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The Journal retracts the article "Inhibition of AKT2 Enhances Sensitivity to Gemcitabine via Regulating PUMA and NF-κB Signaling Pathway in Human Pancreatic Ductal Adenocarcinoma" [...].
Rural and low-socioeconomic status women face social determinants of health barriers leading to disproportionately low rates of breast cancer screening and markedly reduced participation in clinical trials. To address this gap, we developed the WeCARE (Women's Engagement for Cancer Awareness, Resources, and Education) intervention using a community-engaged approach. This paper describes how Community Advisory Board feedback informed the development of Mayo Clinic Health System's WeCARE intervention components. Their input was systematically analyzed using the Consolidated Framework for Implementation Research (CFIR 2.0) to identify determinants of acceptability, appropriateness, and feasibility and to guide actionable refinements to intervention content and delivery.
SERENA-6 is, to our knowledge, the first global registrational study to use prospective circulating tumour DNA (ctDNA) monitoring to identify the emergence of an acquired resistance mutation before clinical progression and then direct a change in therapy in patients with hormone receptor-positive advanced breast cancer. Switching to camizestrant from aromatase inhibitor with continued cyclin-dependent kinase (CDK) 4/6 inhibitor at ESR1 mutation emergence during first-line therapy significantly improved progression-free survival at interim analysis. We report comprehensive results from ESR1 mutation surveillance in SERENA-6, updated progression-free survival, final analysis of second progression-free survival with longer follow-up, and an exploratory analysis of ESR1 mutation ctDNA dynamics on treatment to give a comprehensive report of this new treatment strategy. This double-blind, placebo-controlled, randomised, phase 3 trial was conducted at 264 hospitals and cancer centres in 23 countries and enrolled women with any menopausal status, or men, aged 18 years or older who were receiving first-line treatment with aromatase inhibitor plus CDK4/6 inhibitor for at least 6 months for oestrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer. Patients were required to have an Eastern Cooperative Oncology Group performance status score of 0 or 1. Eligible patients were enrolled and had ctDNA tested for ESR1 mutation every 2-3 months, coinciding with routine clinical assessments, using the Guardant360 CDx assay. Patients with an ESR1 mutation in ctDNA and without radiological progression were randomly assigned (1:1) using block randomisation (stratified by disease site, time of ESR1 mutation detection, time from initiation of aromatase inhibitor plus CDK4/6 inhibitor to randomisation, and CDK4/6 inhibitor) to switch to camizestrant (75 mg orally once daily) with continued CDK4/6 inhibitor (orally at the same dose) or to continue receiving aromatase inhibitor (anastrozole 1 mg or letrozole 2·5 mg orally once daily) plus CDK4/6 inhibitor (orally at the same dose as was received during ESR1 mutation surveillance phase). Palbociclib and ribociclib were dosed, orally, once daily for 21 days and then 7 days with no treatment in 28-day cycles, while abemaciclib was dosed, orally, twice daily every day in 28-day cycles. The SERENA-6 sample size was determined to ensure sufficient power for both the primary endpoint (investigator-assessed according to RECIST 1.1 progression-free survival) and the key secondary endpoint of investigator-assessed second progression-free survival (time from randomisation to disease progression after first subsequent therapy or death). For patients who had experienced a first progression, scans to assess second progression-free survival were conducted every 8-12 weeks. Updated progression-free survival analysis at this data cutoff was descriptive. Efficacy analyses included all randomly assigned patients (intention to treat). This study is registered with ClinicalTrials.gov, NCT04964934, and is ongoing. From June 30, 2021, to June 14, 2024, 3325 patients were screened and 3256 patients received at least one ESR1 mutation test during first-line therapy and 548 patients had a positive ESR1 mutation test by the time of screening closure. 