Search Results (4,591)

Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized B-cell malignancy treatment but paradoxically increase infection susceptibility. Covalent BTK inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib) induce sustained BTK blockade but disrupt immune homeostasis through off-target effects on T-cell and myeloid signaling, contributing to hypogammaglobulinemia and increased risk of bacterial, viral, and opportunistic fungal infections. Non-covalent inhibitors (Pirtobrutinib) and emerging BTK degraders offer more selective inhibition, preserving T-cell function and potentially mitigating infection risk, though their long-term immunological impact requires further study. Infection susceptibility varies across BTK inhibitor generations, reflecting differences in kinase selectivity, modulation of humoral and cellular immunity, and disease-intrinsic immune dysfunction in chronic lymphocytic leukemia. This review examines the mechanistic basis of BTK inhibitor-associated immune dysfunction, compares generational differences in selectivity and safety profiles, and provides evidence-based recommendations for infection risk mitigation in clinical practice. Full article

Compound repurposing is an efficient method to save both time and costs by redirecting previously synthesized small molecules towards new biological targets. In this research, we employ computational methodologies to investigate and assess target engagement of small molecules as tyrosine kinase inhibitors (TKIs). Therefore, compounds TKI.2a, TKI.2b, TKI.6, TKI.16, TKI.19, and TKI.21b identified from our earlier research, undergo assessments of molecular similarity, docking studies, and pharmacophore modeling along with those discovered through database searches. Compounds TKI.2a, TKI.2b, TKI.6, and TKI.19 appear to exhibit multi-target tyrosine kinase inhibitory activities against VEGFR-2 (Vascular Endothelial Growth Factor Receptor), RET (proto-oncogene tyrosine–protein kinase receptor), PDGFRα (Platelet-Derived Growth Factor Receptor alpha), EGFR (Epidermal Growth Factor Receptor), and HER2 (Human Epidermal Receptor) receptors. Pharmacophore models were applied for ligand-based virtual screening using defined parameters to discover candidate compounds that exhibit drug-likeness with FDA (Food and Drug Administration)-approved tyrosine kinase inhibitors. Molecular docking studies identified lead compounds for each biological target based on their overall affinity values and established interactions. Compound ChEMBL2170947 was found to be the most promising candidate for the VEGFR-2 receptor, ChEMBL5019511 for PDGFRα, ChEMBL2216869 for EGFR, and ChEMBL3355044 for HER2. Full article

The orphan insulin receptor-related receptor (IRR), in contrast to its homologs from the insulin receptor family, is activated by a mildly alkaline extracellular medium. We have previously demonstrated that IRR activation is defined by two synergistic sites located in the dimeric extracellular domain. Here, we describe artificial mutations in the IRR transmembrane domain that promote receptor activation. First, using molecular modeling based on the NMR-derived structure, we proposed amino acid substitutions that could enhance non-covalent interactions between the transmembrane segments of the IRR dimer. These mutations were subsequently tested for effects on pH sensing by IRR. We showed that double-mutant A938E-A939R was highly phosphorylated at neutral pH and still sensitive to alkaline pH. Remarkably, the double substitution of V929E-G930R resulted in strong basal phosphorylation of the receptor over the pH titration range. Through site-directed mutagenesis, we demonstrated that the transmembrane domain plays a critical role in IRR activation, allowing for targeted control of functioning of the receptor, including its pH sensitivity. Full article

Cancer progression is closely linked to the enhanced uptake of extracellular amino acids, mediated by specific transporters that support biosynthesis, metabolic activity, and energy production through the tricarboxylic acid cycle. By increasing the expression of these transporters, tumor cells secure a continuous amino acid supply that sustains the proliferation, metabolic balance, and activation of major signaling pathways. While most studies have emphasized post-translational control of amino acid transporters, such as phosphorylation, ubiquitination, glycosylation, and palmitoylation, emerging evidence highlights regulatory crosstalk between these transporters and other membrane proteins, including G protein-coupled receptors and receptor tyrosine kinases. This review summarizes the current literature on the receptor-mediated mechanisms governing amino acid uptake and explores how interactions among families of membrane proteins contribute to the regulation of transporter activity. Full article

