Molecular Pathways Research Articles

The Beneficial Effects of Curcumin on Lipids: Possible Effects on Dyslipidemia-induced Cardiovascular Complications.

Dyslipidemia and altered lipid metabolism are closely involved in the pathogenesis and clinical manifestation of many metabolic and non-metabolic diseases. Therefore, mitigation of pharmacological and nutritional factors together with lifestyle modifications is paramount. One potential nutraceutical exhibiting cell signaling and lipid-modulating properties implicated in dyslipidemias is curcumin. Specifically, recent evidence suggest that curcumin may improve lipid metabolism and prevent dyslipidemia-induced cardiovascular complications via several pathways. Although the exact molecular mechanisms involved are not well understood, the evidence presented in this review suggests that curcumin can provide significant lipid benefits via modulation of adipogenesis and lipolysis, and prevention or reduction of lipid peroxidation and lipotoxicity via different molecular pathways. Curcumin can also improve the lipid profile and reduce dyslipidemia- dependent cardiovascular problems by impacting important mechanisms of fatty acid oxidation, lipid absorption, and cholesterol metabolism. Although only limited direct supporting evidence is available, in this review we assess the available knowledge regarding the possible nutraceutical effects of curcumin on lipid homeostasis and its possible impacts on dyslipidemic cardiovascular events from a mechanistic viewpoint.

Exploring the Promising Role of Guggulipid in Rheumatoid Arthritis Management: An In-depth Analysis.

Guggulipid, an oleo-gum resin extracted from the bark of Commiphora wightii of the Burseraceae family, holds a significant place in Ayurvedic medicine due to its historical use in treating various disorders, including inflammation, gout, rheumatism, obesity, and lipid metabolism imbalances. This comprehensive review aims to elucidate the molecular targets of guggulipids and explore their cellular responses. Furthermore, it summarizes the findings from in-vitro, in-vivo, and clinical investigations related to arthritis and various inflammatory conditions. A comprehensive survey encompassing in-vitro, in-vivo, and clinical studies has been conducted to explore the therapeutic capacity of guggulipid in the management of rheumatoid arthritis. Various molecular pathways, such as cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), PI3-kinase/AKT, JAK/STAT, nitric oxide synthase (iNOS), and NFκB signaling pathways, have been targeted to assess the antiarthritic and anti-inflammatory effects of this compound. The research findings reveal that guggulipid demonstrates notable antiarthritic and anti-inflammatory effects by targeting key molecular pathways involved in inflammatory responses. These pathways include COX-2, VEGF, PI3-kinase/AKT, JAK/STAT, iNOS, and NFκB signaling pathways. in-vitro, in-vivo, and clinical studies collectively support the therapeutic potential of guggulipid in managing rheumatoid arthritis and related inflammatory conditions. This review provides a deeper understanding of the therapeutic mechanisms and potential of guggulipid in the management of rheumatoid arthritis. The collective evidence strongly supports the promising role of guggulipid as a therapeutic agent, encouraging further research and development in guggulipid-based treatments for these conditions.

