Lower Patient Survival Research Articles

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.

PHLPP2: A Prognostic Biomarker in Adenocarcinoma of the Rectum.

Adenocarcinoma of the rectum (READ) is typically diagnosed at advanced stages due to a lack of early-onset spe- cific features. The study used bioinformatics analysis of READ ribonucleic acid sequencing data from The Cancer Genome Atlas database to identify differentially expressed genes (DEGs). Overlapping genes between DEGs and autophagy-associated genes were screened for prognosis-associated DEGs, which were then validated in the OncoLnc database. A total of 129 autophagy-associated DEGs were identified, with 17 genes found to be associated with READ prognosis. Multivariate Cox regression analysis revealed that only the PHLPP2 gene was significantly associated with READ prognosis (hazard ratio = 0.442, P = .026), and its low expression correlated with low survival in patients with brain lower-grade glioma (P = .00623) and pancreatic adenocarcinoma (P = .00109). PHLPP2 expression may serve as a READ-specific prognostic biomarker and is involved in the PI3K-Akt signaling pathway.

Potential harms of emergency department thoracotomy in patients with persistent cardiac arrest following trauma: a nationwide observational study

Emergency department thoracotomy (EDT) was incorporated into traumatic out-of-hospital cardiac arrest (t-OHCA) resuscitation. Although current guidelines recommend EDT with survival predictors, futility following EDT has been demonstrated and the potential risks have not been thoroughly investigated. This study aimed to elucidate the benefits and harms of EDT for persistent cardiac arrest following injury until hospital arrival. This retrospective cohort study used a nationwide trauma registry (2019–2021) and included adult patients with t-OHCA both at the scene and on hospital arrival. Survival to discharge, hemostatic procedure frequency, and transfusion amount were compared between patients treated with and without EDT. Inverse probability weighting using a propensity score was conducted to adjust age, sex, comorbidities, mechanism of injury, prehospital resuscitative procedure, prehospital physician presence, presence of signs of life, degree of thoracic injury, transportation time, and institutional characteristics. Among 1289 patients, 374 underwent EDT. The longest transportation time for survivors was 8 and 23 min in patients with and without EDT, respectively. EDT was associated with lower survival to discharge (4/374 [1.1%] vs. 22/915 [2.4%]; adjusted odds ratio [OR], 0.43 [95% CI 0.22–0.84]; p = 0.011), although patients with EDT underwent more frequent hemostatic surgeries (46.0% vs. 5.0%; adjusted OR, 16.39 [95% CI 12.50–21.74]) and received a higher amount of transfusion. Subgroup analyses revealed no association between EDT and lower survival in patients with severe chest injuries (1.0% vs. 1.4%; adjusted OR, 0.72 [95% CI 0.28–1.84]). EDT was associated with lower survival till discharge in trauma patients with persistent cardiac arrests after adjusting for various patient backgrounds, including known indications for EDT. The idea that EDT is the last resort for t-OHCA should be reconsidered and EDT indications need to be deliberately determined.Trial registration This study is retrospectively registered at University Hospital Medical Information Network (UMIN ID: UMIN000050840).

Association between serum sodium levels within 24 h of admission and all-cause mortality in critically ill patients with non-traumatic subarachnoid hemorrhage: a retrospective analysis of the MIMIC-IV database.

