Invasive Tumor Growth Research Articles

Prevalence and Significance of AGR2 Expression in Human Cancer.

Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing. To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%-100%), urothelial carcinoma (74.6%-100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%-99.6%), and pancreaticobiliary cancers (65.2%-98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%-77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades as well as advanced pT stage (p = 0.0035) in clear cell renal cell carcinoma (ccRCC). Low AGR2 expression was associated with high BRE grade in breast cancer (p = 0.0049), nodal metastasis (p = 0.0275) and RAS mutation (p = 0.0136) in colorectal cancer, nodal metastasis (p = 0.0482) in endometrioid endometrial carcinoma, high grade in noninvasive urothelial carcinoma (p = 0.0003), and invasive tumor growth in urothelial carcinoma (p < 0.0001). It is concluded that AGR2 expression occurs in a broad range of different tumor entities and that AGR2 assessment may serve as a diagnostic aid for the distinction of thyroidal neoplasms and as a prognostic marker in various cancer types.

Prediction of Intraoperative Blood Loss during Surgery of Brain Meningiomas

Abstract Background The utilization of preoperative embolization is a well-established method for reducing intraoperative blood loss during surgery of meningiomas. However, the exact indications and contraindications for this technique remain controversial. Objective The objective of this study is to determine the indications for preoperative embolization of brain meningiomas. Materials and Methods A retrospective analysis of 46 patients who underwent surgical resection of intracranial meningioma from 2020 to the end of 2022 was conducted. Preoperative magnetic resonance imaging (MRI) and computed tomography (CT) data were studied to assess their relationship with the volume of intraoperative blood loss. Results Invasive tumor growth and bone involvement (erosion, hyperostosis) were found to be the most significant factors influencing intraoperative blood loss (p = 0.001). Conclusion This study clearly demonstrates an association between preoperative imaging data and intraoperative blood loss, which may be useful in predicting massive bleeding during surgery.

Tissue Mechanics and Hedgehog Signaling Crosstalk as a Key Epithelial-Stromal Interplay in Cancer Development.

Epithelial-stromal interplay through chemomechanical cues from cells and matrix propels cancer progression. Elevated tissue stiffness in potentially malignant tissues suggests a link between matrix stiffness and enhanced tumor growth. In this study, employing chronic oral/esophageal injury and cancer models, it is demonstrated that epithelial-stromal interplay through matrix stiffness and Hedgehog (Hh) signaling is key in compounding cancer development. Epithelial cells actively interact with fibroblasts, exchanging mechanoresponsive signals during the precancerous stage. Specifically, epithelial cells release Sonic Hh, activating fibroblasts to produce matrix proteins and remodeling enzymes, resulting in tissue stiffening. Subsequently, basal epithelial cells adjacent to the stiffened tissue become proliferative and undergo epithelial-to-mesenchymal transition, acquiring migratory and invasive properties, thereby promoting invasive tumor growth. Notably, transcriptomic programs of oncogenic GLI2, mechano-activated by actin cytoskeletal tension, govern this process, elucidating the crucial role of non-canonical GLI2 activation in orchestrating the proliferation and mesenchymal transition of epithelial cells. Furthermore, pharmacological intervention targeting tissue stiffening proves highly effective in slowing cancer progression. These findings underscore the impact of epithelial-stromal interplay through chemo-mechanical (Hh-stiffness) signaling in cancer development, and suggest that targeting tissue stiffness holds promise as a strategy to disrupt chemo-mechanical feedback, enabling effective cancer treatment.

Abstract PS18-01: Stage Advancement and The Rate of Growth Associated with Preoperative Delay in Patients Having Breast Cancer