Identification of Prognostic Markers and Potential Therapeutic Targets using Gene Expression Profiling and Simulation Studies in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of less than 10% making it one of the most fatal cancers. A lack of early measures of prognosis, challenges in molecular targeted therapy, ineffective adjuvant chemotherapy, and strong resistance to chemotherapy cumulatively make pancreatic cancer challenging to manage. The present study aims to enhance understanding of the disease mechanism and its progression by identifying prognostic biomarkers, potential drug targets, and candidate drugs that can be used for therapy in pancreatic cancer. Gene expression profiles from the GEO database were analyzed to identify reliable prognostic markers and potential drug targets. The disease's molecular mechanism and biological pathways were studied by investigating gene ontologies, KEGG pathways, and survival analysis to understand the strong prognostic power of key DEGs. FDA-approved anti-cancer drugs were screened through cell line databases, and docking studies were performed to identify drugs with high affinity for ARNTL2 and PIK3C2A. Molecular dynamic simulations of drug targets ARNTL2 and PIK3C2A in their native state and complex with nilotinib were carried out for 100 ns to validate their therapeutic potential in PDAC. Differentially expressed genes that are crucial regulators, including SUN1, PSMG3, PIK3C2A, SCRN1, and TRIAP1, were identified. Nilotinib as a candidate drug was screened using sensitivity analysis on CCLE and GDSC pancreatic cancer cell lines. Molecular dynamics simulations revealed the underlying mechanism of the binding of nilotinib with ARNTL2 and PIK3C2A and the dynamic perturbations. It validated nilotinib as a promising drug for pancreatic cancer. This study accounts for prognostic markers, drug targets, and repurposed anti-cancer drugs to highlight their usefulness for translational research on developing novel therapies. Our results revealed potential and prospective clinical applications in drug targets ARNTL2, EGFR, and PI3KC2A for pancreatic cancer therapy.

Mannose: A Promising Player in Clinical and Biomedical Applications.

Mannose, an isomer of glucose, exhibits a distinct molecular structure with the same formula but a different atom arrangement, contributing to its specific biological functions. Widely distributed in body fluids and tissues, particularly in the nervous system, skin, testes, and retinas, mannose plays a crucial role as a direct precursor for glycoprotein synthesis. Glycoproteins, essential for immune regulation and glycosylation processes, underscore the significance of mannose in these physiological activities. The clinical and biomedical applications of mannose are diverse, encompassing its anti-inflammatory properties, potential to inhibit bacterial infections, role in metabolism regulation, and suggested involvement in alleviating diabetes and obesity. Additionally, mannose shows promise in antitumor effects, immune modulation, and the construction of drug carriers, indicating a broad spectrum of therapeutic potential. The article aims to present a comprehensive review of mannose, focusing on its molecular structure, metabolic pathways, and clinical and biomedical applications, and also to emphasize its status as a promising therapeutic agent.

Effects of pomegranate exocarp extract on H. pylori-induced pancreatic EMT: Molecular mechanisms and therapeutic potential

BackgroundPrevious studies have linked Helicobacter pylori infection with pancreatic diseases, including cancer. PurposeTo explore the influence of pomegranate exocarp extract (PEE) on epithelial-mesenchymal transition (EMT) in H. pylori-induced pancreatic rat tissue and to uncover the underlying molecular mechanisms. Study designTwenty-eight rats were divided into six groups: group 1 (negative control), group 2 (H. pylori-infected), group 3 (infected + PEE pretreatment), group 4 (infected + PEE treatment), group 5 (infected + metronidazole treatment), and group 6 (infected + metronidazole/PEE co-treatment). Methods and resultsThis study aimed to assess the effectiveness of pomegranate exocarp extract (PEE) in treating Helicobacter pylori infection and its associated pancreatic tissue changes in Wistar rats. The study involved Forty-eight male rats divided into six groups: H. pylori-infected control, PEE-preventive, PEE treatment, metronidazole treatment, PEE combined with metronidazole treatment, and negative control. The results showed a significant reduction in H. pylori concentration in the antrum in the PEE-treated groups (27.08 %) compared to that in the positive control group (p < 0.05). The group receiving the combined treatment exhibited the highest reduction (55.8 %) in H. pylori concentration (p < 0.005), with no significant difference observed between the PEE-preventive and metronidazole-treated groups. The ELISA results showed that the groups treated with PEE, PEE-preventive, and PEE combined with metronidazole experienced a significant increase in pancreatic E-cadherin levels by 47.7 %, 73.8 %, and 118.06 % respectively, and a substantial decrease in vimentin levels by 16.6 %, 31.6 %, and 43.5 % respectively, compared to the positive control group (p < 0.05). The results of the RT-qPCR analysis showed that the PEE treatment group, as well as the PEE preventive and PEE combined with metronidazole treatment groups, displayed significant downregulation of vimentin, sirtuin1, and lncRNA MALAT-1, and upregulation of E-cadherin compared to the positive control group. However, there was no significant difference between the PEE-preventive and metronidazole-treated groups (p < 0.05). Histopathological analysis showed considerable improvement in pancreatic tissue morphology in the PEE-treated groups. The inflammation score was significantly lower in these groups (p < 0.05), and the combined treatment group exhibited minimal signs of metaplasia and mononuclear cell infiltration. A computational study identified 54 human target genes of bioactive compounds in PEE. These findings shed light on the crucial interactions and pathways in treating pancreatic tumors. Additionally, GO enrichment and KEGG pathway analyses revealed significant pathways, such as the MAPK signaling and RTK pathway, enriched with genes targeted by PEE. Furthermore, evaluation of drug-likeness and ADME properties indicated that ellagic acid possesses drug-like properties and has a high potential for oral absorption. In conclusion, PEE has shown significant therapeutic potential in reducing H. pylori load and improving pancreatic tissue health while influencing key molecular markers and pathways associated with pancreatic tumors.

