Poor Survival Rate Research Articles

Network-Based Transcriptome Analysis Reveals FAM3C as a Novel Potential Biomarker for Glioblastoma.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencingand scRNA-sequencing), which were obtained from TCGA and GEO databases. By using theSTRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next,Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3C‑coregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patientsbut also gavea new insight into a potential resource for future GBM studies.

Novel chemokine biomarkers in melanoma†.

The melanoma tumor microenvironment is a complex milieu of cancer, inflammatory, and stromal cells. In this context, chemokines play a pivotal role in recruiting inflammatory cells and influence the tumor, exerting both pro-tumorigenic and anti-tumoral roles. Interactions between these cells is what ultimately hold together and transform the tumor into an efficient machine. A recent study found that chemokines CCL8, CCL15, and CCL20 were upregulated in melanoma cells when co-cultured with macrophages and were associated with poor survival rates. CCL8 and CCL15 also stimulated melanoma cell growth, invasion, and metastasis, and were highly expressed in tumors prone to metastasize, suggesting these chemokines are attractive and independent biomarkers. Understanding the intricated interactions within the tumor microenvironment could lead to prognostic biomarkers and to the development of new therapeutic strategies for melanoma. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Impact of recurrent intermittent flooding on the yield and growth of Elaeis guineensis

AbstractIncreased frequency and severity of flooding are linked to global warming. Flooding stress can severely affect crop yields and plant survival, and therefore the livelihoods of farmers. An oil palm breeding trial plot consisting of six progenies in Terengganu, Malaysia, happened to be inundated with flooding within a year after planting and annually for 2 years thereafter. Flooding recurred at the 8th year of planting and several times after that within the 14‐year period of monitoring. Due to the uneven terrain in this trial, palms were exposed to various flood levels and were categorized into two flooding groups. Yields and survivability of the palms were not affected by low‐flood levels, in contrast to the palms in lower areas that experienced higher flood levels. Compared to neighbouring non‐flooded trials, palms exposed to high floodwaters generally experienced lower fruit yields, and reduced vertical growth with poorer canopy cover. However, one of the progenies that exhibited a moderate survival rate in high‐flooded areas outperformed the other progenies in terms of yield in these areas. Generally, young oil palms exposed to low floods were able to survive and produce yields that were comparable to palms in non‐flooded areas, though 10%–20% of the low‐flooded palms produced poor yields in the first 3–5 years. In high‐flooded areas however, oil palm survivability ranged from 45% to 73% during the early 3 years and 46%–89% thereafter. Hence, young palms exposed to recurrent flooding of approximately more than 1 m during their early years are likely to become poor yielders with poor survival rates. Observations from this study may assist oil palm farmers in the management of this crop in the event of unexpected flooding.

Modification of mesenchymal stromal cells with silibinin-loaded PLGA nanoparticles improves their therapeutic efficacy for cutaneous wound repair

The use of mesenchymal stromal cells (MSCs) for treating chronic inflammatory disorders, wounds, and ischemia-reperfusion injuries has shown improved healing efficacy. However, the poor survival rate of transplanted cells due to oxidative stress in injured or inflamed tissue remains a significant concern for MSC-based therapies. In this study, we developed a new approach to protect MSCs from oxidative stress, thereby improving their survival in a wound microenvironment and enhancing their therapeutic effect. We produced PLGA nanoparticles loaded with the cytoprotective phytochemical silibinin (SBN), and used them to modify MSCs. Upon internalization, these nanoformulations released SBN, activating the Nrf2/ARE signaling pathway, resulting in threefold reduction in intracellular ROS content and improved cell survival under oxidative stress conditions. Modification of MSCs with SBN-loaded PLGA nanoparticles increased their survival upon transplantation to full-thickness cutaneous wounds and improved wound healing. This study suggests that MSC modification with cytoprotective nanoparticles could be a promising approach for improving wound healing.