Abstract Introduction: For every delay interval between breast cancer diagnosis and surgery we have previously found a relative decline in disease-specific survival of 26% (60 d) and overall survival of 9-10% (30 d). There is, however, little explanation for this. In our experience, patients focus on the likelihood of cancer growth between diagnosis and surgery, and whether preoperative delay might lead to upstaging, with nodal status of particular concern when they are clinically node-negative. With little published data about delay-associated upstaging and no large-scale national data determining how fast tumors grow, this study was performed to determine these rates. Methods: Patients ≥18 years old having stage 0-III breast cancer who received surgery as first treatment between 2010 and 2020 were reviewed in the National Cancer Database (NCDB), the largest national dataset to contain the needed clinical and pathologic staging. Patients were reviewed for correlation between preoperative delay and cancer upstaging, defined as an increase from cT to pT or cN to pN stages, after assessing baseline clinical stage inaccuracy. Accuracy of clinical staging was determined by comparing clinical stages at presentation to pathologic stages at surgeries ≤15 days of diagnosis, assuming negligible tumor growth in that period. cN3 and cT3 tumors were excluded as there is no higher size-dependent pathologic stage. Upstaging probabilities and odds ratios (ORs) were estimated with logistic regression, adjusted for age, race, Hispanic ethnicity, gender, histology, grade, phenotype, and clinical T or N stage. For patients with delays &amp;gt;15 days, adjusted linear regression coefficients of tumor size on preoperative delay were used to estimate primary invasive tumor growth rates. Results: Among 1,040,197 patients, the median time between diagnosis and surgery was 34 days (IQR 23-49), with 11.6% having primary tumoral and 14.6% having nodal upstaging. In the 10.2% of patients where surgery was performed ≤15 days of diagnosis, 13.9% of DCIS, 11.5% of cT1, and 4.5% of cT2 tumors were upstaged (p &amp;lt; 0.0001). For every 30 days of delay between diagnosis and surgery, the ORs for tumor upstaging, adjusted for covariates, were 1.09 for DCIS (95%CI 1.07-1.10, p&amp;lt; 0.0001), 1.12 for cT1 (95%CI 1.10-1.14, p&amp;lt; 0.0001), and 1.16 for cT2 tumors (95%CI 1.14-1.19, p&amp;lt; 0.0001). For invasive tumors, the adjusted 30-d ORs for upstaging in HR+, HER2+, and TN primaries were 1.12 (95%CI 1.11-1.14), 1.11 (95%CI 1.07-1.15), and 1.19 (95%CI 1.15-1.23), respectively (individual p’s &amp;lt; 0.0001). In the 9.8% of clinically N0 (cN0) patients with a diagnosis-to-surgery interval of ≤15 days, 14.2% were upstaged to node-positive. cN0 patients had an adjusted OR for upstaging to node-positive of 1.06 (95%CI 1.05-1.07, p&amp;lt; 0.0001) for every 30 days of delay. The number of 30-d intervals for cT1mi, cT1a, cT1b, cT1c and cT2 invasive primary tumors to grow 1 mm was 7.8, 7.1, 3.9, 2.8, and 2.0, respectively. Conclusions: Even when accounting for clinical stage inaccuracy, longer delays are associated with a quantifiable increase in upstaging and likelihood of becoming node-positive at surgery. This may explain the higher disease-specific and overall mortality associated with preoperative delay found in prior studies. With larger tumors having a higher delay-associated likelihood of upstaging and faster growth rates, delays become more problematic as tumor size increases. This information reinforces the need to minimize preoperative delays by demonstrating their consequences. It also provides data to address some of breast cancer patients’ most pressing preoperative concerns about how fast breast tumors grow and their upstaging potentials while they await treatment. Citation Format: Richard Bleicher, Karen Ruth, Austin Williams, Eric Ross, Andrea Porpiglia, Allison Aggon, Mary Pronovost, Dennis Holmes. Stage Advancement and The Rate of Growth Associated with Preoperative Delay in Patients Having Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS18-01.

Extracellular vesicles secreted by 3D tumor organoids are enriched for immune regulatory signaling biomolecules compared to conventional 2D glioblastoma cell systems.

Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterize extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems. Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterization was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analyzed by high-resolution mass spectrometry. We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR-323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer-associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response. Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.

Transcriptional, growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death expression in melanoma

