Resistance Pathways Research Articles

Abstract PO5-27-10: Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing

Abstract Background: ADCs have had tremendous impact on patient outcomes in breast cancer and are rapidly moving towards second line use. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and resistance to ADC payloads. Method: CatenaBio has developed a novel Multi-Payload-Conjugate (MPC) system capable of attaching distinct payloads at different sites to the same antibody, enabling the production of single-molecule targeted combination therapies with defined DAR. Results: We screened combinations of different payloads targeting several different mechanisms attached to trastuzumab at different drug-antibody ratios to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in both HER2 high and low tumor cell lines. Conclusion: Antibody Drug Conjugates have revolutionized the treatment of high HER2 positive breast cancer. More recently advances have been made in the design of ADCs to expand indications to include HER2 low as well as HER2 negative patients. These constructs offer the next step in ADC design and allow for the combination of multiple mechanisms of action in a single MPC that are highly effective across multiple breast cancer cell lines. These molecules offer the potential to circumvent tumor resistance pathways and deliver deeper and more durable responses. Disclosures: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, and Saurabh Johri are employed by Catena Biosciences. Matthew Francis is a co-founder and advisor to Catena Biosciences. Citation Format: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, Saurabh Johri, Matthew Francis. Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing [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 PO5-27-10.

Analysis of ginseng rusty root symptoms transcriptome and its pathogenesis directed by reactive oxygen species theory.

Ginseng rusty root symptoms (GRS) is a primary disease of ginseng, which seriously decreases the yield and quality of ginseng and causes enormous losses to ginseng production. GRS prevention and control is still challenging due to its unclear etiology. In this study, the phloem tissue of healthy Panax ginseng (AG), the nonred tissue of the phloem epidermis around the lesion (BG), and the red lesion site tissue of GRS (CG) were extracted for mRNA transcriptomic analysis; 35,958 differentially expressed genes (DEGs) were identified and were associated with multiple stress resistance pathways, reactive oxygen species (ROS), and iron ion binding. Further study showed that the contents of O2 •-, H2O2, and malondialdehyde (MDA) were significantly increased in BG and CG tissues. Under anaerobic conditions caused by excessive soil moisture, the overproduction of ROS destroys cell membranes, simultaneously converting Fe2+ to Fe3+ and depositing it in the cell wall, which results in GRS, as evidenced by the success of the GRS induction test.

Fine mapping and characterization of stripe rust resistance gene YrAYH in near-isogenic lines derived from a cross involving wheat landrace Anyuehong

Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a devastating disease in wheat worldwide. Discovering and characterizing new resistance genes/QTL is crucial for wheat breeding programs. In this study, we fine-mapped and characterized a stripe rust resistance gene, YRAYH, on chromosome arm 5BL in the Chinese wheat landrace Anyuehong (AYH). Evaluations of stripe rust response to prevalent Chinese Pst races in near-isogenic lines derived from a cross of Anyuehong and Taichung 29 showed that YrAYH conferred a high level of resistance at all growth stages. Fine mapping using a large segregating population of 9748 plants, narrowed the YRAYH locus to a 3.7 Mb interval on chromosome arm 5BL that included 61 annotated genes. Transcriptome analysis of two NIL pairs identified 64 upregulated differentially expressed genes (DEGs) in the resistant NILs (NILs-R). Annotations indicated that many of these genes have roles in plant disease resistance pathways. Through a combined approach of fine-mapping and transcriptome sequencing, we identified a serine/threonine-protein kinase SRPK as a candidate gene underlying YrAYH. A unique 25 bp insertion was identified in the NILs-R compared to the NILs-S and previously published wheat genomes. An InDel marker was developed and co-segregated with YrAYH. Agronomic trait evaluation of the NILs suggested that YrAYH not only reduces the impact of stripe rust but was also associated with a gene that increases plant height and spike length.

Prostate-Specific Membrane Antigen-Targeted Therapy in Prostate Cancer: History, Combination Therapies, Trials, and Future Perspective.