315 patients (312 [99%] female; 199 [63%] White, 73 [23%] Asian, six [2%] Black or African American, 37 [12%] other, not reported, or with missing race data) were randomly assigned: 157 to camizestrant plus CDK4/6 inhibitor and 158 to aromatase inhibitor plus CDK4/6 inhibitor. After a median follow-up of 23·5 months (IQR 17·9-32·1; data cutoff Jan 2, 2026), median progression-free survival was 16·8 months (95% CI 14·7-19·4) with camizestrant plus CDK4/6 inhibitor versus 9·2 months (7·2-9·7) with aromatase inhibitor plus CDK4/6 inhibitor (hazard ratio [HR] 0·45 [95% CI 0·34-0·59]; nominal p<0·0001); consistent with previous interim analysis. Median second progression-free survival was 25·7 months (95% CI 20·4-30·3) with camizestrant plus CDK4/6 inhibitor versus 19·1 months (16·8-21·0) with aromatase inhibitor plus CDK4/6 inhibitor; HR 0·63 (0·46-0·86; p=0·0037). The most common grade 3-4 adverse events were neutropenia (42 [27%] patients in the camizestrant plus CDK4/6 inhibitor group vs 27 [17%] patients in the aromatase inhibitor plus CDK4/6 inhibitor group) and neutrophil count decreased (35 [23%] vs 30 [19%] patients), while serious adverse events were reported in 24 (15%) versus 29 (19%) patients. There were three deaths considered by the trial investigator to be possibly related to treatment (camizestrant plus CDK4/6 inhibitor group: sudden death, possibly related to camizestrant; aromatase inhibitor plus CDK4/6 inhibitor group: sepsis, possibly related to abemaciclib, and ileus, possibly related to letrozole). Switching to camizestrant plus CDK4/6 inhibitor at ESR1 mutation emergence, versus continuing aromatase inhibitor plus CDK4/6 inhibitor, resulted in sustained progression-free survival benefit that translated into a statistically significant improvement in second progression-free survival. These results further support switching endocrine treatment to camizestrant from aromatase inhibitor upon detection of ESR1 mutation, with continuation of any of the globally approved CDK4/6 inhibitor, to extend first-line treatment benefit. AstraZeneca.
The NLRP3 inflammasome is a major driver of immunopathology, making it a sought-after drug target. In spite of two decades of intense research, its activation mechanism is still poorly understood, impeding inhibitor design. NEK7 was reported to be essential for NLRP3 activation, and several newly identified NLRP3 inhibitors were suggested to act by interfering with their interaction. Here we report that NEK7 accelerates, but is in principle dispensable for NLRP3 activation. The onset of inflammasome activation on the single-cell level was unaltered in the absence of NEK7, yet the rate of cells to undergo inflammasome formation and subsequent pyroptosis was approximately 4-fold reduced. Therefore, therapeutic targeting of the NEK7-NLRP3 interaction might have an incomplete effect, which has to be considered for drug development. We confirmed entrectinib as a NEK7-dependent inhibitor, while other published drug candidates turned out not to rely on its presence. Our results support two possible scenarios for the role of NEK7 in NLRP3 activation: either, NEK7 accelerates one unique pathway of NLRP3 activation, or it is essential for a first, fast pathway, while being dispensable for a second, slower NLRP3 activation pathway.
The ubiquitous human gamma-herpesvirus Epstein-Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a finely regulated life-cycle comprising primary infection, latency and lytic reactivation. Within infected B-cells and epithelial cells, EBV encodes a distinct repertoire of microRNAs (miRNAs), primarily from the BART (BamHI A rightward transcript) and BHRF1 (BamHI H rightward open reading frame) clusters, which play pivotal roles in modulating both viral and host gene expression. These viral miRNAs contribute to key oncogenic processes: by dampening apoptotic responses (e.g., via targeting PUMA, Bim, and PTEN), promoting proliferation of latently-infected B-cells, inhibiting host immune responses (e.g., via down-regulation of CXCL-11 by miR-BHRF1-3), and promoting epithelial-mesenchymal transition (EMT) and metastasis through modulation of E-cadherin and other adhesion molecules. In human lymphomas, such as Burkitt lymphoma, Hodgkin lymphoma, and EBV-positive diffuse large B-cell lymphoma, the interplay of latent viral gene expression, miRNA-mediated regulatory networks, and host microenvironmental factors underlies malignant transformation and disease progression. Emerging evidence also supports the utility of EBV-encoded miRNAs as diagnostic and prognostic biomarkers in EBV-associated cancers. Importantly, therapeutic strategies aimed at interrupting viral miRNA function, restoring host tumor-suppressor pathways, and re-sensitizing tumor cells to immune surveillance hold promise. This review synthesizes current mechanistic insights into EBV-encoded miRNAs in oncogenesis, elaborates on their roles in lymphoma pathogenesis, and evaluates the translational potential of miRNA-targeted therapies in EBV-associated malignancies.
