Lower Survival Rate In Patients Research Articles

Targeting the Tumor Epigenetic Regulator SETDB1 for Tumor Therapy.

Epigenetic alterations are implicated in the early stages of tumorigenesis and are widely recognized as a ubiquitous phenomenon in cancer development. Aberrant epigenetic modifications can alter the expression of target genes, induce heterochromatin formation, and gradually drive normal cells towards immortalized tumor cells with significant consequences. SETDB1 (SET domain bifurcated histone lysine methyltransferase 1), a typical histone me-thyltransferase, promotes the formation of heterochromatin and inhibits the transcription of genes by modifying the methylation of lysine 9 of histone 3. SETDB1 is usually highly ex-pressed in tumors with high copy numbers, accompanied by poor prognosis and low patient survival rates, which is a typical case of abnormal epigenetic modification. We discuss the mechanism of SETDB1 in a variety of cancers and review the epigenetic inhibitors that have been reported in recent years, along with their anti-tumor effects. In addition, we summarize the role of SETDB1 in a variety of diseases and cell functions.

The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer

While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

Comprehensive analysis and experimental verification of the mechanism of anoikis related genes in pancreatic cancer

BackgroundPancreatic cancer (PC), characterized by its aggressive nature and low patient survival rate, remains a challenging malignancy. Anoikis, a process inhibiting the spread of metastatic cancer cells, is closely linked to cancer progression and metastasis through anoikis-related genes. Nonetheless, the precise mechanism of action of these genes in PC remains unclear. MethodsStudy data were acquired from the Cancer Genome Atlas (TCGA) database, with validation data accessed at the Gene Expression Omnibus (GEO) database. Differential expression analysis and univariate Cox analysis were performed to determine prognostically relevant differentially expressed genes (DEGs) associated with anoikis. Unsupervised cluster analysis was then employed to categorize cancer samples. Subsequently, a least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted on the identified DEGs to establish a clinical prognostic gene signature. Using risk scores derived from this signature, patients with cancer were stratified into high-risk and low-risk groups, with further assessment conducted via survival analysis, immune infiltration analysis, and mutation analysis. External validation data were employed to confirm the findings, and Western blot and immunohistochemistry were utilized to validate risk genes for the clinical prognostic gene signature. ResultsA total of 20 prognostic-related DEGs associated with anoikis were obtained. The TCGA dataset revealed two distinct subgroups: cluster 1 and cluster 2. Utilizing the 20 DEGs, a clinical prognostic gene signature comprising two risk genes (CDKN3 and LAMA3) was constructed. Patients with pancreatic adenocarcinoma (PAAD) were classified into high-risk and low-risk groups per their risk scores, with the latter exhibiting a superior survival rate. Statistically significant variation was noted across immune infiltration and mutation levels between the two groups. Validation cohort results were consistent with the initial findings. Additionally, experimental verification confirmed the high expression of CDKN3 and LAMA3 in tumor samples. ConclusionOur study addresses the gap in understanding the involvement of genes linked to anoikis in PAAD. The clinical prognostic gene signature developed herein accurately stratifies patients with PAAD, contributing to the advancement of precision medicine for these patients.

CRISPR-Cas9 potential for identifying novel therapeutic targets in muscle-invasive bladder cancer.

Gene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting.

Changes in the Quality of Life and Nutrition Markers in Transition From End-Stage Kidney Disease to Kidney Transplantation: Insights From a Vietnamese Cohort.

Background Malnutrition is strongly associated with lower quality of life (QoL) and lower survival rates in patients with end-stage kidney disease. However, the impact of renal transplantation on nutrition factors and QoL is unclear. Therefore, this study aims to assess changes in QoL and investigate the relationships with nutrition factors among kidney transplant recipients (KTRs). Materials and methods A longitudinal study included 86 dialysis patients aged 18-65 years who underwent primary kidney transplantation (KTx) and were followed up for one year. Body weight, biochemical parameters, and QoL data were collected before transplantation (T0)and at six months (T6) and 12 months (T12) post-transplantation. Effect size (ES) was used to measure the impact of KTx on QoL and nutritional status from T0 to T12. The predictors of QoL were calculated with β-coefficients and p<0.05 in linear regression. Results The ES of transplantation on the QoL of KTRs was large, at 1.1 for health change, 0.9 for physical health, and moderate (0.7) for mental health (MH) over one year. Hemoglobin and malnourished were affected by KTx, with ES being 2.4 and 0.6, respectively. Linear regression showed that physical health was predicted by hemoglobin (β=0.12, p<0.01), phosphorus (β=7.82, p<0.05), and dose of mycophenolatemofetil (MMF) (β=-0.01, p<0.05). Mental health was predicted by obesity (β=-7.63, p<0.05), hemoglobin (β=0.11, p<0.05), and phosphorus (β=8.49, p<0.01). Health change was indicated by nutritional risk index (NRI) score (β=0.47, p<0.05), total cholesterol (β=3.39, p<0.01), and kidney function (β=0.15, p<0.05). Conclusions The transition from end-stage kidney disease to transplantation has positive impacts on QoL and nutrition markers. Nutritional status, kidney function, and the dose of mycophenolatemofetil are significant determinants of QoL in KTRs.