Elucidation of molecular mechanisms, pathways, and diseases modulated by arsenicals through toxogenomics and multi-omics analysis

Arsenic compounds exist in inorganic and organic forms with inorganic form confirmed as a potent carcinogen. Toxogenomics and multi-omics analysis were used to explore the molecular mechanisms of carcinogenecity induced by arsenicals. Comparative toxogenomics revealed sodium arsenite and arsenate as the most toxic arsenicals to humans, interacting with various genes and altering gene expression through mRNA binding proteins. Both metalloids were classified as Class II toxins by the ProTox II prediction tool, with a lethal dose (LD50) of 149mg/kg body weight. The most frequently interacting genes were HMOX1, CAT, NFE2L2, CASP3, MAPK1, CXCL8, PARP1, TNF, and PYGM. Analysis of TCGA pan-cancer data revealed that 46% of hepatocellular carcinoma patients exhibited alterations in the genes HMOX1, CAT, NFE2L2, CASP3, MAPK1, CXCL8, PARP1, TNF, and PYGM, suggesting their significant role in the development of this disease. The alteration in the gene list decreased the overall patient survival but insignificantly in the Kaplan-Meier curves revealing insignificant role in survival. GSEA suggested significant enrichment of the gene list in pathways involved in the G2M checkpoint, apoptosis, hypoxia, TNFA signaling via NFKB, PI3K AKTMTOR signaling, P53, IFN gamma and inflammatory response pathways revealing the involvement of these pathways. Ten microRNAs (miRNAs) regulated the expressions of the genes involved in the above-mentioned pathways with the significant enrichment in miR-21-3p, miR-206 and mir486a-5p. The relevant pathway and graphical representation of the network of miRNA-target interactions identified by the enrichment analysis along with disease ontologies were predicted. This study will be helpful insight into setting of laboratory experiments.

Molecular pathways of osmoregulation in response to salinity stress in the gills of the scalloped spiny lobster (Panulirus homarus) within survival salinity