In the last decades, the development of PET/CT radiopharmaceuticals, targeting the Prostate-Specific Membrane Antigen (PSMA), changed the management of prostate cancer (PCa) patients thanks to its higher diagnostic accuracy in comparison with conventional imaging both in staging and in recurrence. Alongside molecular imaging, PSMA was studied as a therapeutic agent targeted with various isotopes. In 2021, results from the VISION trial led to the Food and Drug Administration (FDA) approval of [177Lu]Lu-PSMA-617 as a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) and set the basis for a radical change in the future perspectives of PCa treatment and the history of Nuclear Medicine. Despite these promising results, primary resistance in patients treated with single-agent [177Lu]Lu-PSMA-617 remains a real issue. Emerging trials are investigating the use of [177Lu]Lu-PSMA-617 in combination with other PCa therapies in order to cover the multiple oncologic resistance pathways and to overcome tumor heterogeneity. In this review, our aim is to retrace the history of PSMA-targeted therapy from the first preclinical studies to its future applications in PCa.

Reactive Oxygen Species and Salicylic Acid Mediate the Responses of Pear to Venturia nashicola Infection

Reactive oxygen species (ROS) and salicylic acid (SA) are essential signaling molecules in plant cells that participate in responses to biotic and abiotic stresses. Changes in ROS and SA signals during interactions between pear and the pear scab pathogen Venturia nashicola remain unclear. Herein, we analyzed the roles of ROS in the signal transduction pathway of pear scab resistance using the highly resistant Huangguan and susceptible Xuehua cultivars of pear (Pyrus bretschneideri Rehd). Protoplasts, calluses, and leaves were obtained from 14-year-old pear trees and treated with V. nashicola for different periods. The results showed that ROS rapidly accumulated in protoplasts of both cultivars within a 120-min treatment period, but the fluorescence intensity of ROS differed between cultivars. The H2O2 content in fruit-derived calluses of Huangguan peaked at 48 h post-infection at levels 1.85 times higher than those in Xuehua. Induction of H2O2 by V. nashicola in Huangguan was more intense than in Xuehua over a 96-h treatment period. At 96 h post-infection, the malondialdehyde content in leaves of Huangguan was significantly lower than in Xuehua, while the activities of superoxide dismutase, peroxidase, and catalase, and the relative expression levels of PbMnSOD, PbPOD, and PbCAT genes were higher in Huangguan than Xuehua. V. nashicola infection also caused a continuous increase in the leaf SA content of Huangguan, which was 6.76 times higher than in Xuehua at 96 h post-infection, and V. nashicola exposure upregulated the expression of PbPAL, PbICS, PbPR1, and PbPR5. In summary, both ROS and SA participated in the responses of pear trees to V. nashicola infection and played vital roles in the signal transduction pathway of pear scab resistance.

SWATH-MS reveals that bisphenol A and its analogs regulate pathways leading to disruption in insulin signaling and fatty acid metabolism

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC), associated with obesity and insulin resistance. The FDA prohibited the use of BPA-based polycarbonate resins in infant formula packaging; thus, its analogs, viz. Bisphenol S (BPS) and Bisphenol F (BPF) were considered alternatives in epoxy resins, plastics, and food cans. As these analogs might evoke a similar response, we investigated the role of Bisphenols (BPA, BPF, and BPS), on insulin signaling in CHO-HIRc-myc-GLUT4eGFP cells at environmentally relevant concentrations of 2 nM and 200 nM. Insulin signaling demonstrated that Bisphenols reduced phosphorylation of IR and AKT2, GLUT4 translocation, and glucose uptake. This was accompanied by increased oxidative stress. Furthermore, SWATH-MS-based proteomics of 3T3-L1 cells demonstrated that Bisphenol-treated cells regulate proteins in insulin resistance, adipogenesis, and fatty acid metabolism pathways differently. All three Bisphenols induced differentially expressed proteins enriched similar pathways, although their abundance differed for each Bisphenol. This might be due to their varying toxicity level, structural differences, and estrogen-mimetic activity. This study has important implications in addressing health concerns related to EDCs. Given that the analogs of BPA are considered alternatives to BPA, the findings of this study suggest they are equally potent in altering fatty acid metabolism and inducing insulin resistance.

Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors.

The balanced reciprocal translocation t (9; 22) (q34; q11) and the BCR-ABL fusion gene, which produce p210 bcr-abl protein production with high tyrosine kinase activity, are characteristics of chronic myeloid leukemia, a myeloproliferative neoplasm. This aberrant protein affects several signaling pathways connected to both apoptosis and cell proliferation. It has been demonstrated that tyrosine kinase inhibitor treatment in chronic myeloid leukemia acts by inducing oxidative stress and, depending on its level, can activate signaling pathways responsible for either apoptosis or survival in leukemic cells. Additionally, oxidative stress and reactive oxygen species generation also mediate apoptosis through genomic activation. Furthermore, it was shown that oxidative stress has a role in both BCR-ABL-independent and BCR-ABL-dependent resistance pathways to tyrosine kinases, while patients with chronic myeloid leukemia were found to have a significantly reduced antioxidant level. The ideal environment for tyrosine kinase inhibitor therapy is produced by a favorable oxidative status. We discuss the latest studies that aim to manipulate the redox system to alter the apoptosis of cancerous cells.

