Vascular disruption-triggered physiological cascade enables a therapeutic window for fibrin-hypoxia dual-targeting nanomedicines in solid tumors.

Engineering nanomedicine for STING pathway activation: Advancing cancer immunotherapy.

Temporal dynamics of cognitive and non-cognitive behavioral phenotypes and early redox alterations in the intracerebroventricular streptozotocin-rat model of sporadic Alzheimer's disease.

Psoriatic arthritis (PsA) is not an isolated joint disease, but rather an expression of asystemic inflammatory disorder that affects multiple domains along the psoriatic disease continuum. New findings on the pathophysiology of the interleukin (IL)-23/IL-17 axis and the role of enthesitis, as well as the identification of subclinical transition phases between psoriasis and manifest arthritis, are fundamentally changing our understanding of psoriatic disease. The concepts of 'therapeutic windows' and 'interception' suggest that early targeted interventions could have alasting positive effect on the progression of the disease. At the same time, clinical reality requires adifferentiated therapy strategy that considers comorbidities and is oriented towards the individual patient. With awide range of targeted therapies and an improved understanding of the disease's pathophysiology, personalized treatment strategies are becoming the focus of therapy management.

Bletilla striata polysaccharide as a dual-hit biologic: Orchestrating pyroptosis inhibition and trained immunity for chronic wound resolution.

Twice-daily dosing of Dolutegravir is approved for adults with HIV and integrase strand transfer inhibitor resistance, but not for children. Population pharmacokinetic modeling and simulations identified a weight-tiered twice-daily dose for children, predicted to yield dolutegravir exposures within the therapeutic window and provide similar efficacy and safety as seen in adults with HIV-1 and first-generation integrase strand transfer inhibitor resistance.

Synthesis of silicon (IV)-based Phthalocyanine N3-nucleoside conjugates with absorption, aggregation, solvent effects, and in vitro anticancer activity.

Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxicities. Oxidative hepatic metabolism of zongertinib invitro is principally driven by cytochrome P450 (CYP) 3A. It is necessary, therefore, to assess the effect of a strong CYP3A inhibitor on the pharmacokinetics of zongertinib in humans. This study investigated the effect of multiple oral doses of the strong CYP3A inhibitor and regulatory-recommended probe inhibitor of P-glycoprotein (P-gp), itraconazole, on the pharmacokinetics of a single dose of zongertinib in healthy male participants. This open-label, two-period, fixed-sequence, clinical drug-drug interaction study assessed the pharmacokinetics of a 15 mg oral dose of zongertinib in the absence and presence of multiple oral doses of itraconazole. The extent of drug-drug interaction was estimated using the adjusted geometric mean (gMean) ratios (90% confidence intervals [CIs]) for the test (T) treatment (zongertinib and itraconazole) vs. the reference (R) treatment (zongertinib alone). Primary endpoints were the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and the maximum measured plasma concentration (Cmax) of zongertinib. The secondary pharmacokinetic endpoint was AUC for zongertinib from time 0 to the last quantifiable time point (AUC0-tz). Sixteen participants received zongertinib alone (Period 1, R), followed by co-administration with itraconazole (Period 2, T). In terms of zongertinib exposure, the gMean ratio of T to R was 141.2% (90% CI: 126.3-157.7%) for AUC0-∞, 142.8% (90% CI: 126.0-161.9%) for AUC0-tz, and 126.9% (90% CI: 106.6-151.0%) for Cmax. Co-administration with itraconazole resulted in a mild increase in total exposure to zongertinib that was not considered clinically relevant given its wide therapeutic window. These data indicate that the approved 120 mg dose of zongertinib can be administered without dose adjustment in combination with CYP3A/P-gp inhibitors.

Clinical indications and timing of antenatal corticosteroids: A single-centre retrospective study

Pathological platelet activation is central to cardiovascular disorders. Glycoprotein VI (GPVI), a pivotal collagen receptor, is a promising antithrombotic target. While earlier studies focused on the downstream effects of peroxisome proliferator-activated receptor γ (PPARγ) ligands, we recently identified the proximal PPARγ-Src family kinase (SFK) interaction as a key regulatory node. KR-62980 is a novel non-thiazolidinedione (non-TZD) PPARγ modulator designed to minimize traditional TZD-associated adverse effects. Here, we investigated whether KR-62980 operates through this "proximal mechanism." We found that KR-62980 dose-dependently inhibited collagen-induced human platelet aggregation in both washed platelets and platelet-rich plasma. Notably, KR-62980 exhibited a predominant sensitivity toward the collagen-GPVI axis compared to thrombin-induced protease-activated receptor signaling. Mechanistically, KR-62980 targeted the top of the GPVI signaling hierarchy by disrupting the physical and functional association between PPARγ and SFKs (Lyn and Fyn). This blockade suppressed SFK autophosphorylation and dismantled the LAT signalosome, preventing the recruitment of Gads, SLP-76, Btk, and PLCγ2. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPARγ-mediated antiplatelet action, regardless of the agonist's chemical structure. In vivo, oral administration of KR-62980 significantly prolonged thrombotic occlusion time in a mouse carotid artery thrombosis model. Importantly, at therapeutic doses, KR-62980 did not significantly affect tail bleeding time, demonstrating a favorable safety profile with a wide therapeutic window. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPARγ-mediated antiplatelet action and suggest that KR-62980 is a promising candidate for safe antithrombotic therapy.

