Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently at the forefront of type 2 diabetes mellitus (T2DM) and obesity treatment development and usage. However, recent focus on multi-receptor agonism with glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) receptors has been investigated to assess for improved glycemic control, weight loss, and safety profile.

Several dual GLP-1/GIP RAs are currently in development, with the GIP receptor assisting GLP-1 in modulating central and peripheral pathways to prompt weight loss by increasing lipolysis and fat oxidation. Dual GLP-1/Gcg is another novel combination that utilizes the Gcg receptor which increases energy expenditure by stimulating glucose production, fat oxidation, and mobilization of energy stores to promote weight loss. Triple agonism of GLP-1/GIP/Gcg is still mainly being investigated in clinical trials, but preliminary results show similar if not improved glycemic control and weight loss. However, despite the multi-agonist approach, gastrointestinal adverse events do not seem to be mitigated compared to traditional GLP-1 RAs.

The current literature shows promising results for the efficacy of dual and triple agonism of GLP-1/GIP/Gcg receptors. Further research should focus on direct comparative studies between current GLP-1 RAs against these multi-receptor agonist agents.

Huanglian Zhimu decoction (HLZMD), a classical formulation in traditional Chinese medicine, has historically been utilized in the management of diabetes. However, its therapeutic efficacy and the underlying mechanisms in the context of T2DM, particularly in relation to hepatic lipid dysregulation, have yet to be systematically investigated.

To explore the potential therapeutic effects and molecular mechanisms of HLZMD on T2DM.

Initially, a T2DM model was established in spontaneously diabetic Goto-Kakizaki (GK) rats through high-fat diet induction. To elucidate the molecular mechanisms underlying the therapeutic effects of HLZMD, an integrative approach combining hepatic lipidomic profiling and transcriptomic sequencing was employed to identify HLZMD-responsive pathways. Furthermore, the expression levels of key proteins within the PDE4D/cAMP/PKA signaling pathway were quantified via western blotting in both rat liver tissues and palmitic acid-stimulated HepG2 cells. To validate the pathway specificity, pharmacological inhibition experiments were performed using roflumilast, a selective PDE4D antagonist. Lastly, the chemical composition of HLZMD was characterized through ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and molecular docking analysis was conducted to predict potential active components interacting with PDE4D.

In vivo experiments demonstrated that HLZMD significantly ameliorated fasting blood glucose levels and hepatic steatosis in T2DM rats. Lipidomic analysis further revealed that HLZMD effectively restored the homeostasis of diacylglycerols (DG), triglycerides (TG), sterols (ST), sphingolipids (SP), and glycerophospholipids (GP) in the liver. Integrative analyses incorporating lipidomics, transcriptomics, and western blotting suggested that HLZMD-mediated hepatic lipid modulation may be attributed to the regulation of the PDE4D/cAMP/PKA signaling pathway. In vitro, HLZMD treatment resulted in a significant reduction in extracellular glucose concentrations as well as intracellular TC and TG levels. Concurrently, HLZMD markedly upregulated the expression of PDE4D, SIRT1, and PPARγ proteins while downregulating the expression of cAMP, phosphorylated PKA (p-PKA/PKA), and phosphorylated hormone-sensitive lipase (p-HSL/HSL). Notably, pharmacological inhibition with roflumilast, a selective PDE4D antagonist, partially reversed the HLZMD-induced reduction in lipid deposition, supporting the specificity of this pathway in mediating HLZMD's effects. Furthermore, UPLC-Q-TOF-MS identified 80 chemical constituents in HLZMD. Molecular docking analysis predicted that 21 of these compounds may exhibit direct binding affinity for PDE4D, potentially modulating the cAMP/PKA signaling cascade.

This study is the first to provide evidence that HLZMD exerts its pharmacological effects through multi-component interactions with PDE4D, thereby modulating the cAMP/PKA signaling pathway. This regulatory mechanism contributes to the reduction of hepatic lipid accumulation, attenuation of hepatic insulin resistance, and restoration of glucose and lipid metabolic homeostasis.

Cholangiocarcinoma (CCA), a devastating malignancy originating from the bile ducts, is of significant clinical importance due to its rising incidence and poor prognosis. Quinones as being naturally occurring compounds and their frequent utility in anticancer drug development studies seem to be potential sources for the discovery of new chemotherapeutics. In this study, a synthetic naphthoquinone derivative newly synthesized and previously published by our group, named as MK13, has been tested against intrahepatic-CCA (iCCA) cell lines (CCLP1 and HUCCT1). Cell viability was measured with the MTT assay at the doses of 1.56-50 µM for 48 h treatment. Cell death was showed both morphologically with fluorescent double staining and biochemically with flow cytometry analysis of phosphatidylserine translocation. Oxidative stress and DNA damage were also measured with flow cytometry and gene expressions were interpreted via qPCR analysis. MK13 resulted in a strong reduction (about 80%) in viability, especially against CCLP1 cells when compared with doxorubicin. Cell death resulted from apoptosis was shown to be triggered by severe DNA damage that is independent of oxidative stress. Apoptosis was confirmed at molecular level with the upregulation of BAX, a pro-apoptotic BH-3 only protein, and DR5, a cell surface death receptor. MK13 seems to be a promising anticancer compound against iCCA and deserves further attention for in vivo proof-of-concept studies.