Infection with SARS-CoV-2 can cause pancreatic impairment

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes. Herein, we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates (NHPs) models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients. Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans. Minor and limited phenotypic and histopathological changes were observed in adult models. Systemic proteomics and metabolomics results indicated metabolic disorders, mainly enriched in insulin resistance pathways, in infected adult NHPs, along with elevated fasting C-peptide and C-peptide/glucose ratio levels. Furthermore, in elder COVID-19 NHPs, SARS-CoV-2 infection causes loss of beta (β) cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis, activation of α-SMA and aggravated fibrosis consisting of lower collagen in serum, an increase of pancreatic inflammation and stress markers, ICAM-1 and G3BP1, along with more severe glycometabolic dysfunction. In contrast, vaccination maintained glucose homeostasis by activating insulin receptor α and insulin receptor β. Overall, the cumulative risk of diabetes post-COVID-19 is closely tied to age, suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.

TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment

The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.

Abstract SY08-01: Does exercise or fitness deter cancer progression after diagnosis

Abstract SY08-01: Does exercise or fitness deter cancer progression after diagnosis

Abstract LB453: Distinct mechanism of CXCR7 activation in EGFR-mutated NSCLC by chemokines

Abstract Erlotinib and gefitinib, EGFR TKIs, have markedly improved outcomes for NSCLC patients with EGFR mutations. However, resistance eventually develops, with the T790M mutation evident in over 50% of resistant tumors. Other resistance pathways include MET amplification, SCLC transformation, and EMT. Osimertinib, a third-generation EGFR TKI, targets the T790M mutation and is approved as a first-line treatment, reducing the incidence of T790M-related resistance. Nonetheless, non-T790M resistance mechanisms such as mesenchymal transformation are on the rise. The molecular targets or exact mechanisms of EGFR TKI resistance with mesenchymal phenotypes remain elusive. We have discovered that ERK reactivation, commonly found in EGFR TKI-resistant cells with a mesenchymal phenotype, is due to activation of an atypical GPCR, CXC chemokine receptor type 7 (CXCR7). CXCR7 is overexpressed in a cell line, an EGFR TKI-resistant tumor model, and in samples from patients that progressed on EGFR TKIs. Currently, there are no effective CXCR7 inhibitors to evaluate in NSCLC; the mechanisms and ligands for CXCR7 are not fully understood. To evaluate ligand-dependent activation of CXCR7, we generated HEK293 cells and EGFR-mutant NSCLC cells ectopically-expressing CXCR7 and stimulated the cells with CXCL12, a well-documented ligand for CXCR7. Exposures of HEK293 cells with CXCR7 to CXCL12 resulted in the internalization of CXCR7 followed by the activation of the MAPK pathway within 30 minutes of EGFR TKI treatment whereas MAPK activation in EGFR mutant NSCLC cells took 8 hours. MIF activation was also delayed in NSCLC compared to the HEK293 model, requiring the presence of an EGFR TKI. We discovered that CXCR7 co-immunoprecipitated with mutant EGFR in NSCLC cells while CXCR7 did not co-immunoprecipitate when EGFR was inhibited. Furthermore, we discovered additional chemokines including GDF15 that activate the CXCR7-MAPK axis and promote cell migration, a key characteristic of the mesenchymal phenotype in EGFR mutant cells. Taken together, we elucidated a unique mechanism of ligand-induced activation of CXCR7 and downstream MAPK pathway by canonical and putative ligands. This complex mechanism of CXCR7 activation in EGFR mutant NSCLC suggests that preventing the receptor-ligand binding may not be feasible in the context of overcoming EGFR TKI resistance. Citation Format: Laura C. Gunder, Ines Pulido, Jeffrey H. Becker, Malek G. Massad, Takeshi Shimamura. Distinct mechanism of CXCR7 activation in EGFR-mutated NSCLC by chemokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB453.

