Search Results (578)

Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair (pMMR) and microsatellite stability (MSS) metastatic colorectal cancer (mCRC). Inhibition of vascular endothelial growth factor (VEGF) or cytotoxic chemotherapy can boost immunogenicity and has the potential to upregulate ICI efficacy. Methods: A comprehensive electronic literature search was conducted up to April 2025 to identify randomized controlled trials comparing cytotoxic chemotherapy plus bevacizumab with or without ICI. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival (OS), objective response rate (ORR), and severe adverse events (AEs: grade 3 or more). A meta-analysis was performed using random-effects models to calculate hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: Four studies involving 986 patients (With-ICI group, n = 651; Without-ICI group, n = 335) were included. The meta-analysis demonstrated a significant improvement in PFS in the With-ICI group compared with the Without-ICI group, with an HR of 0.82 (95% CI: 0.70–0.96, p = 0.01) without statistical heterogeneity. No significant improvements were observed between the With- and Without-ICI groups in OS and ORR meta-analyses, but the With-ICI group had a favorable trend in OS. A significant increase in serious AEs was not observed in the With-ICI group. Conclusions: This meta-analysis suggests a potential benefit of adding ICIs to chemotherapy plus bevacizumab in pMMR mCRC; however, the evidence remains preliminary and hypothesis-generating, warranting further investigation in biomarker-driven trials and clarification of long-term outcomes. Full article

When non-functioning pituitary adenomas (NFPAs) behave aggressively or recur after first-line surgical treatment, it can be challenging to decide whether and how to escalate therapy. Up to 47% of patients with residual tumor after transsphenoidal surgery will show disease recurrence or progression and may require an intervention. Repeat surgical resection can be attempted in select cases if the tumor is accessible; for the remainder of patients, non-surgical treatment options may need to be considered. Radiotherapy can control tumor growth in 75% of NFPAs, but confers increased risk of hypopituitarism and other disorders. Currently, there are no medical therapies approved for patients with recurrent or aggressive NFPA. However, several have been investigated, including temozolomide, somatostatin receptor ligands, dopamine agonists, immune checkpoint inhibitors, vascular endothelial growth factor inhibitors, and peptide receptor radionuclide therapy. We present a review of the available evidence to provide guidance for pituitary endocrinologists and neuro-oncologists when treating patients with recurrent or aggressive NFPA. Full article

The enterovirus Coxsackievirus B3 causes a range of serious health problems, including aseptic meningitis, myocarditis, and pancreatitis. Currently, Coxsackievirus B3 has no targeted antiviral treatments or vaccines, leaving supportive care as the primary management option. Understanding how Coxsackievirus B3 interacts with and alters the blood–brain barrier may help identify new therapies to combat this often-devastating infection. We reanalyzed a previously published RNA sequencing dataset for Coxsackievirus B3-infected human-induced pluripotent stem-cell-derived brain endothelial cells (iBECs) to examine how Coxsackievirus B3 altered mRNA expression. By integrating GSEA, EnrichR, and iLINCs-based perturbagen analysis, we present a novel, systems-level approach to uncover potential drug repurposing candidates for CVB3 infection. We found dynamic changes in host transcriptomic response to Coxsackievirus B3 infection at 2- and 5-day infection time points. Downregulated pathways included ribosomal biogenesis and protein synthesis, while upregulated pathways included a defense response to viruses, and interferon production. Using iLINCs transcriptomic analysis, MEK, PDGFR, and VEGF inhibitors were identified as possible novel antiviral therapeutics. Our findings further elucidate Coxsackievirus B3-associated pathways in (iBECs) and highlight potential drug repurposing candidates, including pelitinib and neratinib, which may disrupt Coxsackievirus B3 pathology at the blood–brain barrier (BBB). Full article