Hepatocellular carcinoma (HCC) is a major global health concern due to its high prevalence and mortality rate. Although emodin, a natural anthraquinone derivative, has demonstrated in vitro anticancer activity against HCC cells, its specific molecular targets in HCC remain unclear.

This study used an integrated approach combining in silico network pharmacology, molecular docking, molecular dynamics simulations (MDS), and in vitro cytotoxicity assays to evaluate three emodin derivatives: emodin, 3-acetyl emodin (ACE), and 1,3,8-triacetyl emodin (TAEM). Target predictions were performed using the SwissTargetPrediction database, and HCC-related genes were retrieved from cBioPortal. Functional annotations (Gene Ontology and Reactome) identified EGFR and KIT as key targets. Docking simulations were conducted to assess binding affinities, followed by 100 ns MDS to evaluate stability. Cytotoxic effects on HepG2 cells were also assessed.

TAEM showed the strongest binding affinity to both EGFR and KIT and demonstrated the highest cytotoxicity against HepG2 cells (IC50 = 0.021 mM). MDS results indicated that the KIT-TAEM complex was the most stable among all tested combinations, supported by RMSD, RMSF, Rg, protein-ligand distance, and MM-GBSA binding energy analyses.

These findings highlight TAEM as a promising therapeutic candidate for HCC. The study demonstrates the value of integrating computational predictions with experimental validation in early-stage drug discovery.

Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment.

This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility.

Among 410 patients (median age 67 years; 48 % male), 162 (40 %) experienced SRE over a median follow-up of 26.8 months. Seventy-five (18.3 %) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95 % CI 1.47-2.67, p < 0.001) or radiation for pain alone (HR 2.14, 95 % CI 1.57-2.92, p < 0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95 % CI 1.18-2.37, p = 0.004). Prostate cancer histology (HR 1.70, p = 0.02) and metastases to the hip/acetabulum (HR 2.55, p = 0.02) were associated with SRE.

Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.

Bladder cancer is a common malignancy, and its diagnosis is based on invasive procedures such as cystoscopy. Genetic aberrations play an important role in the development of many diseases, including bladder cancer. As a result, identifying the genetic basis of a disease can provide useful information for early diagnosis and therapy. Cell-free DNA (cfDNA) offers a non-invasive approach to extract genetic information, which could be valuable for establishing the genetic cause of bladder cancer. In this study, we analyzed copy number variations (CNV) in urine cfDNA from 20 patients, with cystoscopy confirmed bladder cancer, sequenced by next-generation sequencing (NGS) and their CNV examined using the whole genome sequence. Statistical analysis of the carcinoma samples included Wilcoxon and Chi-square tests (p ≤ 0.005). Different patterns in CNV were identified in Chromosomes 1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 17, 19, and 20 with the chromosome cytobands showing significant difference in variation patterns in patient parameters, such as smoking habit, number of tumors, grade of the tumors, and invasiveness. The genes that exhibited distinct CNV in each chromosomal cytoband have been associated with the development and progression of various cancers including bladder cancer indicating the clinical significance of CNVs as a useful tool for disease diagnosis. Therefore, this study demonstrates that by using NGS, CNV in urine cfDNA can provide valuable information on the state of blader cancer which can be further utilized to investigate therapies or early diagnosis.

Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) predicts favorable outcomes in HER2-positive and triple-negative breast cancer (TNBC). While breast and axillary pCR often coexist, some patients with residual breast disease still achieve axillary pCR. This study evaluated axillary pCR rates and factors in this subgroup, and the potential to omit sentinel lymph node biopsy (SLNB) in selected patients.

We retrospectively reviewed 1043 patients with HER2-positive or TNBC who did not achieve breast pCR after NACT and underwent surgery between 2008 and 2021 at a single institution. Clinicopathological features were compared between axillary pCR and non-pCR groups. Logistic regression analyses identified predictors of axillary pCR.

Axillary pCR was observed in 648 (62.1 %) of 1043 patients who did not achieve breast pCR after NACT. The axillary pCR rate was 91.3 % in clinically node-negative (cN0) patients and 55.4 % in cN-positive patients. Axillary pCR rates decreased as the size of the residual breast tumor increased in both cN0 and cN-positive patients. Axillary pCR rates exceeded 94 % in patients with cN0 and residual tumor size of 1 cm or less. Multivariable analysis identified lower clinical N stage, smaller residual breast tumor size, and absence of lymphovascular invasion as independent predictors of axillary pCR.

A substantial proportion of HER2-positive or TNBC patients without breast pCR after NACT achieved axillary pCR, especially those with cN0 status and small residual tumors. These results support the potential omission of SLNB in selected patients and highlight the need for prospective validation and predictive model development.

To investigate the performance of two segmentation algorithms for nodule volumetric classification at participant/scan level in the NELCIN-B3 cohort (Netherlands and China Big-3), a lung cancer screening program (LCS) using low-dose CT (LDCT).