Abstract LB080: iOTarg screening platform reveals novel mechanisms of colorectal cancer evasion from antigen-specific tumor cell killing by T cells

Abstract While immune checkpoint therapies have revolutionized cancer treatment, their efficacy remains limited in colorectal cancer (CRC) and other malignancies. Tumors employ diverse strategies to evade immune-mediated destruction, hindering the success of immunotherapies. We introduce iOTarg, a robust high-throughput screening platform designed to uncover resistance pathways against T cell-mediated tumor killing within the tumor microenvironment. Focusing on CRC, we utilized iOTarg to dissect evasion mechanisms against antigen-specific T cell (TC) killing. In a representative CRC cell line co-culture system (SW480, HCT116 or COLO-678) with various TC sources, we gained key insights of tumor resistance towards killing. Survivin-specific TCs induce strong tumor lysis while tumor-infiltrating lymphocyte 412 (TIL412) represent a weaker basal killing representative of the situation in the tumor. Knockout of β₂-microglobulin abrogated TC-mediated killing, while c-FLIP knockout significantly enhanced tumor lysis. Intriguingly, PD-L1 blockade had no impact on TC activation or killing, underlining its lack of efficacy in CRC. Screening over 6000 druggable genes revealed several critical candidates, including anti-apoptotic BIRC family members (BIRC2, 3), apoptosis regulators (Bcl-xL, XIAP), TNF signaling regulators (TRAF2, MAP3K7), and genes recently described as sensitization mediators (B3GNT3, CHMP4B). Caspase-8 knockout prevented TC-mediated killing of CRC cells, confirming its crucial role in immune-mediated tumor cell clearance. Further validation in secondary screenings reinforced a subset of genes as strong regulators of tumor cell killing, uncovering an array of CRC resistance mechanisms. Our findings present a pioneering platform delineating resistance mechanisms against T cell-mediated colorectal tumor killing. We identify established and novel targets, offering prospects for novel therapeutics and expanding immune oncology treatment options. This platform holds promise for developing first-in-class therapies targeting the tumor microenvironment, potentially transforming CRC treatment paradigms. Citation Format: Tillmann Michels, Valentina Volpin, Carmen Amerhauser, Claudia Tschulik, Leonie Majunke, Aleksandra Weglarz, Kilian Baritz, Kritika Sudan, Szilvia Bak-Kiss, Alina Huth, Carolin Strobl, Adriana Turqueti-Neves, Nisit Khandelwal. iOTarg screening platform reveals novel mechanisms of colorectal cancer evasion from antigen-specific tumor cell killing by T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB080.

Development and validation of a deep learning-based model to predict response and survival of T790M mutant non-small cell lung cancer patients in early clinical phase trials using electronic medical record and pharmacokinetic data.

Epidermal growth factor receptor (EGFR) T790M mutation is the standard predictive biomarker for third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. While not all T790M-positive patients respond to third-generation EGFR-TKIs and have a good prognosis, it necessitates novel tools to supplement EGFR genotype detection for predicting efficacy and stratifying EGFR-mutant patients with various prognoses. Mixture-of-experts (MoE) is designed to disassemble a large model into many small models. Meanwhile, it is also a model ensembling method that can better capture multiple patterns of intrinsic subgroups of enrolled patients. Therefore, the combination of MoE and Cox algorithm has the potential to predict efficacy and stratify survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations. We utilized the electronic medical record (EMR) and pharmacokinetic parameters of 326 T790M-mutated NSCLC patients, including 283 patients treated with Abivertinib in phase I (n=177, for training) and II (n=106, for validation) clinical trials and an additional validation cohort 2 comprising 43 patients treated with BPI-7711. Furthermore, 18 patients underwent whole-exome sequencing for biological interpretation of CoxMoE. We evaluated the predictive performance for therapeutic response using the area under the curve (AUC) and the Concordance index (C-index) for progression-free survival (PFS). CoxMoE exhibited AUCs of 0.73-0.83 for predicting efficacy defined by best overall response (BoR) and achieved C-index values of 0.64-0.65 for PFS prediction in training and validating cohorts. The PFS of 198 patients with a low risk [median, 6.0 (range, 1.0-23.3) months in the abivertinib treated cohort; median 16.5 (range, 1.4-27.4) months in BPI-7711 treated cohort] of being non-responder increased by 43% [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.40-0.78; P=0.0013] and 50% (HR, 0; 95% CI, 0-0; P=0.01) compared to those at high-risk [median, 4.2 (range, 1.0-35) months in the abivertinib treated cohort; median, 11.0 (range, 1.4-25.1) months in BPI-7711 treated cohort]. Additionally, activated partial thromboplastin time (APTT), creatinine clearance (Ccr), monocyte, and steady-state plasma trough concentration utilited to construct model were found significantly associated with drug resistance and aggressive tumor pathways. A robust correlation was observed between APTT and Ccr with PFS (log-rank test; P<0.01) and treatment response (Wilcoxon test; P<0.05), respectively. CoxMoE offers a valuable approach for patient selection by forecasting therapeutic response and PFS utilizing laboratory tests and pharmacokinetic parameters in the setting of early-phase clinical trials. Simultaneously, CoxMoE could predict the efficacy of third-generation EGFR-TKI non-invasively for T790M-positive NSCLC patients, thereby complementing existing EGFR genotype detection.