Discovery of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine derivatives as potent PI3Kδ/BTK dual-target inhibitors for the treatment of B-cell lymphoma.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), execute essential functions in neural development, homeostasis, and repair. However, their persistent or dysregulated activation is a hallmark of diverse neurological disorders, where they transition from protective sentinels to drivers of chronic neuroinflammation and tissue damage. This duality has spurred the development of therapeutic strategies aimed not merely at suppressing microglial activity, but at fundamentally resetting the CNS immune landscape. Here, we review the paradigm of transient microglial depletion followed by endogenous repopulation, a strategy that effectively replaces a dysfunctional or pathologically primed microglial compartment with a rejuvenated cohort. Emerging evidence demonstrates that repopulated microglia exhibit a distinct phenotype-characterized by attenuated inflammatory profiles, upregulated homeostatic and neurotrophic gene expression, and enhanced phagocytic capacity-thereby conferring neuroprotection and promoting functional recovery across preclinical models of acute injury, neurodegeneration, and demyelinating disease. We critically evaluate the pharmacological and genetic tools used to achieve depletion, synthesize the context-dependent outcomes across disease spectra, and discuss the mechanistic basis for the superior therapeutic profile of the repopulation phase. Finally, we address the key translational challenges-including therapeutic windows, age- and sex-dependent effects, and the gap between rodent models and human biology-that must be overcome to transform this innovative strategy from a powerful experimental tool into a viable clinical modality for reprogramming CNS immunity.

The duality of testosterone in glioblastoma: From targeted therapy to modulation of the tumor microenvironment and neuroprotection.

The development of rheumatoid arthritis (RA) is amultistage process that often begins decades before the first joint symptoms appear. The first critical turning point is the loss of immunological tolerance [1]. Under the influence of chronic stimuli on the mucous membranes increased citrullination of proteins can occur [1]. Particularly in carriers of the shared epitope, the immune system recognizes these altered proteins as "foreign" and thereby produces anticitrullinated protein antibodies (ACPA), marking the onset of systemic autoimmunity [1, 2]. This primordial phase thus represents apotential therapeutic window of opportunity for preventive interventions [3]. In particular, smoking in conjunction with the presence of the shared epitope is associated with an up to 21-fold increased risk for ACPA-positive individuals [4, 5]. Other modifiable environmental factors such as smoking, obesity, diet and periodontitis also contribute to an increased risk of RA development, and thus represent the first key initial focus of primary prevention. In secondary prevention, recent interventional studies in high-risk individuals (ACPA/RF-positive with arthralgia) have shown mixed results: While hydroxychloroquine (STOP-RA) [8] remained ineffective, methotrexate (TREAT EARLIER) [9] was able to delay disease progression, particularly in ACPA-positive patients [9, 10]. Abatacept has so far proven to be the most promising approach (APIPPRA and ARIAA), with asignificant reduction in the progression rate and lasting effects well beyond the treatment period. [11, 12].. The ARIAA long-term data also demonstrate that just 6months of abatacept treatment delays the development of RA for up to 5years, with IgA-ACPA-positive patients benefiting particularly [14]. Modern imaging using magnetic resonance imaging (MRI) and ultrasound enables the detection of subclinical inflammation, with tenosynovitis considered ahighly sensitive early marker [15, 17]. The new EULAR/ACR risk stratification criteria enable the precise identification of high-risk individuals for prevention studies [18, 21]. The combination of lifestyle modifications and targeted drug intervention in high-risk patients could already be revolutionizing RA prevention today.