LHFPL2 Serves as a Potential Biomarker for M2 Polarization of Macrophages in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the kidney, presenting significant challenges for clinical diagnosis and treatment. Macrophages play crucial roles in RCC, promoting tumor progression and warranting further investigation. Previous studies have identified LHFPL2 as a transmembrane protein associated with reproduction, but its relationship with tumors or macrophages has not been discussed. This study utilized transcriptomic sequencing data from 609 KIRC patients in the TCGA database and single-cell sequencing data from 34,326 renal carcinoma cells for subsequent analysis. We comprehensively evaluated the expression of LHFPL2 and its relationship with clinical features, tumor prognosis, immune infiltration, and mutations. Additionally, we further assessed the correlation between LHFPL2 and macrophage M2 polarization using single-cell data and explored its potential as a cancer therapeutic target through molecular docking. The results demonstrated that LHFPL2 is upregulated in RCC and associated with poor survival rates. In clinical staging, the proportion of malignant and high-metastasis patients was higher in the high-LHFPL2 group than in the low-LHFPL2 group. Furthermore, we found that LHFPL2 influences RCC immune infiltration, with its expression positively correlated with various immune checkpoint and M2-related gene expressions, positively associated with M2 macrophage infiltration, and negatively correlated with activated NK cells. Moreover, LHFPL2 showed specific expression in macrophages, with the high-expression subgroup exhibiting higher M2 polarization, hypoxia, immune evasion, and angiogenesis scores, promoting tumor progression. Finally, we predicted several potential drugs targeting LHFPL2, such as conivaptan and nilotinib. Our analysis elaborately delineates the immune characteristics of LHFPL2 in the tumor microenvironment and its positive correlation with macrophage M2 polarization, providing new insights into tumor immunotherapy. We also propose potential FDA-approved drugs targeting this gene, which should be tested for their binding effects with LHFPL2 in future studies.

STEM-03. A NOVEL MOUSE MODEL OF CHOROID PLEXUS CARCINOMA UNRAVELS SEQUENTIAL DEDIFFERENTIATION OF HINDBRAIN CHOROID PLEXUS TISSUE AND REVEALS NEW THERAPEUTIC PROSPECTS

Abstract BACKGROUND Choroid Plexus tumors constitute 10-20% of brain tumors in the first year of life. Among those, Choroid Plexus Carcinomas (CPC) pose a significant challenge due to their aggressiveness, resulting in poor survival rates and long-term adverse effects stemming from intense therapeutic approaches. Although loss of p53 and Sonic hedgehog signaling have been implicated in CPC development, a deeper biological understanding is needed to expand mechanistic insights and advance targeted therapies. METHODS We generated a novel mouse model with a simultaneous loss of TP53 and overexpression of MYCN and Gli2 in central nervous system precursors (hGFAP-cre::P53Fl/Fl::lsl-MYCN::lsl-Gli2). Resulting tumors were histologically characterized and compared to human CPC. Moreover, spatial transcriptomic data were generated for molecular characterization. Finally, mouse tumor-derived cell lines were employed for differentiation analysis and therapeutic testing. RESULTS Examinations at different developmental stages revealed brain tumors in the choroid plexus as well as smaller lesions in the subcallosal cortex with a penetrance of 80% within 18 days. We observed a gradual dedifferentiation of hindbrain CP tissue from day 5 onwards, indicating a continuous developmental sequence corresponding with expanding tumor growth. The mouse model recapitulates early tumor development, aggressive and metastatic growth along with histological features of human tumors. Spatial transcriptomic analysis highlighted chromosomal aberrations as well as other features known from human CPCs and emphasized the disturbance of ciliary pathways in tumor development. In vitro studies revealed rapidly growing tumor cells with stem cell-like differentiation potential and high sensitivity to targeted therapies. CONCLUSION Through in-depth analysis, including multiple data types, we show that our novel CPC mouse model closely resembles human tumors. Our tumors reveal a strict pattern of dedifferentiation implying similar mechanisms in humans. Additionally, primary mouse tumor cells in culture facilitate further in vitro analysis, and newly generated spatial transcriptomic data enables further insights into tumor biology.