An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management.

Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.

Pan-cancer analysis of SLC2A family genes as prognostic biomarkers and therapeutic targets

BackgroundThe major facilitator superfamily glucose transporters (GLUTs), encoded by solute carrier 2A (SLC2A) genes, mediate the transmembrane movement and uptake of glucose. To satisfy the improved energy demands, glycolysis flux is increased in cancers compared with healthy tissues. Multiple diseases, including cancer, have been associated with GLUTs. Nevertheless, not much research has been done on the functions of SLC2As in pan-cancer prognosis or their clinical treatment potential. MethodsThe SLC2A family genes' level of expression and prognostic values were analyzed in relation to pan-cancer. We then examined the association among SLC2As expression and TME, Stemness score, clinical characteristics, immune subtypes, and drug sensitivity. We merged bioinformatics analysis techniques with up-to-date public databases. Additionally, SLC2As from the KOBAS database were subjected to enrichment analysis. ResultsWe discovered that SLC2As' gene expression differed significantly between normal tissues and many malignancies. A number of tumors from various databases demonstrate a relationship between prognosis and SLC2A family gene expression. For instance, SLC2A2 and SLC2A5 were associated with the overall survival (OS) of hepatocellular carcinoma. SLC2A1 was associated with the OS of lung adenocarcinoma and pancreatic adenocarcinoma. Moreover, the SLC2A family gene expression is significantly correlated with the pan-cancer stromal and immune scores, and the RNA and DNA stemness scores. Furthermore, we found that the majority of SLC2As had a strong correlation with the tumor stages in KIRC. The immunological subtypes and all members of the SLC2A gene family exhibited a substantial correlation. Moreover, pathways containing insulin resistance and adipocytokine signaling pathway may influence the progression of some cancers. Finally, there is a significant positive or negative connection between drug sensitivity and SLC2A1 expression. ConclusionOur research highlights the significant promise of SLC2As as prognostic indicators and offers insightful approaches for upcoming exploration of SLC2As as putative therapeutic targets in malignancies.

Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure

Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.

TURMERIC’S HEALING TOUCH: EXPLORING CURCUMIN’S MEDICAL RENAISSANCE

This comprehensive article delves into the multifaceted role of curcumin, a principal component of turmeric, in modern pharmaceuticals, drawing on its long-standing history in traditional medicine systems like Ayurveda and Chinese Medicine. The core of the article investigates curcumin’s emerging role as a formidable anti-aging agent. Curcumin’s antioxidant and anti-inflammatory properties play a pivotal role in addressing age-related disorders. Its efficacy extends to neurodegenerative diseases, cardiometabolic disorders, cancer, and rheumatoid arthritis, owing to its ability to modulate various cellular pathways, enhance drug susceptibility, inhibit cell proliferation, and foster apoptosis. Notably, curcumin enhances the efficacy of chemotherapy drugs, as evidenced in breast cancer treatments, by modulating drug resistance pathways. The article also emphasizes curcumin’s potential in managing diabetes, cardiovascular diseases, and osteoporosis, highlighting its role in reducing cholesterol levels and improving vascular health, and bone metabolism. Confronting the challenge of curcumin’s low bioavailability, the article explores innovative biotechnological solutions, such as nano-delivery systems, which significantly enhance curcumin’s therapeutic potential. The harmonious blend of ancient knowledge and contemporary scientific research highlights the lasting significance of curcumin in medicine, setting the stage for its ongoing incorporation into modern healthcare practices.