Pituitary corticotroph tumors are the primary cause of Cushing's disease. Even after transsphenoidal surgery, residual tumor cells frequently persist, leading to a recurrence rate of approximately 20%. However, safe and effective adjuvant treatments for these residual lesions are lacking. In this study, we analyzed single-cell RNA sequencing data to characterize the transcriptional profile of corticotroph tumors. On the basis of the high activity of the POMC promoter and its transcriptional regulators, we designed an adeno-associated virus vector carrying the pro-apoptotic gene Puma, with expression controlled by the Pomc promoter for lineage-specific targeting. We also developed an injectable, self-assembling peptide hydrogel for the sustained local delivery of the Puma gene and tested its therapeutic efficacy in subcutaneous and post-resection mouse models. Results showed the Pomc promoter drove selective Puma expression in corticotroph tumor cells, inducing mitochondrial membrane potential loss and apoptosis in vitro. In vivo, the virus suppressed tumor growth and lessened systemic tumor effects; when delivered via the hydrogel into surgical cavities, it completely eliminated residual tumors without detectable toxicity in major organs. This targeted, localized strategy, thus has translational potential as an adjuvant therapy for reducing the recurrence of Cushing's disease.
Extrapulmonary neuroendocrine carcinomas (epNECs) are high-grade malignancies that arise from various anatomic sites and follow an aggressive clinical course. Most patients with epNEC present with metastatic disease at diagnosis and face a dismal prognosis, surviving less than a year. Despite treatment, disease progression is common and most patients rapidly succumb to the disease, which may limit participation in prospective clinical trials. Given the grim survival outcomes, in addition to the rarity and heterogeneity of the disease, high-quality data are lacking and epNECs remain poorly understood. While certain prognostic factors have been identified, many of these are controversial and are yet to be validated. This review summarizes existing evidence on survival, key prognostic factors, and the impact on patient quality of life in this understudied group of malignancies. Understanding survival patterns and key prognostic features of this aggressive group of malignancies is crucial to inform clinical decision-making and shape the design of future clinical trials. This review emphasizes a need for multicenter involvement to conduct clinical trials to develop more effective front-line therapies. Additionally, the current limited treatment landscape highlights the need to shift to a personalized, biomarker-driven treatment approach (e.g. DLL3), with a call for comprehensive, standardized biomarker testing for all epNECs.
Recent advances in HER2-directed therapies have improved outcomes for patients with HER2+ advanced/metastatic breast cancer (a/mBC), but disease progression ultimately occurs in most cases. Dual targeting of HER2 with tyrosine kinase inhibitors and antibody-drug conjugates has the potential for non-cross-resistant treatments that improve disease control. HER2CLIMB-04, a single-arm, open-label, phase 2 study, evaluated tucatinib plus trastuzumab deruxtecan (T-DXd) in patients with HER2+ a/mBC who experienced disease progression on or were intolerant of previous HER2-directed therapy and a taxane. Patients with stable or progressing brain metastases (BMs) were permitted. The primary endpoint was confirmed objective response rate (cORR) by the investigator. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A total of 70 patients (median age 57 years, median 2 prior lines for a/mBC) received tucatinib 300 mg orally BID and T-DXd on day 1 of each 21-day cycle. The cORR was 51.4% with a median DOR of 11.9 months (95% CI, 6.0-not estimable); median PFS was 11.5 months, and OS was 28.4 months. The most common treatment-emergent adverse events were diarrhea (80.0%), nausea (77.1%), and fatigue (72.9%). Antidiarrheal prophylaxis, introduced for 44 patients, was associated with reduced any grade diarrhea. Survival outcomes in patients with or without BMs are described. Although the addition of tucatinib to T-DXd did not demonstrate a clear benefit compared with previously demonstrated T-DXd monotherapy efficacy, when given with antidiarrheal prophylaxis, the combination was tolerable and showed clinical activity in patients with HER2+ a/mBC. NCT04539938.