The study aimed to evaluate the relationship between serum sodium and mortality in critically ill patients with non-traumatic subarachnoid hemorrhage. This is a retrospective investigation of critically ill non-traumatic patients with subarachnoid hemorrhage (SAH) utilizing the MIMIC-IV database. We collected the serum sodium levels at admission and determined the all-cause death rates for the ICU and hospital. We employed a multivariate Cox proportional hazard regression model and Kaplan-Meier survival curve analysis to ascertain the relationship between serum sodium and all-cause mortality. In order to evaluate the consistency of correlations, interaction and subgroup analyses were also conducted. A total of 864 patients with non-traumatic SAH were included in this study. All-cause mortality in the ICU and hospital was 32.6% (282/864) and 19.2% (166/864), respectively. Sodium levels at ICU admission showed a statistically significant J-shaped non-linear relationship with ICU and hospital mortality (non-linear P-value < 0.05, total P-value < 0.001) with an inflection point of ~141 mmol/L, suggesting that mortality was higher than normal serum sodium levels in hypernatremic patients. Multivariate analysis after adjusting for potential confounders showed that high serum sodium levels (≥145 mmol/L) were associated with an increased risk of all-cause mortality in the ICU and hospital compared with normal serum sodium levels (135-145 mmol/L), [hazard ratio (HR) = 1.47, 95% CI: 1.07-2.01, P = 0.017] and (HR = 2.26, 95% CI:1.54-3.32, P < 0.001). Similarly, Kaplan-Meier (K-M) survival curves showed lower survival in patients with high serum sodium levels. Stratified analysis further showed that the association between higher serum sodium levels and hospital all-cause mortality was stronger in patients aged < 60 years with a hospital stay of <7 days. High serum sodium levels upon ICU admission are related to higher ICU and hospital all-cause mortality in patients with non-traumatic SAH. A new reference is offered for control strategies to correct serum sodium levels.

Different Expression Pattern of G Protein-Coupled Estrogen Receptor GPER1 in Esophageal Squamous Cell Carcinoma and Adenocarcinoma.

Esophageal carcinoma is a male-dominant malignancy worldwide, and esophageal adenocarcinoma (EAC) shows more significant sex bias than esophageal squamous cell carcinoma (ESCC) in morbidity and mortality. The G protein-coupled estrogen receptor 1 (GPER1) is involved in several sex-related cancers; however, its expression level in esophageal carcinoma has been poorly investigated and its role is not precisely defined, depending on histological types. In the present study, the mRNA levels of GPER1 in esophageal carcinoma were collected from GEPIA and Oncomine databases for meta-analyses. The protein expression levels of GPER1 were detected by immunohistochemistry in the tissue microarray of EAC and ESCC. The GPER1 selective agonist G1, antagonist G15, and siRNA were applied in vitro to investigate their impacts on esophageal cell lines. Analysis of the RNA levels from the databases showed a decreased expression of GPER1 in overall esophageal carcinoma, and low expression levels of GPER1 were found to be associated with low survival of tumor patients. However, in the subgroup of EAC and its precancerous lesion, Barrett's esophagus, overexpression of GPER1 RNA was increased when compared with the normal tissues. The average staining scores of GPER1 protein in the tissue microarray of EAC were significantly higher than normal esophageal samples, and the rate of positive staining increased with the grade of poor tumor differentiation. The scores of GPER1 protein in ESCC tissues were lower than those in the normal tissues. The results from cell line experiments in vitro showed that the GPER1 agonist G1 inhibited proliferation and promoted apoptosis of ESCC cells EC109 with positive expression of GPER1. G1 had no obvious effect on normal esophageal NE2 cells with weak expression of GPER1. In addition, GPER1 RNA knockdown and application of antagonist G15 reversed the effects of G1 on EC109. The results of this study indicate that the expression levels of GPER1 are higher in EAC than in ESCC, which might be correlated with the dimorphic estrogen signaling pathway in different types of esophageal carcinoma.

LncRNA GAS5-hnRNPK axis inhibited ovarian cancer progression via inhibition of AKT signaling in ovarian cancer cells

BackgroundThe incidence of ovarian cancer ranks third among gynecologic malignancies, but the mortality rate ranks first.MethodsThe expression of GAS5 is low in ovarian cancer and is associated with the low survival of ovarian cancer patients according to public ovarian cancer databases. GAS5 overexpression inhibited ovarian malignancy by affecting the proliferation and migratory abilities in OVCAR3 and A2780 cells. GAS5 overexpression increased the rate of cell apoptosis, and the cells were blocked in the G1 phase as assessed by flow cytometry.ResultsWe found that hnRNPK was a potential target gene, which was regulated negatively by GAS5 based on RNA-pulldown and mass spectrometry analysis. Mechanistically, GAS5 affected the inhibition of the PI3K/AKT/mTOR pathways and bound the protein of hnRNPK, which influenced hnRNPK stability. Furthermore, rescue assays demonstrated hnRNPK was significantly involved in the progression of ovarian cancer.ConclusionsOur study showed one of the mechanisms that GAS5 inhibited ovarian cancer metastasis by down-regulating hnRNPK expression, and GAS5 can be used to predict the prognosis of ovarian cancer patients.Graphical