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 &gt;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 (&gt;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 &gt;25, 0.22 for patients &gt;65 years-old, both p &lt; 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.

SNAI2 as a Prognostic Biomarker Based on Cancer-Associated Fibroblasts in Patients With Lung Adenocarcinoma

Background: Lung adenocarcinoma (LUAD) is a common type of malignant tumor with therapeutic challenges. Cancer-associated fibroblasts (CAFs) promote LUAD growth and metastasis, regulate the tumor immune response, and influence tumor treatment responses and drug resistance. However, the molecular mechanisms through which CAFs control LUAD progression are largely unknown. In this study, we aimed to determine the correlations between CAF-related genes and overall survival (OS) in patients with LUAD. Methods: We acquired the gene expression data and clinical information of 522 patients with LUAD patients from The Cancer Genome Atlas (TCGA) and 442 patients with LUAD from the Gene Expression Omnibus (GEO) databases. CAF infiltration levels were assessed using the Microenvironment Cell Population (MCP) counter, the Estimating the Proportions of Immune and Cancer cells (EPIC) algorithm, and Tumor Immune Dysfunction and Exclusion (TIDE) scores. A CAF-related gene network was constructed using the Weighted gene co-expression network analysis (WGCNA). Based on the CAF-related genes, univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analyses were performed to identify prognostic genes. Gene expression levels within the prognostic model were validated using the Cancer Cell Line Encyclopedia (CCLE) databases and Western blotting. Results: Our results demonstrated that high CAF scores were associated with lower survival rates in patients with LUAD. Gene modules that were highly correlated with high CAF scores were closely associated with tissue characteristics and extracellular matrix structures in LUAD. In addition, correlations between CAF scores and responses to immunotherapy and chemotherapy were observed. Finally, we found that SNAI2 expression was higher in lung cancer tissues than in normal tissues. Conclusion: Deepening our understanding of the influence of CAFs on tumor progression and treatment response at the molecular level can aid the development of more effective therapeutic strategies. This study provides important insights into the functional mechanisms of action of CAFs in LUAD and highlights their clinical implications.

Inflammation-Related Gene ADH1A Regulates the Polarization of Macrophage M1 and Influences the Malignant Progression of Gastric Cancer.

Gastric cancer (GC) is a malignant tumor originating from the gastric mucosa epithelium, and there is a low survival rate of GC patients after treatment, with a poor prognostic outcome. The inflammatory response within the tumor microenvironment plays an important role in GC progression. We downloaded GC-related datasets and inflammation-related genes from GEO, TCGA and MSigDB databases, performed differential analysis, protein-protein interaction analysis, immunoinfiltration analysis and Lasso analysis to screen inflammation-related hub genes affecting GC progression, and carried out qRT-PCR for validation. In order to explore the role of ADH1A, we constructed overexpressed plasmids, treated GC cells with cGMP/PKG pathway agonist 8-Br-cGMP, and tested cell functions with CCK8, EdU, Transwell, scratch assay and other experiments. On this basis, GC cells were co-cultured with monocyte THP-1 to explore the effect of ADH1A on the polarization of macrophages. ADH1A was significantly decreased in GC cells, and its expression trend was consistent with the results of bioinformatics analysis. Therefore, we chose ADH1A for subsequent functional validation. Overexpression of ADH1A in GC cells revealed ADH1A's role in inhibiting the activity, proliferation, migration and invasion of GC cells, promoting apoptosis and secretion of IL-6, IFN-γ, CCL5 and CSF2, and facilitating the transformation of macrophages to a pro-inflammatory M1 phenotype. ssGSEA results demonstrated the potential involvement of ADH1A in the cGMP/PKG signaling pathway, and significant changes in the expression of proteins related to the cGMP/PKG signaling pathway. The use of the cGMP/PKG signaling pathway agonist 8-Br-cGMP in ADH1A-overexpressing GC cells substantiated ADH1A's capacity to inhibit the cGMP/PKG signaling pathway, thereby suppressing the malignant progression of GC and promoting the transformation of macrophages to a pro-inflammatory M1 phenotype. ADH1A is able to influence the malignant progression of GC and the transformation of macrophages to the pro-inflammatory M1 phenotype through the cGMP/PKG signaling pathway.

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 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 tubes 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 show that the presence of fibroblasts allows for significantly increased growth rates for H460 cancer. Additionally, the 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.