Scalloped spiny lobster (Panulirus homarus) aquaculture is the preferred strategy to resolve the conflict between supply and demand for lobster. Environmental conditions, such as salinity, are key to the success of lobster aquaculture. However, physiological responses of P. homarus to salinity stress have not been well studied. This study investigated the gill histology, osmoregulation and gill transcriptome of the early juvenile P. homarus (weight 19.04 ± 3.95 g) cultured at salinity 28 (control), 18, and 38 for 6 weeks. The results showed that the gill filaments of P. homarus exposed to low salinity showed severe separation of the cuticle and epithelial cells due to water absorption and swelling, as well as the dissolution and thinning of the cuticle and the rupture of the septum that separates the afferent and efferent channels. The serum osmolarity of P. homarus varied proportionately with external medium salinity and remained consistently above ambient osmolarity. The serum Na+, Cl−, K+, and Mg2+ concentrations P. homarus exhibited a pattern similar to that of serum osmolality, while the concentration of Ca2+ remained unaffected at salinity 18 but significantly increased at salinity 38. Gill Na+/K+-ATPase activity of P. homarus increased (p < 0.05) under the both salinity stress. Salinity 18 significantly increased Glutamate dehydrogenase (GDH) and Glutamicpyruvic transaminase (GPT) activity in the hepatopancreas of P. homarus (p < 0.05). According to transcriptome analysis, versus control group (salinity 28), 929 and 1095 differentially expressed genes (DEGs) were obtained in the gills of P. homarus at salinity 18 and 38, respectively, with these DEGs were mainly involved in energy metabolism, transmembrane transport and oxidative stress and substance metabolism. In addition, the expression patterns of 8 key DEGs mainly related to amino acid metabolism, transmembrane transport and oxidative stress were verified by quantitative real-time PCR (RT-qPCR). The present study suggests that salinity 18 has a greater impact on P. homarus than salinity 38, and P. homarus demonstrates effective osmoregulation and handle with salinity fluctuations (18 to 38) through physiological and functional adaptations. This study provides an improved understanding of the physiological response strategies of P. homarus facing salinity stress, which is crucial for optimizing aquaculture practices for this species.

Glp-1 Mimetics and Autophagy in Diabetic Milieu: State-of-the-Art.

The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways.

GSTA1/CTNNB1 axis facilitates sorafenib resistance via suppressing ferroptosis in hepatocellular carcinoma

The emergence of sorafenib resistance has become a predominant impediment and formidable dilemma in the therapeutic approach for hepatocellular carcinoma (HCC). Although the approval of next-generation drugs as alternatives to sorafenib is a significant development, the concurrent use of inhibitors that target additional key molecular pathways remains an effective strategy to mitigate the acquisition of resistance. Here, we identified Glutathione S-Transferase Alpha 1 (GSTA1) as a critical modulator of sorafenib resistance (SR) in hepatocellular carcinoma (HCC) based on our findings from experiments conducted on recurrent liver cancer tissues, xenograft mouse models, organoids, and sorafenib-resistant cells. Elevated GSTA1 levels are strongly associated with adverse clinical prognoses. The knockout of GSTA1 reinstates sorafenib sensitivity, whereas its overexpression attenuates drug efficacy. Mechanistically, GSTA1 enhances the accumulation of lipid peroxides and suppresses ferroptosis by exerting its peroxidase function to regulate the SR. Notably, the upregulation of GSTA1 expression is mediated by the transcription factor CTNNB1 (β-catenin), resulting in the formation of a cytoplasmic complex between GSTA1 and CTNNB1. This complex facilitates the nuclear translocation of CTNNB1, establishing a positive feedback loop. The combined use of GSTA1 and CTNNB1 inhibitors demonstrated synergistic anti-tumour effects through the induction of ferroptosis both in vitro and in vivo. Our findings reveal a novel regulatory role of the GSTA1/CTNNB1 axis in ferroptosis, suggesting that targeting GSTA1 and CTNNB1 could be a promising strategy to circumvent sorafenib resistance in HCC.

Exploring mesenchymal stem cells homing mechanisms and improvement strategies.

Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.