Safety of dapagliflozin initiation in acute decompensated heart failure patients with reduced left ventricular ejection fraction

Background. Chronic heart failure (CHF) is an immediate cardiological problem. At the same time, acute decompensated heart failure (ADHF) is associated with an extremely unfavorable prognosis and low survival of patients.&#x0D; Aim. To evaluate the safety of sodium-glucose cotransporter-2 inhibitor dapagliflozin early administration in patients with ADHF with a reduced left ventricular ejection fraction (LVEF) regardless of type 2 diabetes mellitus (diabetes).&#x0D; Materials and methods. We used standard CHF therapy and intravenous diuretic therapy in combination with 10 mg dapagliflozin in 43 patients with NYHA class IIIV ADHF. The study mainly included 39 (90.7%) male patients, the mean age was 6012 years (5663), diabetes was in 14 (32.6%) patients. Dapagliflozin was prescribed by a mean of 2 days (13) from admission to the hospital. The parameters were analyzed at the time of inclusion in the study and when CHF compensation was achieved.&#x0D; Results. The median of the length of hospital stay was 7 days (610). LVEF significantly increased during hospitalization from 276 to 307% (p0.001) and the level of NT-proBNP decreased: from 3700 pg/ml (17455331) to 1366 pg/ml (10252878); p=0.007. A decrease in the marker was observed in 90% of patients. Hypotension (decrease in systolic blood pressure BP less than 90 mmHg) was observed in 10 (23.3%) patients. A statistically significant decrease in BP was found: systolic and diastolic BP on admission was 114 mmHg (100126) and 70 mmHg (7080), respectively, when CHF compensation was achieved 110 mmHg (98120) and 70 mmHg (6178); p=0.047 and p=0.013, respectively. The increase in hematocrit during hospitalization was also statistically significant from 43.53.6 to 46.14.9% (p0.001) and this was found in 67% of patients. A total of 4 (9.3%) patients had acute renal injury (decrease in estimated glomerular filtration rate GFR by 25% or more). At the same time, there was no decrease in GFR of less than 15 ml/min/1.73 m2. There was no statistically significant decrease in GFR and an increase in creatinine levels during hospitalization (p=0.214 and 0.173, respectively). Urinary tract infections were observed in 1 (2.3%) patient, transient hypoglycemia in 2 (4.7%) patients, which did not lead to the discontinuation of dapagliflozin. Diabetic ketoacidosis, allergic reactions, syncope, lower extremity amputations were not observed in patients taking dapagliflozin.&#x0D; Conclusion. It can be concluded that dapagliflozin has a favorable safety profile when used in patients with ADHF, regardless of the presence or absence of diabetes.

Fate of concomitant tricuspid regurgitation in patients undergoing coronary artery bypass grafting

ObjectiveOwing to a lack of supportive data, tricuspid regurgitation (TR) is usually not addressed in patients undergoing coronary artery bypass grafting (CABG). Here we evaluated changes in TR degrees over time and its impact on survival in patients undergoing CABG. MethodsWe reviewed the data of 9726 patients who underwent isolated CABG between January 2000 and January 2021. According to preoperative TR severity, patients were stratified into nonsignificant (none to trivial, mild) and significant (moderate to severe) TR groups. We excluded patients who had undergone previous tricuspid valve surgery, pacemaker placement, and concomitant valve or ablative surgery. Propensity score matching and Cox proportional hazards models were used to identify associations between TR grade and the primary outcome of all-cause mortality. The secondary outcome was change in TR severity on the last echocardiogram. ResultsAfter propensity score matching, 380 patients in each group were identified. At baseline, 359 patients had moderate TR (94.5%) and 21 (5.5%) had severe TR. On the last follow-up echocardiogram, TR had improved in 40.5% of the patients in the significant TR group. Kaplan–Meier survival curves showed significantly lower survival in patients with significant preoperative TR compared to those with nonsignificant TR (P < .001). After adjusting for other confounders, survival was no worse in the patients with significant TR group (hazard ratio, 1.05; 95% confidence interval, 0.80-1.38; P = .70). ConclusionsSignificant preoperative TR improved in 40.5% of patients after isolated CABG. After adjusting for other factors, significant TR did not affect long-term survival.