The benefit of adding anti-PD-(L)1 to chemotherapy in untreated advanced PD-L1-negative nonsquamous non-small cell lung cancer (nsqNSCLC) remains unclear. We conducted a systematic review and meta-analysis to determine whether adding anti-PD-(L)1 therapy to chemotherapy improves outcomes in this population. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched in September 2025. Eligible studies were phase III randomized clinical trials comparing frontline chemotherapy plus anti-PD-1 or anti-PD-L1 therapy versus chemotherapy with or without placebo in advanced PD-L1-negative nsqNSCLC. Risk of bias was assessed using the Risk of Bias 2 tool. Random-effects models were used to pool hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) and risk ratios (RRs) for overall response rate (ORR). Twelve trials including 2,084 patients were analyzed. Chemotherapy plus anti-PD-(L)1 improved ORR (RR, 1.61; 95% CI, 1.26-2.05; p = 0.0001), PFS (HR, 0.68; 95% CI, 0.60-0.77; p < 0.00001), and OS (HR, 0.81; 95% CI, 0.70-0.94; p = 0.006). Chemotherapy plus anti-PD-(L)1 therapy may be an effective first-line option for advanced PD-L1-negative nsqNSCLC, although the evidence is limited by subgroup-level data and between-study heterogeneity. Protocol registration: PROSPERO, www.crd.york.ac.uk/prospero, identifier 1371679. Some people with advanced nonsquamous non-small cell lung cancer have tumors that test negative for PD-L1, a marker sometimes used to predict benefit from immunotherapy. It has been unclear whether adding a PD-1 or PD-L1 immunotherapy drug to chemotherapy helps these patients, because individual clinical trials have shown mixed results. We reviewed phase III randomized trials that compared chemotherapy plus a PD-1 or PD-L1 drug with chemotherapy alone or chemotherapy plus placebo. The analysis included 12 trials and 2,084 patients with advanced PD-L1–negative nonsquamous non-small cell lung cancer. Adding immunotherapy to chemotherapy improved tumor shrinkage, delayed cancer growth, and improved overall survival. However, the survival benefit was not identical across all studies, and the analysis was based on subgroup data from larger trials rather than individual patient data. These results suggest that chemotherapy plus a PD-1 or PD-L1 drug is a reasonable first treatment option for many patients with this type of lung cancer. However, treatment decisions should still consider each patient’s overall health, tumor features, possible side effects, and other available treatment options.
In TBCRC 022 (NCT01494662), neratinib and ado-trastuzumab emtansine (T-DM1) demonstrated intracranial activity among patients with HER2-positive breast cancer brain metastases. However, gastrointestinal (GI) toxicities-particularly diarrhea-were common, potentially impacting quality of life. Clinician-reported adverse event (CTCAE) grading may underestimate the patient experience. We report GI toxicities using patient-reported outcomes (PROs) in TBCRC's neratinib-T-DM1 cohort. Patients received neratinib (160 mg daily) and T-DM1 (3.6 mg/kg IV every 21 days). A pre-planned analysis assessed patient-reported GI toxicities during Cycles 1-4 using the Patient-reported Outcomes Measurement Information System (PROMIS) GI Diarrhea scale, Systemic Therapy-Induced Diarrhea Assessment Tool (STIDAT), and PRO-CTCAE. Descriptive statistics and linear mixed effects models evaluated symptom trajectories over time. We evaluated agreement for PRO and clinician-reported data. Forty-four patients enrolled; all completed ≥1 PRO. GI symptom burden increased over Cycles 1-3. PROMIS scores worsened significantly by Cycle 2, with a peak mean increase of 6.62 (95% confidence interval (CI): 2.67-10.59; p = 0.002) at Cycle 3. STIDAT scores also worsened by Cycle 3 (mean change 0.50; 95%CI: 0.11-0.90; p = 0.015). Based on maximum PRO-CTCAE scores, moderate-to-severe symptoms were reported by 20.5% (diarrhea), 24.4% (appetite loss), and 41.0% (constipation). Agreement between PRO-CTCAE and clinician-reported CTCAE was low (kappa <0.2) with clinicians reporting less toxicity. PROMIS and STIDAT scores were significantly correlated. This GI-focused PRO analysis highlights the value of PROs in capturing patient-experienced toxicities that impact quality of life yet are underestimated by clinicians. Incorporating PROs into clinical trials can inform supportive care and prophylactic strategies.