Chronic kidney disease (CKD)-associated anemia is a global health concern and is linked to vascular and ocular complications. Hypoxia-inducible factor (HIF) stabilizers, or HIF prolyl hydroxylase inhibitors (PHIs), are promising candidates for the treatment of CKD-associated anemia. Since hypoxia and angiogenesis are involved in eye diseases, this study examined the effects of HIF-PHIs on metabolism and gene expression in retinal pigment epithelium (RPE) cells. Results revealed that PHIs differentially induced angiogenic (VEGFA, ANG) and glycolytic (PDK1, GLUT1) gene expression, with Roxadustat causing the strongest transcriptional changes. However, Roxadustat-induced angiogenic signals did not promote endothelial tube formation. Moreover, it did not induce oxidative stress, inflammation, or significant antioxidant gene responses in ARPE-19 cells. Roxadustat also reduced the inflammatory cytokine response to tumor necrosis factor-α, including IL-6, IL-8, and MCP-1, and did not exacerbate VEGF expression under high-glucose conditions. Overall, Roxadustat triggered complex gene expression changes without promoting inflammation or oxidative stress in RPE cells. Despite these findings, ophthalmologic monitoring is advised during PHI treatment in CKD patients receiving HIF-PHIs. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Repairing and regenerating tissue barriers is a key challenge in regenerative medicine. Stem cells play a crucial role in restoring the structural and functional integrity of key epithelial barrier surfaces, including the skin and mucosa. This review analyzes the role of dental pulp stem cells (DPSCs) and their derivatives, including extracellular vesicles, conditioned medium, and intracellular factors, in accelerating skin wound healing. The key mechanisms include: (1) DPSCs regulating inflammatory microenvironments by promoting anti-inflammatory M2 macrophage polarization; (2) DPSCs activating vascular endothelial growth factor (VEGF) to drive angiogenesis; (3) DPSCs optimizing extracellular matrix (ECM) spatial structure through matrix metalloproteinase/tissue inhibitor of metalloproteinase (MMP/TIMP) balance; and (4) DPSCs enhancing transforming growth factor-β (TGF-β) secretion to accelerate granulation tissue formation. Collectively, these processes promote wound healing. In addition, we explored potential factors that accelerate wound healing in DPSCs, such as oxidative stress, mechanical stimulation, hypertension, electrical stimulation, and organoid modeling. In addition to demonstrating the great potential of DPSCs for skin repair, this review explores their translational prospects in mucosal regenerative medicine. It covers the oral cavity, esophagus, colon, and fallopian tube. Some studies have found that combining DPSCs and their derivatives with drugs can significantly enhance their biological effects. By integrating insights from skin and mucosal models, this review offers novel ideas and strategies for treating chronic wounds, inflammatory bowel disease, and mucosal injuries. It also lays the foundation for connecting basic research results with clinical practice. This represents a significant step forward in tackling these complex medical challenges and lays a solid scientific foundation for developing more targeted and efficient regenerative therapies. Full article

Cancer therapy-induced hypertension (HTN) is an increasingly recognized complication associated with a wide range of anticancer agents, including vascular endothelial growth factor (VEGF) inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and alkylating agents. The pathogenesis of HTN in this setting is multifactorial, involving mechanisms such as endothelial dysfunction, nitric oxide (NO) suppression, sympathetic nervous system activation, and vascular remodeling. Additional factors, including paraneoplastic syndromes, poorly controlled pain, mood disturbances, and overlapping cardiovascular risk factors like obesity and diabetes, further contribute to the complexity of diagnosis and management. Despite its prevalence and clinical implications, cancer therapy-induced HTN is often addressed using general population guidelines, with limited oncology-specific protocols available. Accurate blood pressure measurement and individualized treatment plans are critical to optimize outcomes and avoid interruptions to cancer therapy. Antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and calcium channel blockers have shown efficacy in both blood pressure control and, in some cases, oncologic outcomes. A multidisciplinary approach involving oncologists, cardiologists, and primary care providers is essential to navigate the interplay between cancer treatment and cardiovascular health. Ongoing research is needed to develop targeted guidelines and improve the long-term care of cancer patients affected by treatment-induced HTN. Full article

Renal cell carcinoma (RCC) accounts for about 403,000 new cases and 175,000 deaths worldwide each year. Clear cell RCC (ccRCC), the most prevalent subtype, is often driven by genetic mutations, such as VHL inactivation, leading to angiogenesis and immune escape. Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed treatment paradigms, yet therapeutic resistance remains a critical challenge. The immunosuppressive nature of the tumor microenvironment (TME) in ccRCC plays a central role in limiting ICI efficacy. Emerging strategies aim to overcome resistance by targeting key components of the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and cytokine signaling. Agents such as nivolumab, pembrolizumab, and ipilimumab have demonstrated the ability to restore T-cell activity and mitigate immune suppression, offering clinical benefit in metastatic ccRCC. However, response rates vary, highlighting the need for rational combination therapies. ICIs combined with VEGF inhibitors have shown promising outcomes in clinical trials, and novel regimens continue to be explored. Risk stratification and personalized treatment selection are increasingly important as the therapeutic landscape evolves. This review synthesizes current advances in immunotherapy for ccRCC, with a focus on mechanisms of resistance and innovative strategies to enhance immune responsiveness. A deeper understanding of TME modulation and strategic combination approaches is essential to improve survival and quality of life for patients with advanced ccRCC. Full article