HGG-53. MULTI-DIMENSIONAL INTEGRATIVE PROFILING IDENTIFIES BCL2L1 METHYLATION AS A PREDICTIVE BIOMARKER FOR MCL-1 ACTIVITY IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) pose a significant challenge as the most aggressive central nervous system tumors in children. The lack of effective treatment and poor survival rates emphasize the critical need for innovative therapies to improve the prognosis of pediatric patients with pHGG. METHODS We executed CRISPR-cas9 knockout (KO) screenings in 65 pediatric and 10 adult high-grade glioma (HGG) cell lines to explore unique functional dependencies associated with pHGGs. Drug assays were carried out to assess the targetability of a gene dependency of interest in pHGG cell lines. Subsequently, Random Forest machine learning algorithm was employed on ‘omics’ datasets to identify biomarkers indicative of drug response. Finally, biomarkers were confirmed through sequencing-based methods across various pediatric cancers. RESULTS CRISPR-cas9 KO screens revealed 8 crucial genes essential for pHGG growth, namely MCL-1, ATIC, DHFR, EED, HDAC2, PARP1, PDK1, PIK3CA and TYMS. Among these, Myeloid Cell Leukemia (MCL-1) was further characterized as it emerged as the top differential genetic dependency in pHGGs. Consistent with this, MCL1 inhibitors exhibited potent anti-cancer activity on 43% of pHGG cell lines. Multi-feature prediction analysis identified 140 features correlated to response. Strikingly, a previously undescribed methylation site within the BCL2L1 locus, cg00300298, ranked in the top 5% of features. Tissue analysis revealed a wide range of other pediatric brain cancers that harbor the BCL2L1 cg00300298 methylation mark as compared to non-malignant brain tissue. Lastly, we validated the utility of BCL2L1 methylation as a predictive biomarker of MCL1 inhibitor sensitivity across a large panel of pediatric brain cancer cell lines. CONCLUSION Using an integrated genomic approach, we identify MCL1 as a distinct therapeutic target in BCL2L1-methylated pediatric brain cancers. This offers a rational approach for stratifying patients who may benefit from MCL1 inhibitors.

Isorhapontigenin inhibition of basal muscle-invasive bladder cancer attributed to its downregulation of SNHG1 and DNMT3b

BackgroundBladder cancer (BC) is among the most prevalent malignant urothelial tumors globally, yet the prognosis for patients with muscle-invasive bladder cancer (MIBC) remains dismal, with a very poor 5-year survival rate. Consequently, identifying more effective and less toxic chemotherapeutic alternatives is critical for enhancing clinical outcomes for BC patients. Isorhapontigenin (ISO), a novel stilbene isolated from a Gnetum found in certain provinces of China, has shown potential as an anticancer agent due to its diverse anticancer activities. Despite its promising profile, the specific anticancer effects of ISO on BC and the underlying mechanisms are still largely unexplored.MethodsThe anchorage-independent growth, migration and invasion of BC cells were assessed by soft agar and transwell invasion assays, respectively. The RNA levels of SOX2, miR-129 and SNHG1 were quantified by qRT-PCR, while the protein expression levels were validated through Western blotting. Furthermore, methylation-specific PCR was employed to assess the methylation status of the miR-129 promoter. Functional assays utilized siRNA knockdown, plasmid-mediated overexpression, and chemical inhibition approaches.ResultsOur study demonstrated that ISO treatment significantly reduced SNHG1 expression in a dose- and time-dependent manner in BC cells, leading to the inhibition of anchorage-independent growth and invasion in human basal MIBC cells. This effect was accompanied by the downregulation of MMP-2 and MMP-9 and the upregulation of the tumor suppressor PTEN. Further mechanistic investigations revealed that SOX2, a key upstream regulator of SNHG1, played a crucial role in mediating the ISO-induced transcriptional suppression of SNHG1. Additionally, we found that ISO treatment led to a decrease in DNMT3b protein levels, which in turn mediated the hypomethylation of the miR-129 promoter and the subsequent suppression of SOX2 mRNA 3’-UTR activity, highlighting a novel pathway through which ISO exerts its anticancer effects.ConclusionsCollectively, our study highlights the critical role of SNHG1 downregulation as well as its upstream DNMT3b/miR-129/SOX2 axis in mediating ISO anticancer activity. These findings not only elucidate the mechanism of action of ISO but also suggest novel targets for BC therapy.