Baseline scans with qualified LDCT images from consecutive NELCIN-B3 participants were included from June 2017 to July 2018. Performance of two software algorithms were independently evaluated by two radiologists: software A (Syngo.via VB30A) by reader 1 and software B (AVIEW v1.1.39.14) by reader 2. According to the NELSON2.0 protocol, nodules with a solid component ≥ 100 mm³ were classified as indeterminate-positive, while all other nodules were classified as negative. Disagreements in classification were resolved by consensus with three senior radiologists. These results served as a reference standard for identifying positive misclassifications (PM) and negative misclassifications (NM).

In total, 300 participants were evaluated comprising 159 women (53.0 %) and 193 (64.3 %) never smokers, with a mean ± standard deviation age of 61.2 ± 7.1 years. There were disagreements in 17 cases: in 11 (11/300, 3.7 %), this was due to differences in nodule selection and nodule type classification between readers; and in 6 (6/300, 2.0 %), this was due to variations in nodule volume metrics between algorithms. Inter-software agreement was almost perfect (κ = 0.88 [95 %CI: 0.83-0.93]). In the consensus read, reader 1/software A generated 12 misclassifications (11 PM, 1 NM), giving a negative predictive value of 99.6 % (95 % CI: 98.9 %-100.0 %). Reader 2/software B generated 5 misclassifications (2 PM, 3 NM), giving a negative predictive value of 98.9 % (95 % CI: 97.7 %-100.0 %).

Two software algorithms (Syngo.via VB30A and AVIEW v1.1.39.14) showed comparable performance for lung nodule volumetric classification at participant/scan level. Further research is needed to confirm the results in other LDCT LCS programs.

Multiple myeloma (MM) is a hematologic cancer affecting plasma cells, characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. Research in recent years has shown that the inhibition of ferroptosis is involved in the pathogenesis of MM. CLEC2 is a C-type lectin receptor family member mainly related to the activation of platelets, which is reported to be lowly expressed in multiple tumors. However, the role of CLEC2 in MM remain unknown. The present study clarified CLEC2's function in MM by exploring its impacts on ferroptosis. Comparing to normal plasma cells (NPCs), CLEC2 was found markedly downregulated in MM cell lines. In CLEC2-overexpressed U266 cells, largely declined cell viability and migrated cell counts, markedly enhanced ROS and MDA levels, and declined SOD activities were observed, accompanied by increased Fe²⁺ levels, upregulated ACSL4, and downregulated GPX4, HIF-1α, and SLC7A11. Moreover, in CLEC2-knockdown OPM-2 cells, greatly increased cell viability and migrated cell counts, sharply repressed ROS and MDA levels, and enhanced SOD activities were observed, along with reduced Fe²⁺ levels, downregulated ACSL4, and upregulated GPX4, HIF-1α, and SLC7A11. In addition, influences of CLEC2 overexpression on proliferation, Fe²⁺ levels, and expressions of ACSL4, GPX4, HIF-1α, and SLC7A11 in U266 cells were remarkably abolished by Fer-1 (an inhibitor of ferroptosis) or HIF-1α overexpression. Collectively, downregulation of CLEC2 in MM facilitated the proliferation and migration of MM cells via regulating HIF-1α-mediated ferroptosis.

Breast cancer is considered to be the most common cancer that affects women worldwide, where it accounts for approximately 38.8% of all cancer cases among females. Luminal subtypes are the most prevalent in Egypt. Small noncoding RNAs also called microRNAs (miRNAs) influence gene expression posttranscriptionally. Since they regulate the epithelial-mesenchymal transition process, which is vital for tumor invasion and metastasis, microRNAs play a critical role in the progression of cancer.

This study has investigated the expression profiles of four microRNAs (miR-101-3p, miR-106a-5p, miR-106b-5p, and miR-130b-5p) and their impacts on genes associated with epithelial-mesenchymal transition (EMT) in luminal breast cancer. Tissue samples from 43 luminal breast cancer patients and 18 controls have been studied via real-time PCR (RT-qPCR). The association between the expression levels was evaluated using the Pearson correlation test. The correlation between the measured variables and numerous clinicopathological characteristics was assessed using the linear regression test.

The results demonstrated that miR-101-3p, miR-106a-5p, and miR-106b-5p were significantly dysregulated, highlighting their possible role as oncogenes or tumor suppressors in the development of breast cancer. EMT markers, especially Twist, SNAI1, and E-cadherin, show significant alterations, indicating the activation of EMT pathways in luminal breast cancer. Correlation analysis showed interactions between miRNAs and EMT-related genes, showing a negative correlation between miR-101-3p and SNAI1, as well as a positive correlation between Twist and miR-106a-5p. Moreover, logistic regression analysis associated expression levels of those miRNAs with clinicopathological characteristics, such as body weight, age, and tumor laterality.

These findings highlight the leading role of miR-101-3p and miR-106b-5p in the progression of luminal breast cancer via interacting with the EMT process and their potential as diagnostic, prognostic, and therapeutic targets.