Background: Cytokine-induced JAK–STAT signaling becomes dysregulated in chronic human diseases, including cancer and autoimmunity, and contributes to immune cell dysfunction. A cytokine-independent approach to activating STAT proteins could “hardwire” pro-survival and effector programs in immune cells to sustain function within diseased tissues. Engineered variants of the herpesvirus saimiri tyrosine kinase interacting protein (TIP) can recruit the SRC family kinase (SFK) LCK to drive STAT phosphorylation and activation. Here, we evaluated the interactome of a TIP-derived, cytokine-independent STAT5 activator and determined whether it could induce STAT5 activation in immune cell lines and primary human CD8+ T cells. Methods: A STAT5 activator (aSTAT5) was characterized by proteomics using affinity purification mass spectrometry (AP-MS) to define its interactome and STAT5 binding specificity. STAT5 phosphorylation was assessed in hematopoietic cell lines and primary human CD8+ T cells. Results: Proteomic analysis confirmed preferential association of aSTAT5 with STAT5 relative to other proteins. In cell-based assays, aSTAT5 induced robust STAT5 phosphorylation in LCK-expressing NK-92 and Jurkat T cells, whereas phosphorylation was not observed in Raji B cells or RAW 264.7 macrophages despite expression of closely related SFKs and STAT5. Cytokine-independent STAT5 phosphorylation supported the viability of NK-92 cells and primary human CD8+ T cells during cytokine withdrawal and preserved the cytotoxic function of CAR T cells. Conclusions: We defined the interactome of a cytokine-independent STAT5 activator and demonstrated its capacity to maintain survival and function in human CD8+ T cells and NK-92 cells. These findings underscore the translational potential of engineered, cytokine-independent STAT5 activation for immune cell therapies. Full article

Caveolin-1 (CAV1) is a 21 kDa Vesicular Integral-membrane Protein essential for the biogenesis of caveolae, invaginations of the plasma membrane that coordinate membrane trafficking, lipid homeostasis, and signal transduction. CAV1 functions as a scaffolding platform that integrates mechanotransduction, endocytosis, and cellular stress responses, thereby modulating vascular integrity, inflammation, metabolism, and tumorigenesis. To comprehensively understand the phosphorylation landscape of CAV1, global phosphoproteomic datasets and their corresponding experimental metadata were systematically curated and integrated from previously published human cellular studies. The phosphorylation sites with the highest detection frequency across these datasets were considered predominant phosphorylation sites. To assess their functional relevance, phosphosites in other proteins (PsOPs) co-regulated with the predominant CAV1 sites, along with their upstream kinases and high-confidence protein–protein interaction partners, were systematically analyzed. Analysis of global human cellular phosphoproteome datasets revealed that tyrosine 14 (Y14) and serine 37 (S37) of CAV1 are the most frequently detected phosphosites across diverse experimental conditions. Notably, many of the co-regulated proteins obtained were associated with carcinogenesis, apoptosis, and cell cycle regulation, including MET and ERBB2. Our analysis revealed SRC, ABL2, ERBB2, ERBB3, LYN, and TEC as potential upstream kinases of CAV1_Y14, whereas CSNK1E and GRK5 were predicted to regulate CAV1_S37. Considering the challenges associated with site-specific interrogation, we employed a global co-regulation analysis approach to characterize CAV1 phosphorylation dynamics. Our findings reveal that key CAV1 phosphosites modulate oncogenic signaling, cytoskeletal remodeling, and membrane organization, providing novel insights into CAV1-mediated cellular functions and its context-dependent role in tumor progression. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a hematological malignancy frequently driven by mutations in the FLT3 gene, particularly internal tandem duplications (FLT3-ITD), which contribute to aberrant cell proliferation and resistance to tyrosine kinase inhibitors (FLT3i). The limitations of current FLT3i therapies, including drug resistance, off-target effects, and poor selectivity, necessitate the development of novel therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) represent a promising approach to achieving degradation of oncogenic proteins. Methods: We developed FLT3-targeting PROTACs based on the previously described compound MA49, with a focus on linker modifications to improve degradation efficiency and pharmacokinetic properties. Results: Among these, compounds MA190 and MA191, containing rigid cyclohexyl-piperidine/piperazine linkers, demonstrate superior degradation of FLT3-ITD in MV4-11 AML cells at nanomolar concentrations, achieving >95% reduction in FLT3-ITD levels, outperforming MA49. In addition to improved kinase selectivity, good solubility, and plasma stability, MA190 and MA191 also exhibit excellent metabolic stability, whereas the predecessor PROTAC MA49 was unstable in microsomal assays. In cellular assays, MA190 and MA191 induce potent apoptosis in FLT3-ITD⁺ AML cells but have minimal effects on cells with wild-type FLT3. Proteomics reveal that MA191 also degrades MAPK14 (p38α), a kinase upregulated in leukemia, in addition to FLT3. Conclusions: Dual targeting of FLT3-ITD and MAPK14 enhances proapoptotic signaling without any cytotoxic effect on normal human HEK293 cells. The co-inhibition using MA191 or a combination of doramapimod (a MAPK14 inhibitor) with a non-degrading FLT3 inhibitor result in greater caspase-3 activation than either treatment alone. This synergistic effect can be a therapeutic advantage, as several oncogenic drivers are switched off simultaneously by MA191. Full article