Unlocking the promise of MANF in diseases: Mechanistic insights and therapeutic potentials.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a ubiquitous neurotrophic factor that exhibits a variety of physiological functions and plays a critical role in the exploitation of therapeutic potential across a range of diseases, including cardiovascular disorders, nervous system diseases, metabolic imbalances, and cancers. In the context of cardiac diseases, MANF significantly promotes cardiomyocyte survival and improves cardiac functionality. Furthermore, MANF not only provides neuroprotection by shielding neurons from damage and promoting nerve regeneration in neurological disorders, but also involves in insulin resistance, lipid metabolism disturbances and fat-containing liver lesions. However, the oncogenic or tumor suppressive function of MANF in cancer remains unclear, requiring further investigation to elucidate its precise role in the process of cancer initiation and progression. This review aims to summarize the latest advancements in understanding the molecular pathways, intricate mechanisms, and therapeutic potential of MANF in the prevention and treatment of various diseases, emphasizing its multifaceted contributions to health and disease management.

Small, but mitey: investigating the molecular genetic basis formite domatia development and intraspecific variation in Vitisriparia using transcriptomics.

Here, we investigated the molecular genetic basis of mite domatia, structures on the underside of leaves that house mutualistic mites, and intraspecific variation in domatia size in Vitis riparia (riverbank grape). Domatia and leaf traits were measured, and the transcriptomes of mite domatia from two genotypes of V. riparia with distinct domatia sizes were sequenced to investigate the molecular genetic pathways that regulate domatia development and intraspecific variation in domatia traits. Key trichome regulators as well as auxin and jasmonic acid are involved in domatia development. Genes involved in cell wall biosynthesis, biotic interactions, and molecule transport/metabolism are upregulated in domatia, consistent with their role in domatia development and function. This work is one of the first to date that provides insight into the molecular genetic bases of mite domatia. We identified key genetic pathways involved in domatia development and function, and uncovered unexpected pathways that provide an avenue for future investigation. We also found that intraspecific variation in domatia size in V. riparia seems to be driven by differences in overall leaf development between genotypes.

Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential.

The pathological hallmarks of various neurodegenerative diseases including Parkinson's disease and Alzheimer's disease prominently feature the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA) has emerged as a distinct autophagic process that coordinates the lysosomal degradation of specific proteins bearing the pentapeptide motif Lys-Phe-Glu-Arg-Gln (KFERQ), a recognition target for the cytosolic chaperone HSC70. Beyond its role in protein quality control, recent research underscores the intimate interplay between CMA and immune regulation in neurodegeneration. In this review, we illuminate the molecular mechanisms and regulatory pathways governing CMA. We further discuss the potential roles of CMA in maintaining neuronal proteostasis and modulating neuroinflammation mediated by glial cells. Finally, we summarize the recent advancements in CMA modulators, emphasizing the significance of activating CMA for the therapeutic intervention in neurodegenerative diseases.

Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.

Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.

Vertical inhibition of p110α/AKT and N-cadherin enhances treatment efficacy in PIK3CA-aberrated ovarian cancer cells.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA, encoding PI3Kalpha (also known as p110α)] is one of the most commonly aberrated genes in human cancers. In serous ovarian cancer, PIK3CA amplification is highly frequent but PIK3CA point mutation is rare. However, whether PIK3CA amplification and PIK3CA driver mutations have the same functional impact in the disease is unclear. Here, we report that both PIK3CA amplification and E545K mutation are tumorigenic. While the protein kinase B (AKT) signaling axis was activated in both E545K knock-in cells and PIK3CA-overexpressing cells, the mitogen-activated protein kinase 3/1 (ERK1/2) pathway was induced selectively by E545K mutation but not PIK3CA amplification. Intriguingly, AKT signaling in these PIK3CA-aberrated cells increased transcriptional coactivator YAP1 (YAP) Ser127 phosphorylation and thereby cytoplasmic YAP levels, which in turn increased cell migration through Ras-related C3 botulinum toxin substrate 1 (RAC1) activation. In addition to the altered YAP signaling, AKT upregulated N-cadherin expression, which also contributed to cell migration. Pharmacological inhibition of N-cadherin reduced cell migratory potential. Importantly, co-targeting N-cadherin and p110α/AKT caused additive reduction in cell migration in vitro and metastases formation in vivo. Together, this study reveals the molecular pathways driven by the PIK3CA aberrations and the exploitable vulnerabilities in PIK3CA-aberrated serous ovarian cancer cells.