Introduction. Melanoma is the most dangerous neoplasm of the skin, characterized by a malignant and aggressive course. Transcriptional and growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death are involved in significant processes of oncogenesis.Aim. To study the expression of components of the AKT/mTOR (mTOR – mammalian target of rapamycin) signaling pathway, transcription and growth factors, expression of AMPK, LC3B, programmed cell death 1 (PD-1), programmed death-ligand 1 PD-L1 and programmed death-ligand 2 (PD-L2) in skin and mucosal tumor tissues.Materials and methods. The study included 21 patients with a verified diagnosis of melanoma of the skin of various localizations and mucous membranes of the nasal cavity T1a–4bN0M0 (I–IV stages) and 18 patients with basal cell carcinoma of the skin of various localizations T1–4N0M0 (I–VIA stages), aged 45 to 72 years old, who were treated in the department of head and neck tumors of the Cancer Research Institute, Tomsk National Research Medical Center. The presence of tumor ulceration was determined by microscopy and registration of the true absence of the epidermis over the tumor or due to traumatization of the epidermis. Expression of components of the AKT/mTOR signaling pathway, transcription and growth factors, expression of AMPK, LC3B, PD-1, PD-L1 and PD-L2 in the tumor tissue was determined by real-time polymerase chain reaction.Results. An increase in the expression of 70 S6 kinase and VHL was found in melanoma tissues compared to basal cell carcinoma. At the same time, the presence of signs of ulceration was associated with a low level of c-RAF, nuclear factor kappa B (NF-kB) p50 and hypoxia-inducible factor 1 (HIF-1) matrix RNA (mRNA) against the background of an increase in the expression of the hypoxia-inducible factor 2 (HIF-2) transcription factor. The study of the molecular features of neoplasms in relation to the tumor thickness according to Breslow revealed the contribution of transcription and growth factors, the intensity of intracellular signaling processes, modification of the microenvironment, autophagy and neoangiogenesis.Conclusion. The molecular and biological features of melanomas associated with invasive tumor growth have been identified. An increase in the expression of 70 S6 kinase and VHL are characteristic of a malignant skin tumor. The presence of signs of ulceration and tumor invasion were associated with a change in the transcriptional characteristics of factors with the induction of key markers, oncogenesis, which contributes to the formation of the invasive potential of the tumor.

Antiphospholipid antibodies as a potential factor of tumor progression

Introduction. Current generally accepted clinical and laboratory criteria for antiphospholipid syndrome (APS) have been clearly determined, which include vascular thrombosis and pregnancy complications in patients with circulating antiphospholipid antibodies (aPLs). However, in the last several years, aPLs have become a common finding in patients with malignancies. Accumulating data provide strong evidence for such association and suggests that thrombosis in cancer patients may be related to aPLs activity. According to global publications, aPLs circulation in cancer patients varies from 15 to 74 %, which may be due to differences in clinical characteristics of cancer patients examined as well as distinct interpretations on aPLs diagnostic tests.Aim: to determine aPLs profile in patients with malignant neoplasms of the female reproductive system, identify an association between aPLs and thrombosis as well as degree of disease progression and outcome.Materials and Methods. A single-center observational study was conducted with 130 women, among which 70 subjects had adenocarcinoma of the uterine body, cervix and ovaries. 60 age-matched apparently healthy women lacking thrombotic complications were included into control group. All study participants were examined for circulating lupus anticoagulantas well as anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein 1 antibodies (anti-β2-GР1), annexin V antibodies, and anti-phosphatidylserine-prothrombin complex antibodies (anti-PS-PT) IgG and IgM by using enzyme-linked immunosorbent assay.Results. Moderate or low aPLs titers were found in 34.2 % of patients with uterine, cervical and ovarian cancer. Ten (14.2 %) of 70 women in main study group had thrombosis so that aPLs were detected only in 5 of 10 women with thrombosis. No significant differences between patients with thrombosis and without thrombotic complications in gynecological cancer were observed. In addition, assessed parameters had no impact on relapse-free survival in cancer patients. However, a significant relation was found between circulating aCLs (IgG, IgM) and anti-PS-PT (IgG, IgM) as well as degree of oncological process. In addition, a significant association was found between aCLs isotype IgG (p = 0.017) and disease relapse.Conclusion. Although thrombosis along with acute thrombosis is a hallmark of APS patients, they demonstrate other non-thrombotic manifestations, one of which is the impact on tumor growth invasion and progression.

Expression of immune checkpoints PD-L1, CTLA4, LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status