Background: Evaluation of gene-level copy number variants (CNVs) for diagnosis and therapeutic decision making has become standard of care with next-generation sequencing (NGS), immunohistochemistry (IHC), and/or fluorescence in situ hybridization (FISH) being used to detect gene amplifications/deletions in tumor tissue. In contrast to most solid tumors, CNS cancers are challenging to evaluate by resection and/or biopsy due to the associated risks with invasive brain surgery that can also result in death or associated morbidity and therefore alternate methods are required.Methods: This study presents the analytical validation of using quantitative PCR (qPCR) to detect gene CNVs directly from cerebrospinal fluid (CSF)-derived DNA and from the Ascent^TM low-pass whole genome sequencing (LP-WGS) libraries, demonstrating concordance with the gold standard of NGS/IHC/FISH used in tumor tissue. Results: The analytical sensitivity of qPCR to detect gene amplification calls for ERBB2 (erb-b2 receptor tyrosine kinase 2) was demonstrated to be 100% and that of EGFR (epidermal growth factor receptor) was 83%, with specificities of 96% and 100%, respectively. The analytical sensitivity of qPCR to detect gene deletions for CDKN2A/2B (cyclin-dependent kinase inhibitor 2A/2B) was 60% and that for MTAP (methylthioadenosine phosphorylase) was 100% with a specificity of 100% for all three genes. Ascent^TM was demonstrated to have a higher sensitivity (100%) when compared to qPCR for the same genes evaluated and demonstrated 100% positive agreement and 100% negative agreement with known CNV status. Conclusions: The results demonstrate that given the paucity of cells in CSF limiting the use of IHC and FISH, qPCR and Ascent^TM provide highly sensitive, novel, minimally invasive methods for the evaluation of gene copy number (CN) status to inform the diagnosis and management of CNS cancers. Full article

Preeclampsia is a pregnancy-specific multisystem disorder and a major cause of maternal and perinatal morbidity and mortality worldwide. This narrative review summarizes current evidence on the principal risk factors and pathophysiological mechanisms involved in its development. The disease is best explained by the two-stage model: in stage 1, inadequate trophoblast invasion and incomplete spiral artery remodeling lead to placental hypoperfusion, hypoxia, and oxidative stress; in stage 2, the hypoxic placenta releases anti-angiogenic and pro-inflammatory factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which trigger systemic endothelial dysfunction and the maternal clinical syndrome. The review highlights the central role of angiogenic imbalance, immune dysregulation, and chronic inflammation in disease progression. Particular emphasis is placed on maternal risk factors such as primiparity, advanced maternal age, obesity, diabetes mellitus, chronic hypertension, multiple pregnancy, prior preeclampsia, genetic susceptibility, and epigenetic regulation. We also emphasize the contribution of microRNAs in relation to placental hypoxia, trophoblast invasion, angiogenesis, endothelial injury and microchimerism to the development of preeclampsia. The review also examines the role of T helper 1 (Th1)/Th2/Th17/regulatory T cells (Treg) imbalance and uterine natural killer cell dysfunction at the maternal–fetal interface. Improved understanding of these interconnected mechanisms may support earlier diagnosis, better risk stratification, and the development of targeted preventive and therapeutic strategies. Full article

Background/Objectives: Bradyarrhythmias are an under-recognized component of cancer therapy-related cardiovascular toxicity. As survivorship improves and exposure to targeted and immune therapies increases, clinicians increasingly face clinically relevant sinus node dysfunction and atrioventricular (AV) conduction disease that may interrupt otherwise effective oncologic treatment. We aimed to synthesize evidence on the incidence, phenotype, mechanisms, and management of bradyarrhythmias across major anticancer drug classes. Methods: We performed a narrative review of PubMed and major clinical guidelines, prioritizing prospective trials and large observational cohorts for incidence estimates, and case reports/series for phenotype and management details. Regulatory prescribing information and pharmacovigilance datasets were consulted to complement trial data. Evidence was organized by drug class and prototypical agents. Results: Bradyarrhythmias ranged from transient sinus bradycardia to high-grade atrioventricular block requiring pacing. The most severe phenotype was associated with immune checkpoint inhibitor-related myocarditis, whereas ALK inhibitors, thalidomide, antimetabolites—particularly 5-fluorouracil—and taxanes showed more reproducible signals for sinus bradycardia. Bradyarrhythmic events were also described with proteasome inhibitors, BTK (Bruton tyrosine kinase) inhibitors, anthracyclines, platinum compounds, high-dose cyclophosphamide, corticosteroids, and other agents, but the strength of evidence varied from regulatory or cohort-based data to isolated case reports. Conclusions: Bradyarrhythmias during cancer therapy are heterogeneous but clinically consequential. Recognition of class-specific patterns, proactive ECG/electrolyte monitoring, and context-specific management (e.g., drug interruption/dose modification, pacing when indicated, risk-factor control) can minimize therapy interruption while maintaining oncologic efficacy. Full article