Identification of a novel GSK3β inhibitor involved in abrogating KRas dependent pancreatic tumors in Wnt/beta-catenin and NF-kB dependent manner

Pancreatic cancer is an aggressive malignancy with a poor survival rate because it is difficult to diagnose the disease during its early stages. The currently available treatments, which include surgery, chemotherapy and radiation therapy, offer only limited survival benefit. Pharmacological interventions to inhibit Glycogen Synthase Kinase-3beta (GSK3β) activity is an important therapeutic strategy for the treatment of pancreatic cancer because GSK3β is one of the key factors involved in the onset, progression as well as in the acquisition of chemoresistance in pancreatic cancer. Here, we report the identification of MJ34 as a potent GSK3β inhibitor that significantly reduced growth and survival of human mutant KRas dependent pancreatic tumors. MJ34 mediated GSK3β inhibition was seen to induce apoptosis in a β-catenin dependent manner and downregulate NF-kB activity in MiaPaCa-2 cells thereby impeding cell survival and anti-apoptotic processes in these cells as well as in the xenograft model of pancreatic cancer. In vivo acute toxicity and in vitro cardiotoxicity studies indicate that MJ34 is well tolerated without any adverse effects. Taken together, we report the discovery of MJ34 as a potential drug candidate for the therapeutic treatment of mutant KRas-dependent human cancers through pharmacological inhibition of GSK3β.

Knowledge and awareness of paediatric basic life support among parents in the Lady Ridgeway Hospital for Children, Colombo, Sri Lanka

Background: Out-of-hospital cardiac arrest in children is uncommon but significant, with poor survival rates and high morbidity. Choking in children is common but less reported with high mortality. Early commencement of cardiopulmonary resuscitation (CPR) in cardiac arrest or following of choking algorithm in a case of choking is important for survival of the victim. Objectives: To survey the knowledge, awareness and attitudes of parents in Sri Lanka regarding paediatric Basic Life Support (BLS) including early treatment of choking.Method: This was a descriptive cross-sectional study and questionnaires were administered to parents of children managed at the Preliminary Care Unit (PCU) and wards 2 and 4 of Lady Ridgeway Hospital, Colombo from October 2022 to January 2023. Sample size was calculated according to the Lwanga and Lemeshow method. Total respondents were 350 out of total participants of 415. The questionnaire consisted of four sections for assessment of demography, knowledge and attitude. Total scores of each aspect were analysed with respect to different factors.Results: Of the participants, 95% did not have BLS training and the largest proportion of them was educated only up to the General Certificate of Education (GCE) ordinary level. Knowledge of specific aspects of BLS or choking was demonstrated by only about 10% of the population. Nearly 50% of parents had identified substandard common practices as correct methods. There was no statistically significant correlation between total score of each aspect and previous observations, training or highest educational level. It was assessed with 95% confidence interval. However, seeing BLS had improved knowledge of basic health (p=0.013). Conclusions: Seeing the procedure on television or other resources had not improved knowledge of BLS. Workshops were the preferred method to improve their knowledge on BLS including the choking algorithm and participants’ educational level was not important in organizing such an event.

Related Clinical Factors of Platinum-Based Chemotherapy Resistance in Patients with Epithelial Ovarian Cancer.