Hepatic Transcriptomics of Broilers with Low and High Feed Conversion in Response to Caloric Restriction

Background: In broiler chickens, the efficient utilization of macro- and micronutrients is influenced by various metabolic pathways that are closely linked to feed efficiency (FE), a critical metric in poultry industry, with residual feed intake (RFI) as the preferred proxy. Feed restriction is considered an approach to address the underlying molecular mechanisms of feed conversion. We hypothesized that broiler chickens with divergent RFI subjected to quantitative feed restriction differ in their pattern of molecular pathways for efficient nutrient utilization in liver as post-absorptive tissue. Methods: Cobb 500FF broiler chickens divergent for RFI (n = 112) were feed-restricted from day 9 until market weight at day 33–37 post-hatch. Based on a previous trial, feed restriction levels were set at 92% (low-RFI birds) and 80% (high-RFI birds) relative to the control groups. Transcriptomic analyses of the liver were conducted. Results: Due to the interaction of the RFI group and feeding regimen, a total of 140 to 507 differentially expressed genes were identified for the respective contrasts, with implications for hepatic metabolism and cellular stress response. Although the broilers did not realize their full growth potential under restrictive feeding (12.4% reduced body weight vs. controls, p = 0.094), the gene expression patterns indicate a lower susceptibility to blood coagulation (KNG1, FGG, and FGB), suggesting that controlled and mild feed restriction could lead to health benefits in less feed-efficient broilers. Moreover, FE traits are shown to be linked to cellular detoxification processes (MGST3 and CYP2AC2) and triacylglycerol syntheses (MOGAT1 and LPIN1). Conclusions: Divergent transcriptional profiles between broiler groups under varied caloric conditions indicate potential for optimizing nutritional management strategies.

The effects of muscle factors irisin on lipid metabolism in breast cancer: A possible mechanism anti-tumor mechanism of physical activity

Breast cancer is the most prevalent cancer in the female population and is a significant cause of global cancer deaths in this group. Obesity increases a woman’s risk of developing breast cancer and has a negative impact on prognosis. Metabolic alterations are an important part of the process of cancer migration; invasion and proliferation, with lipids being a major metabolic substrate for rapid cancer progression, capable of influencing the metabolic crosstalk between tumor cells and other cells in the tumor microenvironment. Physical activity-induced irisin affects the progression of obesity-associated breast cancer and is a new indicator for breast cancer diagnosis. Existing evidence suggests a potential inhibitory effect of physical activity-induced irisin on the progression of breast cancer. A strong association exists between obesity and breast cancer progression and outcomes. This paper discusses how physical activity-induced irisin may achieve cancer suppression by affecting lipid metabolic processes between breast cancer cells and cancer-associated adipocytes, and elucidates the molecular pathways involved in the effects of irisin on cancer lipid reprogramming, thereby helping to prevent the metastatic progression of breast cancer, and ultimately improving the survival rate of this patient group.

TREATMENT OPTIONS FOR RECURRENT MALIGNANT DIFFUSE ASTROCYTOMA (WHO GRADE IV)