Background: Branch retinal vein occlusion (BRVO) represents a segmental retinal ischemic disorder characterized by localized oxidative–inflammatory activation. While redox-driven cytokine responses have been described in central retinal vein occlusion, their role in BRVO-specific macular edema and treatment responsiveness remains unclear. This study investigated whether novel redox-related inflammatory mediators in the aqueous humor are associated with disease severity and structural response to anti-vascular endothelial growth factor (VEGF) therapy in BRVO. Methods: Aqueous humor samples were collected from 30 treatment-naïve patients with BRVO and 19 control patients. Levels of VEGF and the novel redox-related inflammatory factors FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXCL-16, and endocan-1 were measured by suspension array, and the severity of macular edema was evaluated by measuring central macular thickness and neurosensory retinal thickness (TNeuro) by spectral-domain optical coherence tomography. Therapeutic response was assessed one month after intravitreal ranibizumab injection (IRI). Results: Aqueous levels of VEGF, Flt-3L, and endocan-1 were significantly higher in the BRVO group, and levels of Flt-3L, CXCL-16, and endocan-1—markers associated with oxidative endothelial damage and leukocyte recruitment—correlated significantly with each other and with aqueous flare values. Notably, baseline Flt-3L levels significantly correlated with the reduction in TNeuro, suggesting that this redox-sensitive signaling molecule is a potential biomarker for treatment sensitivity. Conclusions: These findings suggest that novel inflammatory factors, potentially driven by oxidative-nitrosative stress, play a pivotal role in the pathophysiology of BRVO. Baseline Flt-3L may serve as a predictive biomarker for structural responsiveness to anti-VEGF therapy in BRVO, suggesting that oxidative–inflammatory signaling contributes not only to disease severity but also to therapeutic heterogeneity. Full article

Sorafenib is a first-line tyrosine kinase inhibitor for malignant tumor treatment, yet its clinical application is greatly restricted by unavoidable cardiotoxicity. Astragaloside IV is a natural compound with prominent cardiovascular protective effects. We first carried out modeling studies including network pharmacology, human proteome microarray screening, molecular docking, and molecular dynamics simulation. Network pharmacology highlighted the hypoxia-inducible factor-1 signaling pathway as a key route; the integrated approach further identified signal transducer and activator of transcription 3 as a novel direct binding target of astragaloside IV with high binding stability. In a mouse model of chronic sorafenib-induced cardiotoxicity, astragaloside IV significantly improved cardiac function, and attenuated myocardial fibrosis, oxidative damage, and cardiomyocyte apoptosis. Mechanistically, astragaloside IV reduced the expression of signal transducer and activator of transcription 3 and hypoxia-inducible transcription factor-1α, and elevated the expression of B-cell lymphoma 2. In cellular experiments, astragaloside IV protected HL-1 cardiomyocytes against sorafenib-induced cytotoxicity and apoptosis through the same signaling pathway. This study confirms that astragaloside IV alleviates sorafenib-induced cardiotoxicity by inhibiting cardiomyocyte apoptosis via targeting the signal transducer and activator of transcription 3/hypoxia-inducible transcription factor-1α/B-cell lymphoma 2 pathway, providing a promising strategy for clinical prevention of chemotherapy-related cardiac injury. Full article