Ovarian cancer is the second most common malignancy in women, but it is a fatal gynecological tumor. Although it has a standard treatment regimen, resistance to chemotherapy makes patients more prone to early recurrence, leading to poor survival rates. Therefore, this study investigated factors related to platinum resistance through a complete analysis of clinical data. Clinical data of patients with ovarian cancer were collected, and the patients were categorized into platinum-sensitive and platinum-resistant groups. By comparing the differences in clinical data between the groups, the key factors affecting platinum resistance were analyzed. We collected the clinical data of patients with epithelial ovarian cancer (EOC) who were admitted to the Department of Oncology of the General Hospital of Ningxia Medical University between January 1, 2019, and December 31, 2020. We conducted univariate and multivariate analyses and evaluated overall survival and progression-free survival using the Kaplan-Meier method. We enrolled 161 patients with EOC, of whom 124 demonstrated platinum sensitivity and 37 demonstrated platinum resistance after the initial platinum-based chemotherapy. Univariate analyses revealed that the International Federation of Gynecology and Obstetrics (FIGO) stage, neoadjuvant chemotherapy, and Fagotti score were associated with an increased risk of platinum resistance for the first recurrence. In multivariate logistic regression analysis, only Fagotti score and neoadjuvant chemotherapy were associated with an increased risk of platinum resistance (odds ratio: 0.372 and 0.328, 95% confidence interval: 0.160-0.863 and 0.141-0.762, p = 0.021 and 0.010, respectively). The sample size of this study was relatively small because of nonstandard treatment of some patients, the absence of clinical data, and failure of follow-up. Patients with EOC exhibiting platinum resistance had a very poor prognosis. The Fagotti score and neoadjuvant chemotherapy appeared to increase the risk of platinum resistance at first recurrence.

Emerging Insights into the PI3K/AKT/mTOR Signaling Pathway and Non-Coding RNA-mediated Drug Resistance in Glioblastoma.

Glioblastoma multiforme [GBM] is a highly aggressive grade IV central nervous system tumor with a dismal prognosis. Factors such as late detection, treatment limitations due to its aggressive nature, and, notably, drug resistance significantly affect clinical outcomes. Despite the effectiveness of Temozolomide [TMZ], a potent chemotherapy agent, the development of drug resistance remains a major challenge. Given the poor survival rates and chemoresistance, there is an urgent need for novel treatment strategies. Non-coding RNAs, particularly microRNAs [miRNAs], offer a promising approach to GBM diagnosis and treatment. These small non-coding RNAs play crucial roles in tumor progression, either suppressing or promoting oncogenic characteristics. The phosphoinositide-3 kinase [PI3K]/AKT/ mTOR pathway, which regulates essential biological processes like proliferation and survival, is a key target of miRNAs in cancer. Studies have underscored the significance of PI3K/AKT/mTOR signaling in drug resistance development and its interplay with non-coding RNAs as mediators of tumorigenesis. This review aims to outline the involvement of PI3K/AKT/mTOR signaling in miRNA modulation and strategies to overcome chemoresistance in GBM.

Exploring the role of pembrolizumab in mesothelioma: A single-arm analysis of available data.

e20097 Background: Malignant Mesothelioma (MMe) is a neoplasm of mesothelium and has a very poor survival rate. Over half the patients of MMe express programmed death-ligand 1 (PD-L1) which binds to the PD-1 receptor on T-cells which in turn suppresses their ability to kill tumors. Pembrolizumab is a PD-1 inhibitor antibody and it has shown efficacy in combating MMe. Our analysis aims to summarize data related to objective response rates (ORR) and adverse effects of Pembrolizumab therapy in MMe patients. Methods: We conducted an online search through PubMed, Cochrane, and Clinicaltrials.gov databases from their inception till January 25, 2024, to identify studies that reported the use of Pembrolizumab in patients with MMe. Data were extracted and analyzed and proportions with their 95% confidence interval have been reported. Onlinemeta v1.0 was used for all analyses. Results: A total of six studies with 549 patients reported the use of Pembrolizumab in patients with MMe. ORR was observed in 36.2% (32.3% - 40.4%; p < 0.01) of patients receiving Pembrolizumab while 20.4% (17.2%- 24.0%; p < 0.01) of patients experienced adverse effects of the therapy. Median survival ranged from 9.5 to 17.3 months whereas progression-free survival ranged from 2.5 to 7.1 months in patients. Conclusions: Pembrolizumab has an ORR and safety profile comparable to other immunotherapies. Further studies are needed to extensively study the drug and its effects in detail in patients with MMe. [Table: see text]

Use of gene expression patterns to identify unique molecular subtypes in muscle invasive bladder cancer: GUSTO.