Perfluorotributylamine-Loaded Albumin Nanoparticles Downregulate Platelet-Derived TGFβ to Inhibit Tumor Metastasis.

Tumor metastasis contributes to the low overall survival of tumor patients, while transforming growth factor-β (TGFβ) has been recognized as a prominently promoting factor in the development of tumor metastasis. Platelets reserve abundant TGFβ, which will be secreted to peripheral blood after activation, and they are the dominant source of circulating TGFβ. Therefore, downregulation of platelet-derived TGFβ is expected to inhibit the metastasis of circulating tumor cells. Here, unfolded human serum albumin (HSA)-coated perfluorotributylamine (PFTBA) nanoparticles were constructed to display a favorable platelet delivery and an antiplatelet effect to downregulate platelet-derived TGFβ in vitro and in blood plasma. PFTBA@HSA-mediated TGFβ downregulation impaired epithelial-mesenchymal transition of tumor cells as well as their migration and invasion behaviors and enhanced immune surveillance of NK cells. Intravenous injection of PFTBA@HSA effectively reduced tumor metastasis on the lungs or liver to improve the survival rate of mice on multiple metastatic models, including CT26 colon cancer, B16F10 melanoma, and 4T1 breast cancer. Compared with the clinical antiplatelet drug ticagrelor, PFTBA@HSA reduced bleeding risk when displaying a favorable downregulation on platelet-derived TGFβ, thereby obtaining a higher therapy benefit. Together, this study confirmed that downregulation of platelet-derived TGFβ by PFTBA@HSA will be a potential approach and therapeutic candidate for the prevention of tumor metastasis.

Pneumatic driven pulsatile ECMO in vitro evaluation with oxygen tanks.

Extracorporeal membrane oxygenation device is a procedure in which mechanical systems circulate blood and supply oxygen to patients with impaired cardiopulmonary function. Current venoarterial systems are associated with low patient survival rates and new treatments are needed to avoid left ventricular dilation, which is a major cause of death. In this study, a new mobile pulsatile ECMO with a pump structure that supplies pulsatile flow by using an oxygen tank as a power source is proposed. In vitro experiments conducted under mock circulation system as like patient conditions demonstrated that 2.8L oxygen can sustain the outflow of 1L/min of pulsatile blood flow for 53min, while a 4.6L tank was able to sustain the same flow for 85min. The energy equivalent pressure evaluation index of the pulsatile blood pump shows that the mobile pulsatile ECMO could supply sufficient pulsatile blood flow compared to the existing pulsatile ECMO. Through in vitro experiments performed under mock circulation conditions, this new system was proven to supply sufficient oxygen and pulsatile blood flow using the pressure of an oxygen tank even while transporting a patient.

FRI-555 - Detection of 1,3-beta-D-glucan increases with the severity of decompensation stages in liver cirrhosis and is associated with lower survival in patients with acute on chronic liver failure

FRI-555 - Detection of 1,3-beta-D-glucan increases with the severity of decompensation stages in liver cirrhosis and is associated with lower survival in patients with acute on chronic liver failure

Comprehensive Glycoprofiling of Oral Tumors Associates N-Glycosylation With Lymph Node Metastasis and Patient Survival