Somatostatin receptor PET imaging is integral to the management of patients with neuroendocrine tumours (NETs), yet standardised criteria for therapy response assessment with the use of this modality are not available. This Policy Review reports the development of the European Neuroendocrine Tumor Society somatostatin receptor PET response assessment framework, established through a structured modified Delphi process coordinated by the European Neuroendocrine Tumor Society. 34 international experts from nuclear medicine, radiology, oncology, endocrinology, surgery, and related disciplines participated in four iterative rounds evaluating 76 statements, with consensus defined as at least 75% agreement. The framework proposes response categorisation based primarily on volumetric changes in somatostatin receptor-expressing target lesions, complemented by assessment of new lesions, rather than reliance on standardised uptake value-based metrics. Partial response is defined by at least 40% reduction in target lesion volume without new lesions, whereas progressive disease is defined by at least 40% volume increase of target lesions or the emergence of new lesions. Complete response requires absence of pathological tracer uptake, and a category of unconfirmed progressive disease is introduced for equivocal cases warranting short-interval reassessment. Although not yet validated against survival outcomes, this expert-derived framework (SSTR-PeRForm) provides a pragmatic foundation for harmonising somatostatin receptor PET-based response assessment in clinical trials and routine practice and represents a key step towards outcome-based validation.
This randomized clinical trial examines 1-year safety and efficacy outcomes in patients who underwent intra-arterial thrombectomy or medical management following an acute ischemic stroke with large-core infarcts.
Methylthioadenosine phosphorylase (MTAP) is deleted in 13% of NSCLC, and MTAP two-copy deleted (MTAPdel) cancer cells are vulnerable to protein arginine methyltransferase 5 inhibitors being examined in trials. Outcomes for MTAPdel NSCLC are poorly characterized. Patients with advanced MTAPdel and MTAPwt NSCLC who underwent large panel, tissue-based, NGS at a single center and received systemic therapy and from 10/2016-3/2024, were included in this retrospective study. Treatments of interest included platinum doublet + anti-PD-(L)1 therapy, anti-PD-(L)1 monotherapy, and docetaxel-based chemotherapy. Baseline characteristics, PFS, and OS were compared between cohorts. Compared to the MTAPwt cohort (n=307), the MTAPdel cohort (n=93) had more female patients (65.6% vs. 51.5%, p=0.018), less of a smoking history (33.3% vs. 49.0% >30 pack-years, p=0.008), more stage IV disease at diagnosis (78.8% vs. 60.9%, p=0.002), lower PD-L1 TPS (37.9% vs. 24.3% TPS <1%, p=0.017), and lower tumor mutational burden (median 7.6 vs. 9.9 mutations/Mb, p=0.012). Patients with MTAPdel (vs. MTAPwt) NSCLC had shorter PFS on anti-PD-(L)1 monotherapy (HR 1.70 [95% CI 1.02-2.82], p=0.040) and platinum doublet + anti-PD-(L)1 therapy (HR 1.89 [95% CI 1.20-2.97], p=0.006) when controlling for histology, age, smoking pack-years, PD-L1 TPS, targetable co-mutations, and treatment line. OS was similar between MTAPdel and MTAPwt cohorts across regimens. MTAPdel NSCLC has more features of aggressive disease, including CNS metastasis, and associates with PD-L1 TPS <1%. Compared to patients with MTAPwt NSCLC, patients with MTAPdel NSCLC have worse outcomes to anti-PD-(L)1-based therapies. Effective therapies targeting MTAPdel NSCLC are needed.
Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate comprising the monoclonal antibody telisotuzumab and the monomethyl auristatin E payload. Primary analysis of the phase 2 LUMINOSITY trial (NCT03539536) revealed Teliso-V monotherapy 1.9 mg/kg elicited durable responses and had generally manageable safety in patients with locally advanced or metastatic c-Met protein overexpressing, EGFR wild-type, nonsquamous NSCLC. We present updated outcomes with approximately 6 months longer follow-up and explore the impact of previous therapies. Patients (≥18 y; had previous therapy including ≤1 chemotherapy) received 1.9 mg/kg Teliso-V every 2 weeks. c-Met protein overexpression (clinical trial assay for MET [SP44] [Roche]) was defined as greater than or equal to 25% tumor cells with 3+ staining intensity (c-Met high: ≥50% 3+; c-Met intermediate: 25 to <50% 3+). Primary end point was the overall response rate by independent central review per the Response Evaluation Criteria in Solid Tumors version 1.1. As of February 21, 2024, 172 patients received at least one dose of Teliso-V; 168 patients (c-Met high, n = 84; c-Met intermediate, n = 84) were evaluable for efficacy. The overall response rate was 29.2% (95% confidence interval [CI]: 22.4-36.7; c-Met high, 34.5% [24.5-45.7]; c-Met intermediate, 23.8% [15.2-34.3]). Median duration of response was 7.2 months (95% CI: 5.5-11.0; c-Met high, 7.2 [95% CI: 4.2-12.0]; c-Met intermediate, 7.2 [95% CI: 4.7-11.5]). Previous therapy (platinum, immune checkpoint inhibitors, or both) did not impact efficacy outcomes. The most common treatment-related adverse event was peripheral sensory neuropathy (any-grade: 31%; grade ≥3: 7%). Teliso-V monotherapy 1.9 mg/kg elicited durable responses, irrespective of the type of previous therapy received, and maintained a manageable safety profile in patients with c-Met protein overexpressing EGFR wild-type, nonsquamous NSCLC. NCT03539536.
Recent conflicting reports regarding the tolerability of PARP inhibitors administered concurrently with breast radiotherapy motivate analysis of adverse events reported in a large national cooperative group trial. From 05/19 to 06/24, we enrolled patients with inflammatory (T4d) non-metastatic breast cancer to a Phase 2 NCI-cooperative group trial, which randomized patients after neoadjuvant systemic therapy selected by the treating physician and modified radical mastectomy to two arms. The control arm was assigned 50 Gy of chest wall and nodal radiotherapy, including bolus, plus 10 Gy boost. The intervention arm was assigned the same radiotherapeutic regimen with 25 mg of olaparib twice daily during radiotherapy. Adverse events were assessed using the CTCAE v5.0 weekly during radiotherapy. This analysis explores the distribution of radiation dermatitis, all acute adverse events in the chest-wall region, and other adverse events through the end of radiotherapy by study arm, where the adverse events were deemed possibly, probably, or definitely treatment-related. Chi-squared tests were used to compare proportions. Among 146 evaluable participants (73 control, 73 intervention), median age was 54.1. No Grade 4 or 5 treatment-related events were reported. Grade 3 radiation dermatitis was reported in 24.7% of patients in the intervention arm and 5.5% in the control arm (p=0.003) during radiotherapy. When considering all acute chest-region adverse events (Table), 24.7% had grade 3 acute adverse events in the intervention arm vs 6.8% in the control arm (p=0.006) during treatment. One patient on the intervention arm had early, confluent telangiectasia throughout the 50 Gy fields with radiation-induced lichenoid dermatitis. Intervention arm patients were more likely to experience Grade 2 or greater gastrointestinal adverse events (17.8% vs 0%, p<0.001) and any grade of laboratory investigation abnormalities (19.2% vs 0%, p<0.001). This analysis suggests continued caution if considering concurrent administration of radiotherapy and olaparib outside of the investigational context.