TPS4621 Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease with poor survival rates that are not improving. Curative treatment includes systemic neoadjuvant chemotherapy prior to radical cystectomy and adjuvant immunotherapy. However, many patients do not respond to chemotherapy or immunotherapy. Histologically similar MIBCs can be classified using gene expression patterns into unique molecular subtypes. Retrospective studies have shown that molecular subtypes each have unique biology and consequently respond differently to treatment. The GUSTO trial tests the hypothesis that outcomes can be optimized through subtype-guided allocation. Methods: Eligible participants are those with confirmed non-metastatic MIBC, an ECOG performance status 0-1, being considered for cisplatin-based neoadjuvant chemotherapy and radical cystectomy. Formalin-fixed diagnostic (TURBT) tumor samples undergo gene expression microarray analysis and characterization using the GUSTO Classifier (consisting of the Veracyte Decipher assay and TCGA_2017 classification system) to determine the molecular subtype: basal, neuronal, luminal infiltrated, luminal or luminal papillary. A total of 320 eligible patients (T2-4a N0 M0 or T(any) N1 M0 MIBC) will be randomized 1:1 to either standard of care treatment (neoadjuvant cisplatin and gemcitabine) or subtype-guided treatment (basal and neuronal subtypes - neoadjuvant cisplatin, gemcitabine, durvalumab and tremelimumab and adjuvant durvalumab; luminal infiltrated - neoadjuvant durvalumab and tremelimumab and adjuvant durvalumab; luminal and luminal papillary - proceeding directly to radical cystectomy). Sites are notified when a patient has been assigned a molecular subtype. Patients and sites in the standard of care arm remain blind to the genomic subtype. The trial has three stages: Stage 1 (after 6 months of recruitment) will assess feasibility of recruitment and molecular subtyping in clinical timelines. Outcomes include recruitment rate, time to, and success of subtype allocation. Stage 2 (after 24 months of recruitment) will confirm recruitment feasibility and assess sample size assumptions. Outcomes are recruitment numbers, distributions of subtypes, and pathological complete response (pCR) in the standard of care arm. A re-estimation of the sample size for stage 3 will be considered. Stage 3 (after 12 months post-cystectomy for the last participant randomized) will assess treatment outcomes using this stratified approach. The primary outcome for Stage 3 is the rate of pCR in each molecular subtype within the experimental arm. Progression between trial stages will be dependent upon achieving pre-defined criteria. Recruitment began in September 2023. The study will open the first 20 sites ready to proceed and is accepting expressions of interest. Clinical trial information: 17378733.

Feasibility study utilizing a combinatorial functional precision medicine platform, Optim.AI, to help guide treatment for pancreatic cancer.