Network Pharmacology Approach to Understanding the Antidiabetic Effects of Pineapple Peel Hexane Extract

The increased interest in exploring alternative treatments for type 2 diabetes mellitus is accompanied by a rise in the prevalence of type 2 diabetes mellitus. Pineapple peel is one of the by-products of pineapple fruit and is known to possess potential for anti-diabetic activity. In this study, the n-hexane extract of pineapple peel was analyzed using network pharmacology methods to ascertain its potential in treating type 2 diabetes mellitus. The GC-MS analysis of the n-hexane extract of pineapple peel revealed the presence of 42 compounds, with 8 of them considered safe as they met the Lipinski Rule of Five criteria for drug-likeness and were classified as safe with toxicity levels in classes IV and V. The pineapple peel extract targeted 55 proteins related to type 2 diabetes mellitus (DMT2), potentially affecting DMT2 through the AGE-RAGE pathway in diabetes complications and insulin resistance. Network pharmacology analysis identified five genes targeted by pineapple peel, namely MAPK1, JAK2, MAPK8, PRKCD, and PPARA. Among these genes, MAPK1 exhibited a higher overall score than the others. Apart from its role in diabetes, MAPK1 is also implicated in cancer.

Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy.

TFP5 is a Cdk5 inhibitor peptide, which could restore insulin production. However, the role of TFP5 in diabetic nephropathy (DN) is still unclear. This study aims to characterize the transcriptome profiles of mRNA and lncRNA in TFP5-treated DN mice to mine key lncRNAs associated with TFP5 efficacy. We evaluated the role of TFP5 in DN pathology and performed RNA sequencing in C57BL/6Jcontrol mice, C57BL/6J db/db model mice, and TFP5 treatment C57BL/6J db/db model mice. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were analyzed. WGCNA was used to screen hub-gene of TFP5 in treatment of DN. Our results showed that TFP5 therapy ameliorated renal tubular injury in DN mice. In addition, compared with the control group, the expression profile of lncRNAs in the model group was significantly disordered, while TFP5 alleviated the abnormal expression of lncRNAs. A total of 67 DElncRNAs shared among the three groups, 39 DElncRNAs showed a trend of increasing in the DN group and decreasing after TFP treatment, while the remaining 28 showed the opposite trend. DElncRNAs were enriched in glycosphingolipid biosynthesis signaling pathways, NF-κB signaling pathways, and complement activation signaling pathways. There were 1028 up-regulated and 1117 down-regulated DEmRNAs inthe model group compared to control group, and 123 up-regulated and 153 down-regulated DEmRNAs in theTFP5 group compared to themodel group. The DEmRNAs were involved in PPAR and MAPK signaling pathway. We confirmed that MSTRG.28304.1 is a key DElncRNA for TFP5 treatment of DN. TFP5 ameliorated DN maybe by inhibiting MSTRG.28304.1 through regulating the insulin resistance and PPAR signaling pathway. The qRT-PCR results confirmed the reliability of the sequencing data through verifying the expression of ENSMUST00000211209, MSTRG.31814.5, MSTRG.28304.1, and MSTRG.45642.14. Overall, the present study provides novel insights into molecular mechanisms of TFP5 treatment in DN.

A carrier-free metal-phenolic network with enhanced ferroptosis-immunotherapy for overcoming tumor resistance and metastasis

The development of multidrug resistance (MDR) is the primary contributor to the failure of cancer treatment, ultimately leading to tumor recurrence and metastasis. Ferroptosis, an iron-dependent cell death form related to the accumulation of lipid peroxidation (LPO), has the potential to circumvent MDR. Furthermore, recent breakthroughs have confirmed that the inhibition of cyclooxygenase-2 (COX-2) not only facilitate LPO and ferroptosis, but also suppress the expression of p-glycoprotein. Therefore, the combination of immunogenic ferroptosis with COX-2 inhibitors may be an enticing approach for overcoming tumor resistance and metastasis. Herein, polyphenolic COX-2 inhibitors are first screened using molecular docking, enzyme-linked immunosorbent assay, and combination index analysis. Then, a carrier-free metal-phenolic networks are constructed based on the coordination between polyphenolic COX-2 inhibitors and Fe3+, and DOX and dopamine-modified hyaluronic acid are directly decorated using a one-pot process. The nanosystem can selectively inhibit the COX-2 pathway, thereby suppressing the expression of p-glycoprotein and enhancing Fe3+-induced ferroptosis; Additionally, the nanosystem demonstrates excellent photothermal performance, promoting ferroptosis and synergistically triggering strong immune responses against tumor metastasis. The RNA-seq analysis further confirmes the transcriptomic alterations in drug resistance and ferroptosis pathways induced by the nanosystem. Taken together, this study provides a promising strategy for efficient cancer treatment.