Orthodontic-induced gingival enlargement (OIGE) affects approximately 15-30% of patients undergoing orthodontic treatment and remains largely unpredictable, often relying on subjective clinical assessments made after irreversible tissue changes have occurred. S100A4 is a well-characterized marker of activated fibroblasts involved in pathological tissue remodeling. This was a cross-sectional precision biomarker study that analyzed gingival tissue samples from three groups: healthy controls (n = 60), orthodontic patients without gingival enlargement (n = 31), and patients with clinically diagnosed OIGE (n = 61). Immunohistochemical analysis quantified S100A4-positive fibroblasts, type I collagen synthesis, and microvascular density. Advanced statistical analyses included multivariate logistic regression, machine learning-based validation, causal mediation analysis, and survival modeling for risk stratification. The density of S100A4-positive fibroblasts was significantly higher in OIGE patients (245.8 ± 38.7 cells/mm2) compared to orthodontic controls (165.3 ± 29.4 cells/mm2) and healthy individuals (98.2 ± 18.5 cells/mm2) (p < 0.001; η2 = 0.891). Multivariate analysis confirmed S100A4 as an independent predictor of OIGE (OR = 1.028 per cell/mm2; 95%CI 1.021-1.035; p < 0.001). Machine learning validation demonstrated high predictive accuracy (AUC = 0.946). Survival analysis identified distinct risk strata: individuals with S100A4 densities > 180 cells/mm2 had a 78% probability of developing OIGE within 24months, compared to 12% for those with < 130 cells/mm2. S100A4 demonstrates 95% predictive accuracy for OIGE, supporting its role in personalized risk stratification and early preventive interventions during a defined therapeutic window. This study presents the first validated precision biomarker in orthodontics with the potential to prevent an estimated 180,000-360,000 OIGE cases globally each year.

Sustained release PLGA microspheres loaded with a bone-affinity Bmp2 enhance fracture healing and mitigate heterotopic ossification.

An estimated 1.4 million children live with HIV-1, yet major gaps remain in understanding neonatal pathogenesis and curative strategies. Nonhuman primate (NHP) infant and mother-infant models provide a critical platform to investigate immune development, elucidate age-specific mechanisms of infection, and evaluate treatment responses, aspects that cannot be directly studied in humans. Newborn macaques exhibit exaggerated gut and lymph nodes seeding, absent interferon-I responses, and accelerated progression compared to juveniles, while ultra-early antiretroviral treatment (ART, day 3) achieves 80% postanalytical treatment interruption (ATI) control that collapses by day 5 due to rapid reservoir fixation. Immunotherapies reveal mechanistic constraints: interleukin-15 agonists paradoxically prolong infected cell survival, whereas CD4-mimetics and BCL-2 inhibitors reduce proviral loads. Germline-targeting SOSIP vaccines elicit superior broadly neutralizing antibodies (bNAb) precursors in infants versus adults, though maternal antibody transfer remains inefficient. Neonatal AAV-delivered bNAbs exploit immune tolerance to confer multiyear protection against SHIV challenges. NHP models, via timed infections, longitudinal and multitissue sampling, and safe ATI, dissect therapeutic windows guiding clinical translation. Advancing mother-infant NHP research is therefore essential to support the development of pediatric strategies for ART-free remission, a goal that remains challenging to achieve.

Salivary osteocalcin as a biomarker for periodontal disease progression and treatment response: a prospective longitudinal study.

Bioorthogonal catalysis holds great promise for precision cancer therapy, yet its clinical translation is critically hindered by the lack of reliable control over catalytic activity. Uncontrolled "always-on" catalysis or irreversible activation prevents timely termination, making it difficult to confine prodrug activation within a safe therapeutic window. To address this challenge, we developed an ultrasound-recharging-regulated closed-loop bioorthogonal system integrating on-demand activation, enhanced catalytic performance, and self-termination, enabling precise in vivo prodrug activation. Mechanistically, pyroelectric polarization of BaTiO3 induces deposition of sub-nanometer Pd clusters whose catalysis is initially silenced by rapid oxidative passivation. Upon ultrasound stimulation, the piezoelectric BaTiO3 core generates a built-in electric field that reduces surface Pd2+ to catalytically active Pd0, thereby activating bioorthogonal reactions while promoting charge separation and reactive oxygen species generation. Simultaneously, piezoelectric screening charges accelerate interfacial electron transfer, significantly enhancing catalytic kinetics. Crucially, rapid repassivation after ultrasound cessation leads to complete catalytic deactivation, establishing a closed bioorthogonal cycle following a single stimulus. In vitro and in vivo studies demonstrate that the activated species induce immunogenic cell death while avoiding side effects from persistent catalysis. This work presents a safe, controllable, and efficient paradigm for bioorthogonal catalytic therapy, advancing its clinical translation.

The role of transcription-coupled nucleotide excision repair (TC-NER) during mammalian forebrain development.