Search Results (727)

Background/Objectives: The therapeutic arsenal for axial spondyloarthritis (axSpA) now includes multiple biologic and targeted synthetic DMARDs (b/tsDMARDs). Following the failure of an advanced therapy, clinicians may either cycle (switch to another drug with the same mechanism of action) or swap (switch to a drug with a different mechanism). The optimal strategy remains unclear. This study aimed to compare the real-world effectiveness of cycling versus swapping in axSpA patients. Methods: This mono-centric, retrospective observational study included axSpA patients who failed ≥1 line of b/tsDMARD therapy. Subsequent treatment courses were classified as cycling (CG) or swapping (SG). Drug retention rates were compared using Kaplan–Meier analysis. A Cox proportional hazards model identified factors associated with treatment persistence. Results: We analyzed 156 patients (59 radiographic, 97 non-radiographic), corresponding to 343 treatment courses (CG: 213; SG: 130). Retention rates at 1, 2, and 3 years were 62.7%, 49.3%, and 39.2% (CG) versus 69.8%, 47.8%, and 31.8% (SG) (HR: 1.13, 95% CI: 0.83–1.53; p = 0.442). In the multivariable model, only a more recent prescription year was associated with higher discontinuation risk (HR: 1.08 per year, 95% CI: 1.03–1.12; p < 0.001). Conclusions: In this real-world cohort, cycling and swapping strategies demonstrated comparable treatment persistence over three years following advanced therapy failure in axSpA. The choice of subsequent therapy should be individualized, as no strategy proved superior. Full article

Background and purpose: With the emergence of HER2 antibody–drug conjugates, new treatment options have been provided to patients with breast cancer, especially those with low HER2 expression. The biology of HER2-low breast cancer is not yet well understood. This study included the largest sample size thus far to explore the different clinicopathological characteristics, pathological complete responses (pCRs), and prognoses of HER2-low cancers compared with those of HER2-0 and HER2-high cancers. Methods: This study included 14,642 female breast cancer patients and 544 female patients with breast cancer from the TCGA. A logistic regression model was used to determine predictive factors for pCR. K–M curves and log-rank tests were applied to determine OS and DFS. Results: Compared with HER2-0 and HER2-high patients, the HER2-low group had a greater proportion of members in the N1–2 group and with grade I–II disease, a tumor size ≤ 20 mm, a Ki-67 index ≤ 14%, and invasive cancer. Among the HR+ subtypes of the HER2-low subgroup, the distribution of pathological types, pN stages, Ki-67 values, and tumor sizes significantly differed. In the triple-negative breast cancer subtypes of HER2-low patients, the distributions of age, pathological type, histological grade, and Ki-67 index were significantly different. The Ki-67 index and pathological type were independent factors that affected the pCR of the axillary lymph nodes. HER2 expression was mostly driven by patients who switched to or from HER2-low expression after neoadjuvant chemotherapy. The pCR rate and survival did not differ markedly across the three HER2 subtypes. Conclusions: HER2-low breast cancer is distinct from HER2-0 and HER2-high breast cancer with respect to clinicopathological characteristics. HER2-low breast cancer is highly unstable during chemotherapy; therefore, reevaluating HER2 expression may provide new treatment strategies for some patients after neoadjuvant therapy. Full article

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. 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

Rational design of smart nanogels for drug delivery requires molecular-level understanding of how structural evolution and drug–carrier interactions couple under multiple stimuli. Here, pH/temperature dual-responsive P(NIPAM-co-AAc) nanogels containing 0–20 mol% AAc were investigated by combining all-atom molecular dynamics simulations with in vitro ibuprofen (IBU) release experiments under acidic (pH 2.75) and weakly basic (pH 7.4) conditions at 298 and 310 K. The simulations identified CA-5-L-298 as the most retained system, with the lowest IBU diffusion coefficient (0.92 × 10⁻⁷ cm² s⁻¹) and no dissociated molecules under the adopted criterion, whereas CA-15-H-310 showed the highest diffusivity (8.61 × 10⁻⁷ cm² s⁻¹) and dissociated fraction (22%). Consistently, in the urea-free release experiments, CA-15-H-310 exhibited the highest 24 h cumulative release (69.4%), while CA-5-L-298 remained among the low-release systems (35.9%). Pore analysis, hydrogen-bond statistics, MM/PBSA calculations, and urea-competition experiments together support the view that IBU release is influenced by both mesh steric sieving and polymer–drug affinity switching, and correlation analysis provides quantitative support for linking the MD descriptors with the experimental release behavior. Overall, the simulations reproduce the qualitative trends in the experiments and provide a molecular-level framework for rationalizing the observed release behavior in dual-responsive nanogels. Full article