e13614 Background: Functional screening methods are increasingly applied to guide patient treatment and could be beneficial in indications with poor survival and response rates, such as pancreatic cancer. However, challenges faced when implementing ex vivo testing include complexities in obtaining sufficient tumor cells for different cancer types and maximizing the number of treatments tested with limited sample material. The latter is especially significant in informing clinical decision making as combination therapies are common with cancer, exponentially increasing the number of regimens to select from. To address this hurdle, we developed Optim.AI, a combinatorial functional precision medicine platform, which utilizes efficiently designed experiments and small data AI to expand to over 530,000 phenotypic response data points and predictively rank all actionable treatments within a 12-drug panel. In this feasibility study, we explored the application of Optim.AI on patient-derived tumor cells in pancreatic cancer. Methods: We established a procedure to run Optim.AI with isolated tumor cells from pancreatic cancer patients. After dissociation, these cells were then incubated to allow for 3D organoid formation within the following week. Upon organoid formation, the cells were treated with an FDA-approved panel of chemotherapy and targeted drugs. Cell viability was quantified post-drug treatment for analysis with Optim.AI software to rank all possible single to 4-drug combinatorial therapies for report generation. Results: The viability of the cells post-processing was high (mean = 97.4% live cells), passing the quality check of having at least 60% live cells before proceeding with Optim.AI testing. The success rate of organoid formation was 100% within 1 week of sample processing. The turnaround time from the receipt of samples to dissemination of the reports to clinicians was approximately a week (mean = 7.67 days). Z’ factor, a measurement of statistical effect size for high throughput screening, was demonstrated to be more than 0.5 for the reports generated, indicative of very good assays. The top ranked drug combinations were sensitive, with their normalized cell viability reported to be under 0.2, while the prior line of treatment was shown to be resistant, 100% concordant with previously observed clinical outcomes. Notably, Gemcitabine with either a HDAC or PI3K inhibitor was ranked high amongst the reports generated. Conclusions: Optim.AI had a high success rate in generating reports within a very short timeframe for pancreatic cancer. Comparing the top ranked therapies against the prior lines of treatment allows the clinicians to better evaluate the alternative treatments. Based on this initial feasibility study, Optim.AI could potentially be viable in guiding clinicians in managing treatment options for pancreatic cancer patients.

Tumour microenvironment programming by an RNA–RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA–RNA-binding protein complex LOC–DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood–brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA–RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

Survival of primary gallbladder cancer in the United States: SEER database analysis from 2000-2020.

e16210 Background: Primary gallbladder cancer is a rare but aggressive cancer with poor outcomes. Our study aims to understand the survival trends of patients with Primary gallbladder cancer (PGC) and analyze the prognosis factors based on cases registered in the SEER database from 2000 to 2020. Methods: We usedSEER*Stat Version 8.4.3 software to extract primary gallbladder carcinoma cases from SEER 17 registries (2000-2020). 20,143 patients were included in the study. Those with unconfirmed histology were excluded. We analyzed overall mortality and primary gallbladder cancer-specific mortality (CSM) using a Cox proportional hazards model. The survival analysis was carried out using the Kaplan–Meier method and the log-rank test was used to compare survival curves. Results: There was an overall increase in gallbladder cancer cases by 23% in 2010-2020 compared to 2000-2010. There was no significant cancer-specific mortality difference identified between males and females (HR = 1.009; CI: 0.972-1.046). Non-Hispanic blacks had higher overall mortality (HR = 1.134; CI: 1.010-1.273) amongst different ethnicities. Crude analysis revealed overall mortality was higher among patients aged above 80 years (HR = 9.857; CI: 6.257-15.528). Crude analysis also revealed significantly higher cancer-specific mortality for cholangiocarcinoma (HR = 1.622; CI:1.509-1.744) amongst histological subtypes. Gallbladder cancer-specific mortality was high with regional disease (HR = 3.115; CI: 2.839-3.419) and increased significantly with distant metastases (HR = 7.169; CI 6.512-7.891). Treatment with surgery, chemotherapy, or radiation alone or in combination improved survival among patients. Conclusions: There is a significant increase in gallbladder carcinoma mortality even among patients with regional disease, and it was worse with metastatic disease. With limited early-stage diagnoses and poor overall survival rates, we recommend further research to develop effective screening methods, understand risk factors, and explore effective preventive and therapeutic strategies for primary gallbladder cancer.

The Combination of Auranofin and Celecoxib Suppresses Local Synovial Sarcoma Progression In Vivo.

Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase inhibitor, and celecoxib (CE), an anti-inflammatory drug, significantly impedes the local progression of osteosarcoma (OS). However, the role of redox regulation in SS remains to be elucidated. This study aimed to investigate the efficacy of combined treatment of AUR and CE on the local progression of SS in vivo. Nu/nu mice were implanted with the human SS cell line, Aska-SS, and treated with vehicle control, AUR, or a combination of AUR and CE (AUR-CE). Primary tumor size and weight were evaluated for the study duration and upon resection, respectively. Hematoxylin and eosin (H&E) and Ki-67 staining were performed to assess the local progression of SS. A statistically significant reduction in tumor size and weight was observed in the AUR- and AUR-CE-treated groups upon excision compared to that in the vehicle-treated group. The AUR-CE-treated group showed synergistic inhibition of local tumor growth. H&E staining of local SS tumors revealed decreased cell density and nuclear deformation in the AUR- and AUR-CE-treated groups compared to those in the vehicle-treated group. Immunohistochemical staining revealed a statistically significant decrease in Ki-67-positive cells in the AUR-CE-treated group compared to the vehicle-treated group. The combination of AUR and CE showed significant potential for delaying the local progression of SS. These findings support the repurposing of AUR and CE as early treatment options for SS.