Study of the features of expression of immune checkpoint proteins PD-L1, CTLA4 and LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status. The study group consisted of 32 patients with a morphologically confirmed diagnosis of colon cancer; all of them underwent surgical treatment in the form of hemicolonectomy or resection. The work assessed samples of tumor tissue obtained as a result of surgery, the study was carried out in 3 stages: morphological examination of histological slides of colon tumors at the light-optical level, immunohistochemistry examination of tumor samples to determine the dMMR/pMMR status of carcinoma using a panel of antibodies to proteins of the unpaired nucleotide repair system MLH1, MSH2, MSH6 and PMS2, multiplex analysis of PD-L1, CTLA4, LAG3, CD3+, CD8+, CD163+ markers using the Vectra 3.0.3 tissue scanning system (Perkin Elmer, USA). Significant differences in the expression of PD-L1, CTLA4, LAG3 in the area of the invasive tumor margin were revealed between the dMMR and pMMR groups of colon adenocarcinomas in patients comparable in clinical and morphological characteristics and treatment. In the group of tumors with dMMR status, an increase in the expression of all studied markers was noted. The number of CD3+ TILs was also significantly higher in the invasive margin of tumors with dMMR status. Similarly, in this group of colon carcinomas, a large number of CD163+ macrophages were noted both in the center and in the invasive margin zone. No statistically significant differences were found in the expression of immune checkpoints and the composition of TILs in the central zone of tumors with different MMR status. A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.

An efficient many-objective optimization algorithm for computation offloading in heterogeneous vehicular edge computing network

Vehicular Edge Computing (VEC) provides flexible distributed computing paradigm for vehicular network through computation offloading. With the advent of a growing of modern vehicle applications, the challenge for VEC network to fulfill the expansive demands from various suppliers, users and environments is increasingly prominent. This paper formulates a many-objective computation offloading problem in heterogeneous VEC network aiming to fulfill the diversified optimization requirements, including minimizing the task completion time, energy consumption and resource costs as well as load balance. A many-objective optimization algorithm named MaOITGO-CO is proposed to solve the formulated problem based on ITGO (Invasive Tumor Growth Optimization) by simulating the growth patterns of tumor cells. Specifically, considering the characteristics of computation offloading in VEC scenarios such as mobility, real-time requirements and the variety of tasks and resources, four types of tumor cells are equipped with different search strategies to enhance the search effectiveness and efficiency. The simulation results show that the proposed approach can provide high quality Pareto solutions for computation offloading problem, which outperforms other widely used algorithms in terms of convergency and diversity. Furthermore, the results of scalability experiments validate the availability of MaOITGO-CO when the problem is extended to different scales of both tasks and computing resources.

EPCO-45. CELLULAR HIERARCHIES OF ETMR ARE SHAPED BY ONCOGENIC MICRORNAS AND RECEPTOR-LIGAND INTERACTIONS

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive brain tumor that predominantly occurs in children under the age of four years. Most children succumb within 10 months of diagnosis, typically due to invasive tumor growth and therapy-refractory behavior. 95% of ETMR harbor activating genetic alterations of the chromosome 19 microRNA cluster (C19MC). Despite the identification of this presumed oncogenic driving event, its biological consequences remain understudied and targeted therapy options are lacking. Here, we set out to further explore the intracellular heterogeneity of ETMR and shed light onto its oncogenic mechanisms with the goal to identify novel therapeutic targets for this dismal disease. We have compiled and analyzed a cohort of 11 ETMR tumors using single-cell RNA sequencing and multiplexed spatial imaging. We reveal a common, spatially distinct cellular hierarchy, closely resembling physiological brain development. This hierarchy spans a highly proliferative neural stem cell-like population that gives rise to more differentiated neuron-like cells. C19MC, predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA interactions. Targeting specific C19MC members by antisense oligonucleotides results in reduced cell proliferation, suggesting potent new avenues for future therapeutic approaches. Seeking more immediate therapeutic targets, we performed comprehensive cell-cell interaction analyses and reveal that FGF-FGFR and Delta-Notch interactions are important to maintain oncogenic signaling across malignant cell populations. These interactions were successfully targeted using small molecule inhibitors in preclinical models and in one ETMR patient. Taken together, we identify different malignant ETMR cell populations that follow a common developmental hierarchy, explore the regulatory reach of C19MC activation, and identify an oncogenic receptor-ligand interaction network. Targeting this interaction network opens a powerful new rationale for more effective ETMR therapies.

Inducible overexpression of a FAM3C/ILEI transgene has pleiotropic effects with shortened life span, liver fibrosis and anemia in mice.