Background/Objectives: KRAS G12C mutations define a clinically actionable subset of solid tumors, particularly non–small cell lung cancer. Clinical responses to approved covalent inhibitors remain limited by intrinsic and acquired resistance, highlighting the need for structurally distinct inhibitor scaffolds to expand therapeutic options. The objective of this study was to identify novel covalent binders targeting the KRAS G12C switch-II pocket through large-scale in silico screening and experimental validation. Methods: More than 1.9 million small molecules from diverse commercial libraries were screened using covalent docking, followed by multi-stage refinement incorporating molecular dynamics simulations, MM/GBSA free-energy estimation, and cancer-focused QSAR modeling. Results: This integrated workflow yielded 50 prioritized compounds spanning several chemically distinct scaffold classes. These candidates displayed favorable predicted binding energetics, stable ligand-protein interactions over extended simulation timescales, and low structural similarity to clinically approved KRAS G12C inhibitors sotorasib and adagrasib. Benchmarking against these clinical agents, using identical computational parameters, yielded comparable predicted binding energies for several candidate molecules. In cellular NanoBRET target-engagement assays, selected scaffolds, including K788-7251 and AN-989/14669131, exhibited sub-micromolar engagement of KRAS G12C with minimal endothelial cytotoxicity. Conclusions: Collectively, these findings identify structurally distinct, KRAS G12C inhibitor chemotypes and provide tractable starting points for the development of next-generation targeted therapies. Full article

Introduction: Despite proven efficacy of anti-TNF agents in inflammatory bowel disease, primary non-response affects up to one-third of patients, while secondary loss of response occurs at 13–21% per patient-year, often requiring dose optimization or switching to alternative advanced therapies. Methods: The present single-center cohort study at the University Hospital of Ioannina included biologic-naïve patients receiving anti-TNF therapy as their first biologic treatment. First anti-TNF treatment failure was defined as discontinuation due to persistent IBD activity despite maximal dose optimization (infliximab 10 mg/kg every 4 weeks, adalimumab 40 mg weekly). Patients with measurable anti-drug antibodies prior to anti-TNF dose intensification or discontinuation were excluded. Of 528 anti-TNF-treated patients, 286 (173 with CD, 113 with UC) met the inclusion criteria and were included in the final statistical analysis. Results: Anti-TNF failure occurred in 32.7% of Crohn’s (CD) and 32.9% of ulcerative colitis (UC) patients. Multivariable Cox regression identified complicated phenotype (stricturing or/and penetrating CD; HR = 1.9, p = 0.032) and concomitant corticosteroid use at anti-TNF initiation (HR = 2.03, p = 0.012) as independent predictors of anti-TNF failure in CD. Age at CD diagnosis showed a trend for statistical significance (HR = 1.02, p = 0.061), and after stratification, age at diagnosis ≥ 40 years conferred higher risk (HR = 1.93, p = 0.016), alongside persistent effects of complicated phenotype (HR = 1.83, p = 0.027) and corticosteroid use (HR = 2.01, p = 0.013). In UC patients, female sex predicted anti-TNF failure (HR = 2.13, p = 0.025). IBD-related bowel resection occurred in 26.6% of patients with CD and in 5.3% of patients with UC. Conclusions: Anti-TNF failure remains common despite optimization. Identifying immunogenicity-independent predictors may enable personalized treatment strategies and improve outcomes. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

Breakthrough invasive fungal infections (bIFIs) are a challenging serious complication in high-risk hematologic patients and allogeneic hematopoietic stem cell transplantation recipients that may negatively impact their outcome. Despite advances in antifungal prophylaxis, diagnostics, and supportive care, bIFI occurrence reflects a complex interaction between host immunosuppression, emergence of resistant pathogens and pharmacological variables, including subtherapeutic drug exposure. Candida spp. have shifted towards non-albicans yeasts, whereas breakthrough mold infections more frequently involve non-fumigatus Aspergillus, Mucorales, Fusarium spp., and Scedosporium/Lomentospora spp. Early clinical recognition, rapid therapy escalation, aggressive diagnostic investigation, a switch to liposomal amphotericin B-based regimens in patients on azole prophylaxis, and therapeutic drug monitoring are essential to improve outcomes. Reducing the growing global burden of bIFIs will also require improved access to high-quality diagnostics and strengthened educational and stewardship efforts that prioritize antifungal resistance as an urgent health concern. Full article