Human papillomavirus (HPV) 18 E6 oncoprotein drives cervical carcinogenesis by degrading p53, enabling uncontrolled cell proliferation. In this study, we developed novel trans-activator of transcription (TAT)-conjugated Affibody molecules (TAT-ZHPV18E6) targeting HPV18 E6 for therapeutic applications. High-affinity Affibody variants were screened by phage display using recombinant HPV18 E6 expressed in Escherichia coli. Three candidates (TAT-ZHPV18E6: 4, 59, 352) exhibited high binding affinity, with equilibrium dissociation constant (KD) ranging from 10-6 to 10-4 M, with TAT-ZHPV18E6: 59 showing superior specificity for native HPV18 E6 in HeLa229 cells, as validated by surface plasmon resonance (SPR), enzyme-linked immunosorbent assay (ELISA), and immuno-fluorescence. In vivo near-infrared fluorescence imaging of DyLight 755-labeled TAT-ZHPV18E6: 59 in tumor-bearing mice demonstrated rapid tumor accumulation (peak at 2 h) and prolonged retention (> 12 h). Mechanistically, TAT-ZHPV18E6: 59 restored p53 stability and upregulated pro-apoptotic factors (Bax, PUMA) and cell cycle regulator p21. Notably, combined treatment with TAT-ZHPV18E6: 59 and E7-targeting TAT-ZHPV18E7: 228 combinatorial enhanced apoptosis and suppressed HeLa229 proliferation, as confirmed by CCK-8 and clonogenic assays. These results demonstrate the utility of TAT-ZHPV18E6 Affibody molecules as targeted agents, highlighting combinatorial E6/E7 targeting as a potent strategy for HPV18-driven cervical cancer therapy. KEY POINTS: • TAT-ZHPV18E6: 59 achieved high affinity for HPV18 E6, enabling precise molecular targeting. • Demonstrates dual utility for in vivo imaging and p53-dependent tumor suppression. • Dual targeting of E6/E7 yields synergistic therapeutic efficacy in cervical cancer models.
Apart from vigilance and flight, anti-predator defense behavior in horses has not been well documented despite its importance during natural selection. In this study, observations of a feral herd (around 140) of Venezuelan horses sympatric with puma and jaguar divided such defense into precaution and reaction. Group living and the avoidance of danger areas are precautionary measures enhanced by the stallion's vigilance and his actions to keep small foals with the band. Reactions to perceived threats comprise communication of alarm; bunching, or cohesion, as a primary response; massed flight following self-organizing principles; and reassembly of bands. Stallions usually initiated this behavioral process. Stallions' initial reactions to perceived threats were "investigation", "move away", "run away", and "stampede", and resulting herd behavior was categorized into 27 responses. Data analysis through Observation Oriented Modeling indicated that each category of initial stallion response to perceived threats was associated with a recurring pattern of subsequent herd behavior. Prominent behaviors enhanced cohesion and synchrony, as well as velocity and direction matching. A fourth observed category was the cohesive "run to band" of a startled outlying member, in which the individual's alarm might transmit to the band or the band's calm transmit to the individual. The results emphasize the importance of communication, social cohesion, and synchronous action in times of perceived threats, their continuous practice during maintenance activities, and the social needs and understanding management of domestic horses.
To improve the unsteady aerodynamic response of the IAR 330 PUMA rotor, the present analysis provides a two-dimensional (2D) CFD-based framework for rotor blade sections integrated with trailing-edge flaps (TEFs). From a biomimetic perspective, the TEF is treated as an engineering abstraction of the adaptive aft-chord and camber variation observed in natural flyers, providing a controlled morphing envelope for aerodynamic-load regulation. The scientific contribution consists of an integrated assessment of the NACA 13112 section over an extended TEF deflection range, the comparison of several relative TEF chord lengths, and the transfer of the section-level framework to a four-section representation of the IAR 330 PUMA rotor. First, the effect of TEF deflection on the trajectory and strength of the dynamic stall vortex (DSV) is examined for a pitching NACA 13112 airfoil with a chord length of c=0.6 m and a pitching axis located at x/c=0.25. The pitching motion was prescribed in ANSYS Fluent through a user-defined function (UDF), imposing a hysteresis variation of the angle of attack (AoA) from α=-3° to α=23°, while flap deflection angle (β) varied from β=-20° to β=8°, corresponding to upward and downward TEF deflection, respectively. The second part of this study extends the same pitching law to real-scale rotor blade sections under hovering flight conditions. For the rotor simulations, the Multiple Reference Frame (MRF) model was used for the steady-state analysis, whereas a Sliding Mesh interface was adopted for the transient computations. A 2D pressure-based solver was employed, together with the SST k-ω turbulence model, the Unsteady Reynolds-Averaged Navier-Stokes (URANS) formulation, and a coupled pressure-velocity scheme. The rotational speed was set to ω=265 RPM, corresponding to a local tangential velocity of approximately U=145 m/s at the analysed radius of r=5.225 m and to a local Mach number of M≈0.43. The ideal-gas assumption and energy equation were employed to account for compressibility effects. Among the investigated IAR 330 PUMA rotor-section configurations, the TEF with a chord length of cf=0.25c TEF provided the most balanced aerodynamic response, reducing the peak pitching-moment coefficient by approximately 32% relative to the baseline airfoil.