In sheep production, due to the limitations of breeding conditions, the uteri of ewes are often infected with bacteria, resulting in the failure of embryo implantation or loss, causing huge losses to the sheep industry. Therefore, in this study, by using RT-qPCR, Western blot, and immunofluorescence, we investigated the effects of LPS infusion on the immune microenvironment and endometrial receptivity, which play an important role in the process of embryo implantation in ruminants, during the three critical periods of embryo implantation in sheep. The results showed that LPS infusion at day 12, day 16, and day 20 significantly increased the expression of Th1 cytokines (TNF-α, IL-1β, IL-8, IL-6), while significantly decreasing the expression of Th2 cytokines (IL-4 and IL-10) and disrupting the expression of implantation factors, such as ITGB3, ITGB5, VEGF, and LIF, in the endometrial tissues of sheep. Additionally, the protein expression level of TLR4 and the phosphorylation level of ERK were significantly elevated at day 12, day 16, and day 20 after LPS infusion, suggesting that LPS may impair endometrial receptivity through the TLR4/ERK pathway. Validation was conducted in a receptive model of sEECs using TLR4 and ERK phosphorylation inhibitors. Compared with the LPS group, TLR4 and ERK phosphorylation inhibitors significantly reduced the expression of TLR4 and p-ERK, down-regulated Th1 cytokines, up-regulated Th2 cytokines, and alleviated the disruption of genes for attachment. Treatment with 50 μM PTE can significantly alleviate the abnormal expression of implantation genes caused by LPS, and its mechanism may be related to the regulation of the ERK signaling pathway. Full article

Atrial fibrillation (AF), the most prevalent clinically significant cardiac arrhythmia, is characterized by chaotic atrial electrical activity and currently affects an estimated 2.5–3.5% of the global population. Its pathogenesis involves ion channel dysfunction, inflammatory cascades, and structural remodeling processes, notably fibrosis. Angiogenesis, the physiological/pathological process of new blood vessel formation, plays a multifaceted role in AF progression. This review synthesizes evidence highlighting angiogenesis’s dual role in AF pathogenesis: while excessive or dysregulated angiogenesis promotes atrial remodeling through fibrosis, and electrical dysfunction via VEGF, ANGPT, and FGF signaling pathways, compensatory angiogenesis exerts protective effects by improving tissue perfusion to alleviate ischemia and inflammation. Therapeutically, targeting angiogenic pathways—particularly VEGF—represents a promising strategy for modulating structural remodeling; however, non-selective VEGF inhibition raises safety concerns due to cardiovascular toxicity, necessitating cautious exploration. Emerging evidence highlights that anti-cancer agents (e.g., ibrutinib, bevacizumab) impair endothelial homeostasis and elevate AF risk, underscoring the need for cardio-oncology frameworks to optimize risk–benefit ratios. Preclinical studies on angiogenesis inhibitors and gene therapies provide mechanistic insights, but clinical validation remains limited. Future research should prioritize elucidating mechanistic complexities, developing biomarker refinement, and implementing interdisciplinary strategies integrating single-cell sequencing with cardio-oncology principles. This review emphasizes the imperative to clarify angiogenic mechanisms, optimize therapeutic strategies, and balance pro-arrhythmic versus compensatory angiogenesis, in pursuit of personalized AF management. Full article

Gallbladder cancer (GBC) is a highly aggressive malignancy with a propensity for lymph node metastasis (LNM), which significantly worsens prognosis. This review explores the molecular mechanisms underlying LNM in GBC, focusing on the roles of vascular endothelial growth factors (VEGFs), chemokines, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), hypoxia-inducible factors (HIFs), and non-coding RNAs (ncRNAs) in shaping the tumor microenvironment (TME). Unique features of GBC, such as its bile-rich microenvironment and hypoxia-driven lymphangiogenesis, are highlighted. We discuss how these factors promote lymphangiogenesis, immune evasion, and extracellular matrix (ECM) remodeling, collectively facilitating LNM. Potential therapeutic targets, including VEGF-C/D pathways, matrix metalloproteinase (MMP) inhibitors, and immune-modulating therapies, are also reviewed. Future research integrating single-cell omics and patient-derived organoid models is essential for advancing precision medicine in GBC. Full article