Introduction: Sequencing therapy for Crohn’s disease (CD) is currently being intensively discussed due to the development of novel drugs and lack of standardized criteria for drug positioning in first- and further-line treatment. The aim of this study was to compare the efficacy of a second-line advanced therapy in Romanian patients with CD who have failed an anti-TNF agent. Methods: We performed a multicenter retrospective study that included adult patients with CD who had secondary loss of response after an initial response with an anti-TNF drug. The main outcome was clinical remission at 12 weeks of second-line treatment (CDAI < 150). The secondary outcomes included clinical response (decrease in CDAI ≥ 70 points), persistence of therapy at 1 year and rates of adverse events. Results: From 2008 to 2024, 216 patients were either switched to another anti-TNF or swapped to another therapeutic class, due to the failure of a first anti-TNF drug. Secondary lines of treatment included infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), ustekinumab (UST). The highest rate of clinical remission (81%) was obtained with the sequence ADA-IFX in 26/32 (81%) patients and ADA-UST in 62/82 (76%) patients, followed by IFX-UST in 22/33 (67%) and IFX-ADA 34/51 (67%). Persistence in therapy at 1 year was better for the sequence ADA-UST (73%) and IFX-UST (67%) and ADA-IFX (63%) compared to IFX-ADA (59%) and IFX-VDZ (44%) (p < 0.001). Conclusions: There were significant baseline differences between the treatment groups, so this study represents an unadjusted comparison between the results obtained with different biologics in second-line treatment for Crohn’s disease. In patients with CD who have failed a first anti-TNF, the highest rate of clinical remission at 12 weeks was obtained with second-line IFX and UST whilst vedolizumab showed lower efficacy. UST demonstrated the most favorable long-term treatment persistence at 1 year. Full article

This work develops a fuzzy piecewise fractional derivative (FPFD) model for cancer-immune-angiogenesis dynamics under uncertainty. Five fuzzy state variables track tumor cells, immune effectors, vessel density, oxygen, and drug concentration. We employ fuzzy triangular numbers with $\alpha$-cut interval arithmetic using constrained fuzzy arithmetic model parametric uncertainty, with numerical values. Oxygen-dependent carrying capacity follows a Hill-type function; hypoxia-induced angiogenesis follows a decreasing Michaelis–Menten function. The model transitions at $t_1=50$ days from memoryless fuzzy classical derivative to fuzzy ABC fractional derivative of order $\psi$. The transition time $t_1=50$ days is biologically justified based on experimental observations of the angiogenic switch in solid tumors, which typically occurs within 4–8 weeks post-inoculation. Positivity, boundedness, Lipschitz continuity, existence, and uniqueness of fuzzy solutions are proved via Banach fixed-point theorem in a weighted norm. A basic reproduction number interval ${\mathcal{R}}_0=[{\underline{\mathcal{R}}}_0,{\overline{\mathcal{R}}}_0]$ is derived; local and global stability conditions are established for disease-free and endemic equilibria using fuzzy differential inclusions. Global sensitivity analysis using latin hypercube sampling with $N=500$ samples explores the range of possible outcomes across the fuzzy parameter support. In the numerical implementation, we use a fourth-order fuzzy Runge–Kutta method (Phase I), and a fractional Adams–Bashforth–Moulton predictor-corrector method (Phase II), ensuring preservation of fuzzy number characteristics. Full article