FAM3C/ILEI is an important factor in epithelial-to-mesenchymal transition (EMT) induction, tumor progression and metastasis. Overexpressed in many cancers, elevated ILEI levels and secretion correlate with poor patient survival. Although ILEI's causative role in invasive tumor growth and metastasis has been demonstrated in several cellular tumor models, there are no available transgenic mice to study these effects in the context of a complex organism. Here, we describe the generation and initial characterization of a Tet-ON inducible Fam3c/ILEI transgenic mouse strain. We find that ubiquitous induction of ILEI overexpression (R26-ILEIind) at weaning age leads to a shortened lifespan, reduced body weight and microcytic hypochromic anemia. The anemia was reversible at a young age within a week upon withdrawal of ILEI induction. Vav1-driven overexpression of the ILEIind transgene in all hematopoietic cells (Vav-ILEIind) did not render mice anemic or lower overall fitness, demonstrating that no intrinsic mechanisms of erythroid development were dysregulated by ILEI and that hematopoietic ILEI hyperfunction did not contribute to death. Reduced serum iron levels of R26-ILEIind mice were indicative for a malfunction in iron uptake or homeostasis. Accordingly, the liver, the main organ of iron metabolism, was severely affected in moribund ILEI overexpressing mice: increased alanine transaminase and aspartate aminotransferase levels indicated liver dysfunction, the liver was reduced in size, showed increased apoptosis, reduced cellular iron content, and had a fibrotic phenotype. These data indicate that high ILEI expression in the liver might reduce hepatoprotection and induce liver fibrosis, which leads to liver dysfunction, disturbed iron metabolism and eventually to death. Overall, we show here that the novel Tet-ON inducible Fam3c/ILEI transgenic mouse strain allows tissue specific timely controlled overexpression of ILEI and thus, will serve as a versatile tool to model the effect of elevated ILEI expression in diverse tissue entities and disease conditions, including cancer.

Multi-objective computation offloading based on Invasive Tumor Growth Optimization for collaborative edge-cloud computing

Multi-objective computation offloading based on Invasive Tumor Growth Optimization for collaborative edge-cloud computing

Approach to the Patient With Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is usually associated with severe symptomatic primary hyperparathyroidism (PHPT) and accounts for less than 1% of all cases of PHPT and approximately 0.005% of all cancers. PC most commonly occurs as a sporadic disease and somatic CDC73 mutations can be detected in up to 80% of cases. Approximately 30% of patients harbor a germline mutation of the CDC73 gene. Preoperative diagnosis of PC is difficult because no disease-specific markers are available, and PC should be suspected in patients with severe hypercalcemia and end-organ complications. The diagnosis is based on the evidence of invasive tumor growth at histology and/or metastases. En bloc resection of the tumor, together with the ipsilateral thyroid lobe and adjacent structures, should be performed by an experienced surgeon when PC is suspected. This surgical approach reduces the risk of recurrence and metastasis and offers the highest chance of cure. Nonetheless, PC has a recurrence rate of 40% to 60% and, if feasible, multiple surgical procedures should be performed. When surgery is no longer an option, medical treatment is aimed to reduce hypercalcemia and target organ complications. Targeted agents have been effectively used in a few cases. We describe herein a patient with severe PHPT due to PC and provide a systematic diagnostic and treatment approach. A thorough review of the medical history, a typical clinical and biochemical phenotype and, in some cases, the revision of the histological examination provide the clues for the diagnosis of PC.

Multi-Omics Identification of Genetic Alterations in Head and Neck Squamous Cell Carcinoma and Therapeutic Efficacy of HNC018 as a Novel Multi-Target Agent for c-MET/STAT3/AKT Signaling Axis.

Amongst the most prevalent malignancies worldwide, head and neck squamous cell carcinoma (HNSCC) is characterized by high morbidity and mortality. The failure of standard treatment modalities, such as surgery, radiotherapy, and chemotherapy, demands the need for in-depth understanding of the complex signaling networks involved in the development of treatment resistance. A tumor's invasive growth and high levels of intrinsic or acquired treatment resistance are the primary causes of treatment failure. This may be a result of the presence of HNSCC's cancer stem cells, which are known to have self-renewing capabilities that result in therapeutic resistance. Using bioinformatics methods, we discovered that elevated expressions of MET, STAT3, and AKT were associated with poor overall survival in HNSCC patients. We then evaluated the therapeutic potential of our newly synthesized small molecule HNC018 towards its potential as a novel anticancer drug. Our computer-aided structure characterization and target identification study predicted that HNC018 could target these oncogenic markers implicated in HNSCC. Subsequently, the HNC018 has demonstrated its anti-proliferative and anticancer activities towards the head and neck squamous cell carcinoma cell lines, along with displaying the stronger binding affinities towards the MET, STAT3, and AKT than the standard drug cisplatin. Reduction in the clonogenic and tumor-sphere-forming ability displays HNC018's role in decreasing the tumorigenicity. Importantly, an vivo study has shown a significant delay in tumor growth in HNC018 alone or in combination with cisplatin-treated xenograft mice model. Collectively with our findings, HNC018 highlights the desirable properties of a drug-like candidate and could be considered as a novel small molecule for treating head and neck squamous cell carcinoma.