Vascular endothelial growth factor (VEGF), also known as VEGF-A, has been reported to mediate various diseases, including cancer and wet age-related macular degeneration (wAMD). Despite the fact that VEGF inhibitors are commercially available and appear to be effective in clinical applications, adverse effects have been caused by these treatments. There is an unmet need for developing novel VEGF-targeted treatments against these diseases. Resveratrol, a phytochemical derived from fruits and vegetables, has shown promising potency in suppressing VEGF-mediated bioactivities through a series of in vitro and in vivo testing models. Herein, we report that RE-1, a synthetic resveratrol-type analog, displays robust inhibitory activities against VEGF and its downstream signaling pathways, surpassing its parental molecule, resveratrol. In addition, the drug capabilities of RE-1 were evaluated. As a newly synthesized chemical, RE-1 could be considered for subsequent pharmacological development targeting VEGF-related diseases. Full article

Background/Objectives: Peritoneal dialysis (PD) is a renal replacement therapy for patients with kidney failure. Managing PD patients often involves addressing a complex interplay of comorbidities and complications, necessitating the use of multiple medications. This study aimed to systematically characterize commonly co-prescribed drugs in PD and to identify novel drug combinations that may target dysregulated molecular mechanisms associated with PD’s pathophysiology. Methods: We analyzed clinical records from 702 PD patients spanning 30 years, encompassing over 5500 prescription points. Using network-based modeling techniques, we assessed drug co-prescription patterns, clinical outcomes, and longitudinal treatment trends. To explore potential drug repurposing opportunities, we constructed a molecular network model of PD based on a consolidated transcriptomics dataset and integrated this with drug–target interaction information. Results: We found commonly prescribed drugs such as furosemide, sucroferric oxyhydroxide, calcitriol, darbepoetin alfa, and aluminum hydroxide to be integral components of PD patient management, prescribed in over 30% of PD patients. The molecular-network-based approach found combinations of drugs like theophylline, fluoxetine, celecoxib, and amitriptyline to possibly have synergistic effects and to target dysregulated molecules of PD-related pathomechanisms. Two further distinct categories of drugs emerged as particularly interesting in our study: selective serotonin reuptake inhibitors (SSRIs), which were found to modulate molecules implicated in peritoneal fibrosis, and vascular endothelial growth factor (VEGF) inhibitors, which exhibit anti-fibrotic properties that are potentially useful for PD. Conclusions: This comprehensive exploration of drug co-prescriptions in the context of PD-related pathomechanisms provides valuable insights for opening future therapeutic strategies and identifying new targets for drug repurposing. Full article

Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC, BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors. Full article

Objectives: To evaluate the efficacy of faricimab in patients with neovascular age-related macular degeneration (nAMD) that did not respond to other VEGF inhibitors. Methods: This retrospective study included the eyes of patients diagnosed with nAMD who had been switched to faricimab treatment due to the persistence of intraretinal fluid (IRF) and/or subretinal fluid (SRF), despite monthly anti-VEGF treatment with aflibercept, bevacizumab, or ranibizumab using the treat and extend regimen, and who had received at least three faricimab injections following the switch. Best-corrected visual acuity (BCVA) measurement and optical coherence tomography (OCT) analysis were performed at each visit, and the OCT results were graded by two independent readers. Results: We included 41 eyes of 39 patients (21 male, 18 female) with a mean age of 80.5 ± 8.1 years. The median duration of anti-VEGF treatment prior to the switch to faricimab was 5.0 years, with a median of 53 injections. Complete resolution of IRF and SRF was observed after the first dose of faricimab in 12 eyes (29.3%) and after the third dose in 15 eyes (36.6%). Twenty-eight eyes reached a follow-up time after a switch of at least 12 months, with a median of 10 faricimab injections. Of these 28 eyes, 10 eyes (35.7%) exhibited complete IRF/SRF resolution; treatment intervals were extended beyond 4 weeks in 21 eyes (80.7%), and 8 eyes (28.6%) presented complete IRF/SRF resolution under extended treatment intervals at month 12. Central retinal thickness after 12 months was reduced from a median of 368.0 µm to 297.5 µm (p < 0.001), and the BCVA remained stable (p = 0.057). No adverse events were reported throughout the entire treatment period. Conclusions: In nAMD patients with poor anti-VEGF treatment response, complete and fast fluid resolution and the extension of treatment intervals can be reached by switching to faricimab, even after years of prior unsuccessful therapy. Full article