Ovarian dysfunction resulting from metabolic or toxic injury is characterized by follicular depletion, stromal remodeling, oxidative stress, and endocrine dysregulation. Placenta-derived mesenchymal stem cells (PD-MSCs) have been proposed as a potential therapeutic approach due to their paracrine factors, including placental growth factor (PlGF). However, the pathways through which PD-MSCs exert protective effects on the ovary remain insufficiently defined. In this study, we examined whether PD-MSC transplantation ameliorates ovarian injury in a thioacetamide (TAA)-induced ovarian insufficiency model and explored the signaling events potentially associated with this response. Female rats were administered TAA for 12 weeks, and PD-MSCs were transplanted at week 8. We assessed ovarian morphology, fibrosis, oxidative stress markers, hormonal profiles, and follicle development. Complementary in vitro experiments using TAA-treated KGN granulosa-like cells were performed to investigate potential mechanistic associations. PD-MSC transplantation improved ovarian architecture, reduced collagen deposition, enhanced follicle growth, and mitigated oxidative stress. These changes were accompanied by increased PlGF expression and enhanced activation of fms-like tyrosine kinase-1 (Flt-1), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant pathways. In vitro, PD-MSCs coculture similarly attenuated oxidative stress and partially improved mitochondrial membrane potential in damaged KGN cells. Together, these findings suggest that PD-MSCs ameliorate ovarian structural damage and oxidative stress in TAA-induced injury, potentially through paracrine mechanisms partly involving PlGF/Flt-1-associated antioxidant signaling. This work supports the therapeutic potential of PD-MSCs for metabolic or toxicant-induced ovarian insufficiency while underscoring the need for further studies to fully delineate the specific contribution of PlGF and its interaction with downstream antioxidant pathways. Full article

Desmoid tumors (DTs) are rare, fibroblastic neoplasms characterized by locally aggressive behavior, unpredictable clinical trajectories, and a substantial impact on patient quality of life despite minimal metastatic potential. Although the underlying biology of DTs remains incompletely defined, associations with prior trauma, hormonal exposure, and aberrant Wnt/β-catenin signaling—including somatic CTNNB1 mutations and germline APC alterations seen in Familial Adenomatous Polyposis—have informed both historical and contemporary therapeutic approaches. Management strategies have evolved from surgery-dominant paradigms toward individualized, multimodal treatment algorithms emphasizing systemic medical therapy, as reflected in current NCCN and Desmoid Tumor Working Group recommendations. This review focuses on the medical management of DTs, tracing the evolution from earlier noncytotoxic therapies, including antiestrogen agents such as tamoxifen, to modern systemic options supported by prospective and randomized data. We summarize available evidence for four principal classes of medical therapy: nonsteroidal anti-inflammatory drugs, cytotoxic chemotherapy (with particular emphasis on anthracycline-based regimens), tyrosine kinase inhibitors—most notably sorafenib—and the emerging class of γ-secretase inhibitors. Recent phase III data supporting the efficacy of nirogacestat highlight a shift toward mechanism-based, targeted treatment with demonstrable benefits in progression-free survival, symptom control, and patient-reported outcomes. Collectively, these advances underscore a maturing therapeutic landscape in which systemic therapy plays a central role in disease control, symptom palliation, and preservation of function for patients with advanced desmoid tumors. Full article

Background: Accurate prognostic stratification is essential for clinical decision-making in metastatic renal cell carcinoma (mRCC). Although the International Metastatic RCC Database Consortium (IMDC) model is widely used, its discriminatory capacity may be limited in specific clinical subpopulations. The Royal Marsden Hospital (RMH) score, based on serum albumin, lactate dehydrogenase, and the number of metastatic sites, has not been evaluated as a prognostic tool in patients with de novo mRCC receiving first-line tyrosine kinase inhibitor (TKI) therapy. Methods: We retrospectively analyzed the data of 149 patients with de novo metastatic renal cell carcinoma who received first-line TKI therapy (pazopanib, sunitinib, or cabozantinib) at two tertiary oncology centers in Turkey. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: The median OS and PFS were 23.1 months (95% CI: 19.4–26.8) and 9.4 months (95% CI: 7.0–11.8), respectively. The OS showed a stepwise decline across RMH risk groups, ranging from 40.7 months in patients with an RMH score of 0 to 8.6 months in those with an RMH score of 3. In the multivariate analysis, the RMH score (HR 1.29, 95% CI: 1.03–1.61; p = 0.026) and sarcomatoid differentiation (HR 2.01, 95% CI: 1.09–3.72; p = 0.025) were independently associated with worse OS. The IMDC score did not retain independent prognostic significance (p = 0.129). The RMH score was not significantly associated with PFS after multivariable adjustment, and the IMDC score was not significantly associated with PFS in univariate analysis and was therefore not entered into the multivariable PFS model. Conclusions: The RMH score independently predicted overall survival in patients with de novo mRCC receiving first-line TKI therapy, whereas the IMDC score did not retain independent prognostic significance in this cohort. Given its simplicity and reliance on objective parameters, the RMH score may provide complementary prognostic information in this patient population; however, external validation in independent cohorts is required before broader clinical implementation can be considered. Full article