TRLS-11. A PHASE 1 STUDY OF SAVOLITINIB IN RECURRENT, PROGRESSIVE, OR REFRACTORY MEDULLOBLASTOMA, HIGH-GRADE GLIOMA, DIFFUSE INTRINSIC PONTINE GLIOMA, AND CENTRAL NERVOUS SYSTEM (CNS) TUMORS HARBORING MET ABERRATIONS: A PEDIATRIC BRAIN TUMOR CONSORTIUM TRIAL

Abstract Aberrant mesenchymal epithelial transition receptor (MET) activation leads to neoplasia, promotes invasive tumor growth, angiogenesis, and metastasis. Deregulation of MET signaling pathway is frequently observed in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. A phase 1 first-in-children trial of the MET inhibitor savolitinib was performed in children with recurrent, progressive or refractory medulloblastoma, high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and other CNS tumors harboring MET aberrations. The study sought to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of savolitinib using a Rolling-6 design given orally once daily continuously, and to describe its toxicity profile and pharmacokinetics (PK). Once the MTD was established, a PK expansion cohort was opened to enrollment. This will be followed by an efficacy expansion cohort for patients whose tumors harbor activating genomic MET aberrations. Tumor tissue and blood were collected as part of correlative studies in consenting subjects. Twenty-eight patients enrolled (median age:12 years; range: 6-21); one patient was deemed ineligible, and 22 patients were evaluable for dose finding. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose limiting toxicities were reported in 2 subjects and consisted of grade 3 fatigue and grade 3 ALT elevation. The most common grade 3/4 toxicities were: neutropenia (7.7%) and lymphopenia (7.7%). One partial response was observed in a patient with recurrent HGG on dose level 1 (150 mg/m2). As of the most recent data freeze, the patient had completed 35 treatment courses. Sustained stable disease was experienced by 3 other patients with recurrent DIPG who remained on treatment for a median of 9 cycles (range: 4-24). Correlative studies are ongoing and will be presented. Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Antitumor activity was observed.

A Two-Stage Multi-Objective Task Scheduling Framework Based on Invasive Tumor Growth Optimization Algorithm for Cloud Computing

A Two-Stage Multi-Objective Task Scheduling Framework Based on Invasive Tumor Growth Optimization Algorithm for Cloud Computing

Anti-HERV-K Drugs and Vaccines, Possible Therapies against Tumors.

The footprint of human endogenous retroviruses (HERV), specifically HERV-K, has been found in malignancies, such as melanoma, teratocarcinoma, osteosarcoma, breast cancer, lymphoma, and ovary and prostate cancers. HERV-K is characterized as the most biologically active HERV due to possession of open reading frames (ORF) for all Gag, Pol, and Env genes, which enables it to be more infective and obstructive towards specific cell lines and other exogenous viruses, respectively. Some factors might contribute to carcinogenicity and at least one of them has been recognized in various tumors, including overexpression/methylation of long interspersed nuclear element 1 (LINE-1), HERV-K Gag, and Env genes themselves plus their transcripts and protein products, and HERV-K reverse transcriptase (RT). Therapies effective for HERV-K-associated tumors mostly target invasive autoimmune responses or growth of tumors through suppression of HERV-K Gag or Env protein and RT. To design new therapeutic options, more studies are needed to better understand whether HERV-K and its products (Gag/Env transcripts and HERV-K proteins/RT) are the initiators of tumor formation or just the disorder's developers. Accordingly, this review aims to present evidence that highlights the association between HERV-K and tumorigenicity and introduces some of the available or potential therapies against HERV-K-induced tumors.