While altered protein glycosylation is regarded a trait of oral squamous cell carcinoma (OSCC), the heterogeneous and dynamic glycoproteome of tumor tissues from OSCC patients remain unmapped. To this end, we here employ an integrated multi-omics approach comprising unbiased and quantitative glycomics and glycoproteomics applied to a cohort of resected primary tumor tissues from OSCC patients with (n = 19) and without (n = 12) lymph node metastasis. While all tumor tissues displayed relatively uniform N-glycome profiles suggesting overall stable global N-glycosylation during disease progression, altered expression of six sialylated N-glycans was found to correlate with lymph node metastasis. Notably, glycoproteomics and advanced statistical analyses uncovered altered site-specific N-glycosylation revealing previously unknown associations with several clinicopathological features. Importantly, the glycomics and glycoproteomics data unveiled that comparatively high abundance of two core-fucosylated and sialylated N-glycans (Glycan 40a and Glycan 46a) and one N-glycopeptide from fibronectin were associated with low patient survival, while a relatively low abundance of N-glycopeptides from both afamin and CD59 were also associated with poor survival. This study provides insight into the complex OSCC tissue N-glycoproteome, thereby forming an important resource to further explore the underpinning disease mechanisms and uncover new prognostic glycomarkers for OSCC.

CSNK2A2 promotes hepatocellular carcinoma progression through activation of NF-κB pathway

Introduction and ObjectivesBreast and non-small cell lung cancers harbor an upregulated CSNK2A2 oncogene that encodes the protein kinase CK2 alpha', a catalytic subunit of the highly conserved serine/threonine kinase CK2. However, its role and biological significance in hepatocellular carcinoma (HCC) remains unclear. Materials and MethodsWestern-blotting and immunohistochemistry were used to measure the expression of CSNK2A2 in HCC tumor tissues and cell lines. CCK8, Hoechst staining, transwell, tube formation assay in vitro and nude mice experiments in vivo were used to measure the effects of CSNK2A2 on HCC proliferation, apoptosis, metastasis, angiogenesis and tumor formation. ResultsIn the study, we showed that CSNK2A2 was highly expressed in HCC comparison with matched control tissues, and was linked with lower survival of patients. Additional experiments indicated that silencing of CSNK2A2 promoted HCC cell apoptosis, while inhibited HCC cells migrating, proliferating, angiogenesis both in vitro and in vivo. These effects were also accompanied by reduced expression of NF-κB target genes, including CCND1, MMP9 and VEGF. Moreover, treatment with PDTC counteracted the promotional effects of CSNK2A2 on HCC cells. ConclusionsOverall, our results suggested that CSNK2A2 could promote HCC progression by activating the NF-κB pathway, and this could serve as a biomarker for future prognostic and therapeutic applications.

AKR1B1 inhibition using NARI-29-an Epalrestat analogue-alleviates Doxorubicin-induced cardiotoxicity via modulating Calcium/CaMKII/MuRF-1 axis

The clinical use of doxorubicin (Dox) is narrowed due to its carbonyl reduction to doxorubicinol (Doxol) implicating resistance and cardiotoxicity. Hence, in the present study we have evaluated the cardioprotective effect of AKR1B1 (or aldose reductase, AR) inhibitor NARI-29 (epalrestat (EPS) analogue) and its effect in the Dox-modulated calcium/CaMKII/MuRF1 axis. Initially, the breast cancer patient survival associated with AKR1B1 expression was calculated using Kaplan Meier-plotter (KM-plotter). Further, breast cancer, cardiomyoblast (H9c2), and macrophage (RAW 264.7) cell lines were used to establish the in vitro combination effect of NARI-29 and Dox. To develop the cardiotoxicity model, mice were given Dox 2.5 mg/kg (i.p.), biweekly. The effect of AKR1B1 inhibition using NARI-29 on molecular and cardiac functional changes was measured using echocardiography, fluorescence-imaging, ELISA, immunoblotting, flowcytometry, High-Performance Liquid Chromatography with Fluorescence Detection (HPLC-FD) and cytokine-bead array methods. The bioinformatics data suggested that a high expression of AKR1B1 is associated with significantly low survival of breast cancer patients undergoing chemotherapy; hence, it could be a target for chemo-sensitization and chemo-prevention. Further, in vitro studies showed that AKR1B1 inhibition with NARI-29 has increased the accumulation and sensitized Dox to breast cancer cell lines. However, treatment with NARI-29 has alleviated the Dox-induced toxicity to cardiomyocytes and decreased the secretion of inflammatory cytokines from RAW 264.7 cells. In vivo studies revealed that the NARI-29 (25 and 50 mg/kg) has prevented the functional, histological, biochemical, and molecular alterations induced by Dox treatment. Moreover, we have shown that NARI-29 has prevented the carbonyl reduction of Dox to Doxol in the mouse heart, which reduced the calcium overload, prevented phosphorylation of CaMKII, and reduced the expression of MuRF1 to protect from cardiac injury and apoptosis. Hence in conclusion, AKR1B1 inhibitor NARI-29 could be used as an adjuvant therapeutic agent with Dox to prevent cardiotoxicity and synergize anti-breast cancer activity.

