 40% compared to the untreated cells. We speculated that the alteration of collective polarization leads to migration speed changes, and this phenomenon was elucidated using the cellular Potts model. In addition to intracellular force modulation and cytoskeletal reorganization, glioma-CMVs altered drug diffusion within glioma spheroids by downregulating the mechano-signaling protein YAP-1 while also marginally enhancing the associated apoptotic events. Our results suggest that glioma-CMVs can be applied as an adjuvant to current treatment approaches to restrict tumor invasion and enhance the penetration of reagents within tumors. Considering the broad impact of mechano-transduction on cell functions, the regulation of cell mechanics through CMVs can provide a foundation for alternative therapeutic strategies.

E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma

Ribonucleotide reductase (RR) is a rate-limiting enzyme that facilitates DNA replication and repair by reducing nucleotide diphosphates (NDPs) to deoxyribonucleotide diphosphates (dNDPs) and is thereby crucial for cell proliferation and cancer development. The E2F family of transcription factors includes key regulators of gene expression involved in cell cycle control. In this study, E2F8 expression was significantly increased in most cancer tissues of lung adenocarcinoma (LUAD) patients and was correlated with the expression of RRM2 through database and clinical samples analysis. The protein expression of E2F8 and RRM2 were positively correlated with tumor–node–metastasis (TNM) pathological stage, and high expression of E2F8 and RRM2 predicted a low 5-year overall survival rate in LUAD patients. Overexpression and knockdown experiments showed that E2F8 was essential for LUAD cell proliferation, DNA synthesis, and cell cycle progression, which were RRM2-dependent. Reporter gene, ChIP-qPCR, and DNA pulldown–Western blot assays indicated that E2F8 activated the transcription of the RRM2 gene by directly binding with the RRM2 promoter in LUAD cells. Previous studies indicated that inhibition of WEE1 kinase can suppress the phosphorylation of CDK1/2 and promote the degradation of RRM2. We further showed here that the combination of E2F8 knockdown with MK-1775, an inhibitor of WEE1 being evaluated in clinical trials, synergistically suppressed proliferation and promoted apoptosis of LUAD cells in vitro and in vivo. Thus, this study reveals a novel role of E2F8 as a proto-oncogenic transcription activator by activating RRM2 expression in LUAD, and targeting both the transcription and degradation mechanisms of RRM2 could produce a synergistic inhibitory effect for LUAD treatment in addition to conventional inhibition of RR enzyme activity.

Evaluation of Anticancer Activity of 76 Plant Species Collected in Andalusia (Spain) against Lung Cancer Cells.

Every year, cancer kills millions of people around the world. Finding more selective anticancer agents is essential to improve the low survival rates of patients with metastatic cancers. Since the research of natural products is a valuable approach to the discovery of new compounds and the Iberian flora offers a rich source of unstudied plants, we have carried out a random screening of 76 plant species from 43 families collected in Andalusia (South of Spain). Using non-malignant cells (HaCaT) and lung cancer cells (A549), we found that the extract from Arum italicum Mill. subsp. italicum (Araceae), Mandragora autumnalis Bertol. (Solanaceae), Rhamnus alaternus L. (Rhamnaceae), and Lomelosia simplex (Desf.) Raf. subsp. dentata (Jord. & Fourr.) Greuter & Burdet (Dipsacaceae) showed selective cytotoxicity against lung cancer cells. Extracts of plant species belonging to the Iridaceae family showed high selective activity against cancer cells, highlighting that the Xiphion xiphium (L.) M.B. Crespo, Mart.-Azorín & Mavrodiev flower extract was more selective against lung cancer cells than the standard anticancer drugs, cisplatin and 5-fluorouracil. This extract also showed modest selective cytotoxicity against bladder carcinoma cells (T24). The number of cells in the G1 phase increased after treatment with the extract from Xiphion xiphium. Our research indicates that various plants are potential sources for the isolation and development of new anticancer drugs.