A hybrid technique for transformer-less grid-tie Hybrid Renewable Energy Source with reduction of common mode leakage current

A hybrid method for transformer-less grid-tie hybrid Renewable Energy Source (HRES), such as photovoltaic (PV) and wind energy system (WES) with minimization of common mode leakage current is proposed in this manuscript. The proposed system is the combined execution of Vascular Invasive Tumor Growth (VSTG) Optimization Algorithm and extreme gradient boosting (XGBOOST) named VSTG-XGBOOST control topology. The main intention of transformerless grid-connected HRES system is “to lessen the leakage current, maximum power point (MPP) extraction and maximal power point tracking (MPPT), the active and reactive power controller, and having the unity power factor. To attain the above-mentioned aims, the following actions have been performed in this proposed work. Two turn-off snapper circuits are inserted parallel to the switches to share the input DC voltage among snubber capacitors. By then, VSTG is used to estimate the optimal gain parameters under various source currents as normal value is used to generate the optimal control signal database offline. Based on the attained dataset, the XGBOOST forecasts the optimal control signals of the grid-connected HRES inverter in the online way. This control technique allows two sources to supply the load separately depending on the availability of the energy sources and keeps common DC voltage constant.

FOSL1 promotes tumor growth and invasion in ameloblastoma.

BackgroundFOSL1, a key component of the Activating protein-1 (AP-1) transcriptional complex, plays an important role in cancer cell migration, invasion, and proliferation. However, the impact of FOSL1 in ameloblastoma (AM) has not been clarified. Herein, we aimed to assess the expression of FOSL1 and investigate its functional role in AM.MethodsThe expression of FOSL1 was examined based on an immunohistochemistry analysis of 96 AM samples. Cell proliferation, migration, invasion, and tumorigenesis were assessed using Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and sphere formation assays. RNA sequencing (RNA-seq) was employed to investigate the molecular alterations of AM cells upon FOSL depletion. Microarrays of AMs were downloaded from the Gene Expression Omnibus (GEO) database for bioinformatics analysis. In addition, patient-derived AM organoids were used to evaluate the therapeutic value of the AP-1 inhibitor.ResultsFOSL1 was detected in the nuclei of AMs and upregulated in conventional AMs compared to unicystic AMs and normal oral epithelium. Compared with primary AM, FOSL1 expression was significantly increased in recurrent AM. Genetic knockdown of FOSL1 suppressed the proliferation, migration, invasion, and sphere formation of AMs. Similar results were also observed by pharmacological inhibition of AP-1 activity. Moreover, the AP-1 inhibitor T5224 impeded the growth of organoids derived from AM patients. Mechanistically, our Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA) results revealed that depletion of FOSL1 inactivated kinetochore metaphase signaling and the epithelial–mesenchymal transition pathway and then impaired the aggressiveness of AM cells accordingly.ConclusionFOSL1 promotes tumor recurrence and invasive growth in AM by modulating kinetochore metaphase signaling and the epithelial–mesenchymal transition pathway; thus, it represents a promising therapeutic target for AM treatment.

Inhaled Indomethacin-Loaded Liposomes as Potential Therapeutics against Non-Small Cell Lung Cancer (NSCLC).

Most lung cancer instances are non-small cell lung cancers (NSCLC). As stated by recent literature, cycloxygenase-2 (COX-2) is upregulated in lung adenocarcinomas. COX-2 relates to enhanced cell proliferation and reduced apoptosis; both of which are essential for an invasive tumor growth and metastasis. Thus, COX-2 inhibition forms an important checkpoint. Drug repurposing and nano drug delivery systems will enable the faster and more efficacious drug development. This study was designed to prepare, characterize, and establish superior effectiveness of indomethacin (IND), (a nonselective COX-2 inhibitor) as liposomes (IND-Lip). IND-Lip were made using thin film hydration method andphysicochemical properties were characterized. Cell viabilitywas performed on NSCLC cell lines (A549, H1299 and H460) Clonogenic, spheroidal, caspase and COX-2 assays were then carried out. IND-Lip were found to have optimum physicochemical properties. Based on IC50value of 38.4 ± 4.9µM, A549 cells were used for further assays. From clonogenic assay, % colonies were found to be 25.5 ± 9.5% at 200µM of IND-Lip. IND-Lip performed significantly better in ex-vivo tumor reduction in 3D spheroid assay at 200μM concentration, compared to plain IND by Day 15. Finally, a significant inhibition of COX-2 as well as induction of caspase in all IND treated groups was observed. It is of note that liposomes demonstrated a superior efficacy in all studies compared to the plain drug. IND through liposomal delivery system can be a potentiallybeneficial strategy for lung carcinoma. However, further clinical studies andin-vivoresearch are essential to comprehend the complete view of this approach.