Features Importance in Acute Kidney Injury After Liver Transplant: Which Predictors Are Relevant?

Acute kidney injury after liver transplant results from several interconnected factors related to graft, recipient, intraoperative, and postoperative events. The random decision forest model enables an appreciation of each factor's contribution, which may be helpful in setting up a preventive strategy. This study aimed to evaluate the importance of covariates at different times (pretransplant, end of surgery, postoperative day 7) with a random forest permutation algorithm. We used a retrospective singlecenter cohort of patients, without preoperative renal failure, who underwent primary liver transplants from deceased donors (N =1104). Significant covariates for stage 2-3 acute kidney injurywere included in a random forest model, and features importance was evaluated with mean decrease accuracy and Gini index. Stage 2-3 acute kidney injury occurred in 200 patients (18.1%) and was associated with lower patient survival, even after exclusion of early graftloss. At univariate analysis, recipient factors (serum creatinine level, Model for End-Stage Liver Disease score, body weight, body mass index), graft variables (weight, macrosteatosis), intraoperative factors (number of red blood cells, duration of surgery, cold ischemia time), and postoperative event (graft dysfunction) were associated with kidney failure. The pretransplant model found that macrosteatosis and graft weight contributed to acute kidney injury. The postoperative model indicated that graft dysfunction and the number of intraoperative packed red blood cells were ranked as the 2 most essential factors in posttransplant renal failure. The application of a random forestfeature identified graft dysfunction, even transient and reversible, and the number of intraoperative packed red blood cells as the 2 most crucial contributors to acute kidney injury,thus indicating that prevention of graft dysfunction and bleeding are key points to limit the risk of renal failure after liver transplant.

Abstract LB232: Targeting MEK activity in pancreatic tumors resistant to the combination of 5FU, irinotecan, and oxaliplatin promotes response to immunotherapy

Abstract FOLFIRINOX, a chemotherapy regimen consisting of 5FU, Leucovorin, Irinotecan, and Oxaliplatin, has been a first-line standard of care for patients with pancreatic adenocarcinoma (PDAC) for the last decade. However, low patient survival rates following treatment highlight frequent occurrence of resistance. Hence there is increasing interest in developing appropriate models of FOLFIRINOX resistance to identify subsequent line therapies. We have generated PDAC cell lines that exhibit acquired resistance to a combination of 5FU (F), Irinotecan (I), and Oxaliplatin (O) (FIO) in vitro. In mice, they form tumors that resemble FOLFIRINOX neoadjuvant-treated PDAC patients in regard to immune cell infiltration and a lack of response to single-agent anti-PD-1 therapy. We also show that similar to human PDAC tumors treated with neoadjuvant FOLFIRINOX, FIO-resistant tumors exhibit increased ERK1/2 phosphorylation. We demonstrate that the MEK inhibitor Trametinib reprograms the FIO-resistant tumors, but not the parental tumors, towards a less immunosuppressive tumor immune microenvironment. Importantly, Trametinib sensitizes FIO-resistant tumors to anti-PD-1 therapy, with the combination treatment significantly enhancing the cytolytic activity of the infiltrating CD8 + T cells and increasing tumor cell death. Taken together, our findings identify enhanced MEK/ERK signaling as a therapeutic target in FOLFIRINOX-resistant PDAC tumors, and suggest evaluating the combination of Trametinib and anti-PD-1 therapy in patients who progress on FOLFIRINOX. Citation Format: Thao D. Pham, Anastasia E. Metropulos, Nida Mubin, Dhavan N. Shah, Christina Spaulding, Mario Shields, David J. Bentrem, Hidayatullah G. Munshi. Targeting MEK activity in pancreatic tumors resistant to the combination of 5FU, irinotecan, and oxaliplatin promotes response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB232.