Establishment and validation of a prognostic scoring model based on disulfidptosis-related long non-coding RNAs in stomach adenocarcinoma.

Stomach adenocarcinoma (STAD), a frequently occurring gastrointestinal tumour, is often detected late and has a poor prognosis. Long non-coding RNAs (lncRNAs) significantly affect tumour development. Recent studies have identified disulfidptosis as a previously unexplained form of cell death. Herein, we aimed to examine the predictive value of disulfidptosis-related lncRNA models for the clinical prognosis and immunotherapy of STAD. STAD-related transcriptomic data were obtained from The Cancer Genome Atlas (TCGA), whereas genes associated with disulfidptosis were identified from previously published papers. A risk prediction model for disulfidptosis-related lncRNAs was developed using the Cox regression and least absolute shrinkage selection algorithm methods. The accuracy of the model was confirmed using calibration curves, and the biological functions were analysed using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA). Finally, the tumour mutation burden (TMB) and tumour immune dysfunction and exclusion (TIDE) algorithms were used to screen drugs that are sensitive to STAD. The risk prediction models were constructed using seven disulfidptosis-related lncRNAs. The validated results were consistent with the predicted ones, with significant survival differences. When combined with clinical data, the risk scores were used as independent prognostic markers. Based on the tumour mutation load, the high-risk patient group had a poorer survival rate as compared with the low-risk patient group. Further studies were conducted to understand the different groups' inconsistent responses to immune status; subsequently, relatively sensitive drugs were identified. Overall, seven markers of disulfidptosis-related lncRNAs associated with STAD were found to facilitate prognostic prediction, suggesting new ideas for immunotherapy and clinical applications.

Elucidating the Role of Let-7d-5p and OLR1 in the Progression and Prognosis of Oral Squamous Cell Carcinoma via FAK/P53 Signaling Axis.

Despite advances in oral squamous cell carcinoma (OSCC) diagnosis and treatment, the five-year survival rate remains low, underscoring the need for improved biomarkers and therapeutic strategies. This study investigated the role of let-7d-5p microRNA (miRNA) and its target gene OLR1 in OSCC, focusing on their implications in tumor progression, metastasis and potential as therapeutic targets. Employing next-generation sequencing and bioinformatic tools, we profiled differentially expressed miRNAs in metastatic OSCC cell lines, identifying let-7d-5p as a key down-regulated miRNA and OLR1 as a novel target of let-7d-5p. We validated this interaction using luciferase reporter assays and studied the biological effects of modulating let-7d-5p and OLR1 expression on OSCC cell proliferation, migration, invasion, and stemness. Additionally, we analyzed clinical data to establish the relevance of OLR1 expression in OSCC prognosis. Our findings revealed let-7d-5p as a potent suppressor of OSCC metastasis, primarily by targeting and down-regulating OLR1. OLR1-silencing reduced OSCC cell invasiveness, migration, and stemness, indicating its prominent role in tumor progression. Mechanistically, let-7d-5p modulates a signaling cascade involving FAK, SRC, PAXILLIN, and p53, influencing cellular apoptosis and chemoresistance. Clinically, elevated OLR1 expression significantly correlates with advanced OSCC stages and poorer survival rates, highlighting its potential as a prognostic marker and therapeutic target. Our study uncovers the significance of the let-7d-5p-OLR1 axis in OSCC pathogenesis, offering novel insights for future therapeutic interventions.