The objective of this study was to investigate the ability of patient-reported/administered outcomes to capture disability worsening and progression independent of relapse activity (PIRA) in multiple sclerosis (MS). We included patients from the longitudinal multicenter MS PATHS cohort with ≥3 assessments and >6 months follow-up. PIRA was defined on the patient-determined disease steps (PDDS) and self-administered tests assessing walking speed, manual dexterity, and processing speed, in the absence of self-reported relapses. We assessed (i) prevalence of PDDS/self-administered test-based disability worsening and PIRA definitions; (ii) their concurrent validity, through the association with worsening and PIRA definitions based on the expanded disability status scale (EDSS; Barcelona subcohort); and (iii) their clinical meaningfulness, through the correlation with brain magnetic resonance imaging (MRI) and quality-of-life (QoL) data trajectories. We included 9,088 patients (73% female patients; age = 46.8 years; disease duration = 14.2 years). Over a 3-year follow-up, 4,066 (45%) patients worsened on ≥1 patient-reported/administered outcome, of which 2,357 (58%) developed PIRA. In the Barcelona subcohort (N = 279), 68 (24%) patients developed EDSS-based worsening, of which 30 (44%) developed EDSS-based PIRA; 99 of 279 (35%) worsened on ≥1 patient-reported/administered test, of which 78 of 99 (79%) had PIRA. Worsening (but not PIRA) on PDDS was associated with EDSS-based worsening (odds ratio = 3.03 [1.42; 6.43], p = 0.004). PDDS/self-administered-test-based worsening or PIRA strongly correlated with accelerated brain atrophy and T2 lesion volume increase compared to non-worseners (p < 0.05), and showed worse QoL (p < 0.05). Despite only partial agreement with EDSS-based definitions, PDDS/self-administered test-based worsening and PIRA definitions were clinically meaningful, by identifying patients with greater brain damage and poorer QoL, supporting their use in clinical practice. ANN NEUROL 2026.
Finding prognostic factors for early and late relapses in operable breast cancer (BC) could improve relapse risk stratification; but there is a lack of real-world data with long enough follow-up. To investigate clinical and pathological features related to early versus late relapses in a real-world cohort of BC patients. To identify factors related to early (≤ 2 years) and late (≥ 5 years) relapse in women with stage I-III BC, hormone receptor (HR)-positive and human epidermal growth factor receptor 2-negative (HER2-), and HR-negative (HR -)/HER2 - by immunohistochemistry from El Álamo IV registry, logistic regression model was performed. To explore relapse dynamics, multivariate Cox regression models and annual hazard rates of relapses were reported. Of the 1493 relapses, early, intermediate, and late relapses represented 28.3%, 29.7%, and 42.1% of all relapses, respectively. In 1050 patients, of both early and late relapses, age > 70 years (odds ratio [OR] 5.13; 95% confidence interval [CI] 3.23-8.15), stage III (OR 3.22; 95% CI 1.90-5.46), histological grade 3 (OR, 2.93; 95% CI 1.69-5.10), and HR - /HER2 - subtype (OR 10.26; 95% CI 6.55-16.05) were associated with an increase of early relapse risk. Annual hazard rate of loco-regional relapses (LRR) steadily increased over time in patients with HR + /HER2 - tumors, while those with HR - /HER2 - tumors exhibited a fluctuating pattern. For distant relapses (DR), the hazard rate peaked at 2 years and then rise steadily in HR + /HER2 - tumors whereas remained variable in HR - /HER2 - tumors. In multivariate Cox model, LRR was associated with stage, subtype, and histological grade, while DR was additionally influenced by age. Age at diagnosis, stage, histological grade, and tumor subtype were associated with distinct relapse timing patterns. These findings support further research into relapse dynamics and predictors by analyzing real-world data.