Objectives We present the case of a 37-year-old female who underwent partial resection in 2018 for a diffuse fibrillary astrocytoma (WHO II) that invaded almost the entire right cerebral hemisphere. The patient followed conventional radiotherapy and chemotherapy. She presents after 6 years of regularly follow-ups with left hemiparesis, intracranial hypertension syndrome and tumor recurrence on MRI. The patient underwent another surgical intervention and the new histopathological diagnosis was diffuse astrocytoma grade IV. Therapeutic options for these patients are limited considering the fact that a gross total resection or a conventional re-irradiation could impact the quality of life. Therefore, exploring new therapeutic methods, such as targeted molecular therapy like EGFR antagonists or proteasome inhibitors, or proton therapy, should be considered. Material and Methods We conducted extensive research in two public medical databases for information related to the molecular pathways and management of primary and recurrent malignant astrocytoma and relevant articles were selected. Subsequently, we correlated this information with our direct experience in our case and discussed the observed results. Results Treatment modalities for these patients include reintervention, re-irradiation and second line chemotherapeutics. In relapsing cases the goal of reintervention is both to alleviate symptoms and obtain tumoral tissue for immunohistochemical analysis for identification of the new mutations. Conventional re-irradiation for large lesions carries high risks of producing both short-term and long-term side effects, impacting the quality of life. Alternatively, proton therapy minimizes the risk of adverse events due to Bragg peak reducing the irradiation of the surrounding tissue. Conclusions Genetic characterization of these lesions can facilitate targeted molecular therapy and help in establishing the prognosis. Re-irradiation of malignant astrocytomas with proton therapy is an effective treatment measure allowing for comparable tumor control to conventional radiotherapy.

Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer.

Ki67 index (KI) and mitotic index (MI) are proliferation markers with established prognostic value in breast carcinomas. While KI is evaluated immunohistochemically and reported as a percentage, MI is determined visually and reflects total mitotic cells in 10 high-power fields. Our objective was to integrate KI and MI into a novel metric; the cell cycle traverse rate (CCTR). Given the lack of prognostic and predictive biomarkers in TNBC, we sought to assess the potential of CCTR as a risk-stratification tool for chemotherapy-treated TNBC patients from two independent cohorts: the Nottingham group (n = 124) and the Norway group (n = 71). We evaluated the ability of CCTR to predict survival after adjuvant chemotherapy for TNBC patients (n = 195) in two independent cohorts. Using immunohistochemistry and RNA sequencing, we determined the differences in immunohistochemical biomarkers, gene ontologies, molecular pathways and immune cell fractions based on CCTR. TNBC shows a significantly lower median CCTR compared to luminal A (p < 0.01), luminal B (p < 0.01), and HER2+ samples (p < 0.01). CCTR outperformed both KI and MI in effectively risk-stratifying TNBC patients suggesting that combining KI and MI into a single metric, namely CCTR, could serve as a superior prognostic marker for Breast Cancer Specific Survival (BCSS) (p = 0.041). CCTR-high group exhibited enriched expression of various oncogenic signatures, including angiogenesis, epithelial-to-mesenchymal transition (EMT), Hedgehog signaling, hypoxia, Notch signaling, PI3K-AKT-mTOR signaling, TGFβ signaling, p53 signaling, and TNFα signaling via NFκB. These findings suggest the potential involvement of these pathways in the aggressiveness and clinical outcomes of TNBC patients. Collectively, these findings suggest that CCTR offers superior predictive information compared to KI and MI alone with respect to long-term outcomes from adjuvant chemotherapy in patients with TNBC that may guide treatment decision making.

Boolean network modeling and its integration with experimental read-outs : An interdisciplinary presentation using a leukemia model.

The limited availability of suitable animal models and cell lines often impedes experimental cancer research. Wet-laboratory experiments are also time-consuming and cost-intensive. In this review, we present an in silico modeling strategy, namely, Boolean network (BN) models, and demonstrate how it could be applied to streamline experimental design and to focus the effort of experimental read-outs. Boolean network models allow for the dynamic analysis of large molecular signaling pathways and their crosstalks. After establishing and validating aspecific tumor model, mechanistic insights into the tumor cell behavior can be gained by studying the trajectories of different tumor phenotypes. Also, tumor driver and drug target screenings can be performed. These automatic screenings can help to identify new intervention targets and putative biomarkers for tumor evolution, hence guiding new wet-laboratory experiments. The goal of this round-up is to demonstrate how to establish, validate, and use BN modeling and its crosstalks in classic wet-laboratory research using achronic lymphocytic leukemia (CLL) BN model.