Background and Clinical Significance: Patients with a left ventricular assist device (LVAD) are at risk of ventricular arrhythmias, which are generally hemodynamically tolerated if they occur. In such cases, patients may experience painful implantable cardioverter-defibrillator (ICD) shocks. Case Presentation: A 71-year-old patient with a history of dilated cardiomyopathy caused by a phospholamban (PLN) gain-of-function mutation, with a primary prevention ICD and an LVAD, presented with multiple ICD shocks which she experienced as painful and traumatic. She was found to have ongoing ventricular fibrillation with apparent hemodynamic stability. Conversion to sinus rhythm was achieved through intravenous administration of antiarrhythmic drugs followed by external defibrillation using stacked shocks. Due to the traumatic nature of the shocks, the shock function of the ICD was turned off. Nearly two months later, the patient presented for a second time and was again found to have ventricular fibrillation which had been present for at least six weeks. Conversion to sinus rhythm was unsuccessful and the patient was discharged to her home with an advanced care plan and her LVAD was deactivated. The patient died two months later. Conclusions: Patients with an LVAD can remain hemodynamically stable for prolonged periods of time during ventricular arrhythmias. ICD shocks are therefore mostly experienced as painful and even traumatic. Therefore, the routine use of ICD shock therapy in patients with an LVAD should be reconsidered. Adjustment of ICD programming to higher rates and longer detection may be warranted. Further investigation is warranted regarding a switch to devices with an alarm function rather than therapies for tachyarrhythmias. Full article

The safe and precise regulation of therapeutic gene expression remains a major challenge for mammalian synthetic biology and cell-based therapies. Many existing inducible systems rely on non-mammalian regulatory components or ligands with limited clinical compatibility. Designer receptors exclusively activated by designer drugs (DREADDs) offer a human G protein-coupled receptor (GPCR)-based framework for pharmacological control of intracellular signaling, yet their application as clinically relevant gene-regulation platforms remains underexplored. Here, we report a clozapine-responsive gene switch that couples a designer GPCR to signaling-dependent transcriptional control. By linking clozapine-activated receptors to cyclic adenosine monophosphate (cAMP)- or calcium-responsive synthetic promoters, receptor activation is converted into robust transgene expression across a broad dynamic range, with sensitivity to sub-nanomolar to low-nanomolar clozapine concentrations. In vivo, alginate-encapsulated reporter cells implanted in C57BL/6J mice responded to systemic or local clozapine administration with efficient secretion of a reporter protein, achieving robust induction at low daily doses (0.3 mg/kg) following either oral administration or local delivery. Together, these results establish a human GPCR-based clozapine-responsive gene switch that integrates regulation by a clinically used small molecule with modular transcriptional outputs, providing an additional approach for pharmacologically controllable gene expression in mammalian cells and in vivo. Full article

G protein-coupled receptor kinase 5 (GRK5) is an important therapeutic target involving cardiovascular diseases, cancer, and inflammatory disorders. However, the features of its activation as an essential function regulation process have been poorly understood, limiting related drug development. The work utilizes a molecular dynamics simulation coupled with an interpretable machine learning model to identify key structure and dynamics determinants distinguishing the active and inactive states of GRK5. Benefiting from the unbiased and data-driven framework, the work reveals that the active site tether (AST) is a dominant activation-associated feature, acting as a conformational switch that regulates kinase domain movements. Beyond this canonical element, we also uncover two previously underappreciated structure modules contributing to GRK5 activation, such as the coupling interaction between the α10/α11 helix interface with the N-terminal lipid-binding domain (NLBD) in the active state, and the α5 helix region that facilitates large-scale RH domain reorientation. Conformation dynamics analyses further indicate that GRK5 activation involves disruption of the interdomain interactions and interaction coupling between AST, αN-helix, kinase domain N-lobe, NLBD, and α10/α11 hinge. These observations provide valuable insights into understanding the GPK5 activation mechanism and also highlight the power of machine learning in capturing functionally conformational changes, and in turn offering a methodological guideline for the studying of the protein function mechanism. Full article

Azobenzene derivatives constitute a prototypical class of photoresponsive molecular switches with broad utility in synthetic chemistry and biomedical research, owing to their distinctive physicochemical properties. Recent molecular engineering has enabled red-shifted photoisomerization into the visible biological window, thereby enhancing tissue penetration and reducing phototoxicity. This review systematically surveys contemporary advances in azobenzene-based photoswitchable systems with a specific focus on medicinal chemistry and photopharmacology. Emphasis is placed on rational design strategies—including ortho-functionalization, heteroaryl substitution, and bridged diazocine scaffolds—that improve photophysical properties, thermal stability, and photostationary state distributions. Particular attention is devoted to the integration of these novel azobenzene motifs as privileged pharmacophores, highlighting their emerging therapeutic applications in neurological modulation, enzyme inhibition, receptor targeting, and oncology, as well as their translational potential in drug discovery and photodynamic therapy. Full article