High FN1 expression is associated with poor survival in esophageal squamous cell carcinoma.

Esophageal cancer (EC) is a serious threat to human health. The expression of fibronectin 1 (FN1) in esophageal squamous cell carcinoma (ESCC) remains controversial. The purpose of this study was to elucidate the expression of FN1 in ESCC and to assess the value of FN1 in the prognosis of ESCC patients. 100 ESCC patients from January 2015 to March 2016 were recruited in this study. qRT-PCR and immunohistochemistry (IHC) were used to detect FN1 mRNA and protein expression. The correlation between FN1 expression levels and prognosis of ESCC patients was analyzed. The qRT-PCR results showed that the expression of FN1 mRNA was significantly higher in ESCC tumor tissues than in adjacent esophageal tissues (P < .01). IHC results showed that FN1 protein was expressed in both tumor cells and stroma. High expression of FN1 mRNA and FN1 protein in ESCC tumor tissues was significantly correlated with the depth of tumor invasion, lymph node metastasis and clinical stage of the tumor (P < .05). Survival analysis revealed that patients with higher FN1 mRNA and protein expression had significantly lower survival rates than those with lower FN1 mRNA or protein expression (P < .01). Multivariate cox regression analysis showed that high FN1 protein expression in ESCC tumor tissues was an independent risk factor for low survival in ESCC patients (P < .05). High expression of FN1 protein in ESCC tumor tissue is an independent poor prognostic factor. FN1 protein could be a potential target for the treatment of ESCC.

Abstract 1653: Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. KRAS mutations and LKB1 inactivation commonly occur in NSCLC and are associated with poor prognosis. Several studies enunciate the role of the immune system in lung cancer progression through cancer cells' ability to escape immune surveillance. Therefore, understanding NSCLC progression requires the examination of the molecular mechanisms behind this process. The importance of oxidative phosphorylation (OXPHOS) and mitochondrial metabolism in lung cancer has been continuously emphasized; OXPHOS and mitochondrial biogenesis markers predict low survival in NSCLC patients. Additionally, heme is an essential molecule in the OXPHOS pathway, and previous studies have shown that heme sequestration using heme sequestering protein 2 (HeSP2) arrests tumor progression. HeSP2 can potentially normalize the tumor immune microenvironment (TIME) via multiple mechanisms including the normalization of vessels which may promote immune cell infiltration, the reduction of hypoxia which may promote antitumor immune function, and the reduction of heme levels which potentially decreases the production of immunosuppressive enzymes requiring heme as a cofactor. In this study, control and HeSP2-treated tumors generated from a genetically engineered mouse model LSL-KrasG12D LKB1-/- (LSL-KRASG12D; LKBloxP/loxP; LSL-Luciferase (KLLuc) infected with AdenoCre virus and sacrificed at 10 months were used for immunohistochemical analysis. We examined immune markers under HeSP2 treatment to determine the immune system response to heme targeting and its effects on tumor progression. Results demonstrated that HeSP2 can modulate the tumor immune microenvironment increasing the levels of immune markers, which suggests that heme targeting can potentiate immunotherapy efficacy in lung cancer treatment. Citation Format: Maria del Carmen Chacon Castro, Eranda Berisha, Narges Salamat, Li Zhang. Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1653.

Abstract 1238: Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells

Abstract Abstract Background Unlike Breast cancer (BRCA) luminal subtypes, Triple negative breast cancer (TNBC) subtype lacks expression of estrogen receptor-α (ERα/ESR1), progesterone receptor (PGR) and/or epidermal growth factor (EGF) family receptor HER2/ERBB2 where patients do not benefit from endocrine and HER2 based therapies in addition to its poor differentiation that results in greater aggressiveness and poorer prognosis. The 60 KD Heat shock protein (HSP60) is a Mitochondrial protein that plays a role in stabilizing and refolding proteins and is regulated by HSPD1 gene. In normal cells, HSPD1 gene expression is controlled, however in TNBC, HSPD1 overexpression is common and is associated with poor cancer-specific survival. This study aims to understand downstream signaling pathways dependent on the function of HSPD1 in TNBC. Method To understand downstream signaling pathways dependent on the function of HSPD1, we analyzed the transcriptomic profiles of metastatic MDA-MB-231-WT and HSPD1-KD cells. Results Bioinformatics data analysis shows that HSPD1 is overexpressed in TNBC, particularly in basal subtype. High expression of HSPD1 related to low survival in breast cancer patients. HSPD1 KD in MDA-MB-231 cells identified several differentially regulated genes (DEG) as compared to WT MDA-MB-231 cells by RNA-seq analysis. Pathway analysis of DEG showed downregulation of mitochondrial respiration, thermogenesis, citric acid cycle, PD-1 signaling while upregulation of estrogen dependent gene expression, estrogen mediated signaling, nuclear receptor transcription pathway. These suggests that HSP60 overexpression in TNBC promotes basal type phenotype. Downregulation of HSP60 expression upregulated hormone receptors, particularly estrogen receptor (ESR1) and androgen receptor (AR) expression, thus inducing basal to luminal switch in MDA-MB-231 cells. These findings suggest that loss of HSPD1 significantly Induces plasticity in TNBC. Conclusion Our results suggest that loss of HSPDI in the context TNBC cells may promotes oncogenic transformation to an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the upregulation of Estrogen-receptors signaling pathways. Ongoing analyses will be performed to identify the possible links between loss of HSPD1 and key transcription factors that define mammary epithelial cell differentiation. Citation Format: Muhammad G. Khodary, Alehegne W. Yirsaw, Temesgen Samuel, Clayton Yates, Deepa Bedi. Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1238.

220 Sex Differences in Cardiac Damage in Aortic Stenosis

OBJECTIVES/GOALS: Sex differences in aortic stenosis (AS) are vastly underestimated, contribute to disparities in treatment and worse outcomes for women including disproportionately higher mortality rates. This study aims to investigate sex differences in extent of cardiac damage (CD) from pressure overload in AS that may help account for the observed disparities. METHODS/STUDY POPULATION: CD in AS refers to a series of pathologic changes in the myocardium that occur due to chronic pressure overload imposed on the left ventricle by a progressively stenotic aortic valve (AV). These changes are associated with poor outcomes and lower survival in patients with AS. To acquire a deeper understanding of the factors and mechanisms affecting differences in the long-term survival and management of patients with AS, we are proposing to assess baseline stage of CD on echocardiography, and changes in transvalvular hemodynamics and CD stage (Δ CD) over time, in patients with moderate and severe AS at one of 2 large tertiary-care hospitals in MA. We also plan to assess time to and performance of aortic valve replacement (AVR), stratified by hemodynamic severity of stenosis and CD stage, and their interaction with sex. RESULTS/ANTICIPATED RESULTS: We hypothesize that women will have a higher stage of CD on their initial echocardiogram (TTE), demonstrating moderate or greater severity of AS, than men with the same hemodynamic severity of valvular stenosis. We additionally hypothesize that those with more advanced cardiac damage stage will likely have masking of transvalvular progression on echocardiogram. Finally, we anticipate that women will have AVR performed less frequently than men and will have minimal improvement in their Kansas City Cardiomyopathy Questionnaire (KCCQ) scores post-AVR indicative of more heart failure symptoms and a lower quality of life. DISCUSSION/SIGNIFICANCE: This study will seek to better understand sex-based differences in extent of cardiac damage to pressure overload in aortic stenosis (AS) to minimize treatment and outcome disparities for women and allow for more individualized and patient-centered care.