Hard-to-heal wounds, such as diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs), remain associated with poor healing outcomes despite optimised standard care. Although classified by aetiology, these wounds share common pathophysiological features that may be amenable to mechanism-targeted therapies. This manuscript aims to describe the design, scientific rationale and statistical framework of a mechanism-driven basket trial evaluating wound therapies across multiple wound aetiologies. This multicentre, randomised, sham-controlled clinical trial was designed under a master protocol using aetiology-specific baskets. Adults with hard-to-heal DFUs or VLUs who failed to demonstrate adequate healing during a standardised run-in period were randomised 1:1 within each basket to standard care plus active therapy or standard care plus sham. Subject and assessor blinding, harmonised standards of care, and centralised endpoint adjudication were employed. The primary endpoint within each basket was complete wound closure by 12 weeks, confirmed at two consecutive visits. Bayesian statistical methods incorporating conservatively discounted historical control data via power priors were used to enhance efficiency while preserving indication-specific inference. The basket design enabled simultaneous evaluation of a single mechanism-targeted intervention across heterogeneous wound aetiologies while maintaining methodological rigour, regulatory alignment and interpretability. Independent analysis of each basket preserved aetiology-specific conclusions while benefiting from shared infrastructure and standardised procedures. This master-protocol basket trial adapted principles established in oncology to wound care, offering an innovative and scalable framework for evaluating therapies targeting shared biological barriers to healing. The approach may accelerate evidence generation and inform future clinical development strategies in hard-to-heal wounds.
The nuclear pore complex (NPC) is the only gateway between the nucleus and the cytoplasm in eukaryotic cells. Its nucleoplasmic face is decorated by the nuclear basket, a filamentous structure with important roles in mRNA export and chromatin organization. In contrast to major parts of the nuclear pore scaffold, the architecture of the nuclear basket remains poorly defined. Here, we investigate the interactions required for formation and maintenance of the nuclear basket in vivo using budding yeast. Although previous work has often focused on Mlp1, the largest and most abundant nuclear basket protein, we demonstrate that its paralogue, Mlp2, also plays a central role in nuclear basket architecture. Mlp2 can interact with the NPC scaffold independently of Mlp1, and interactions between the coiled-coil regions of both proteins stabilize their binding. Furthermore, the N-termini of both Mlp1 and Mlp2 are required for recruitment of Pml39. In addition, we show that Pml39 uses its N- and C-terminal helices to recruit additional Mlp1 subunits. We propose a refined model of nuclear basket architecture with a stoichiometry of 4:2:1 per spoke for Mlp1:Mlp2:Pml39.
Many molecular-targeted oncology drugs have been successfully developed. The mechanism to target some specific molecules gives us the expectation that the molecular-target drug is effective over multiple tumor types and histologies. Then, simultaneous evaluation of multiple subtypes is motivated, and the basket trials aim to realize it, in which each subtype is called a basket. Although the single-arm design with simple exact binomial inference is routinely used for Phase 2 trials in standard oncology drug development, almost all recent proposals of statistical methods for basket trials are Bayesian methods of complexity. To fill the gap, the one-sample Mantel-Haenszel procedure was developed, which consists of the exact test of the global null hypothesis, the Mantel-Haenszel-type estimation of the treatment effect, and identification of effective baskets via the generalized information criterion (GIC). This paper points out an undesirable feature of the GIC in the previous research and develops an alternative one. The new GIC is free of the undesirable feature and more efficiently borrows information across baskets, which is a relevant feature for basket trials. Through numerical studies, we demonstrate that the new GIC outperforms the original one.
This study developed kinetic models to describe the growth and metabolism of MDCK adherent cells cultured in basket bioreactors. These models were used to predict cell density, nutrient consumption, and metabolite concentrations at key stages of the culture process in basket bioreactors, helping to overcome sampling limitations caused by environmental conditions and bioreactor design. Experimental data, including cell density and glucose and lactate levels were obtained at different time points from 5 L bioreactors. Model parameters were estimated by nonlinear fitting in MATLAB. Kinetic models were established based on the Logistic and Luedeking-Piret equations, and a perfusion dilution item was introduced considering the perfusion culture. The prediction performance of the models was evaluated based on the goodness-of-fit, regression, and error distribution. The models were then validated with independent experimental data from 40 L basket bioreactors. The results showed that MDCK cells cultured in the 5 L bioreactor entered the plateau phase between 96 h and 108 h, with the maximum cell density reaching (795.13±16.22)×104 cells/mL. The specific growth rate peaked with a value of 1.01/d at the time point of 36 h. During the plateau phase, the maximum lactate production rate was 1.71 mmol/(L·h), while the glucose consumption rate reached 2.21 mmol/(L·h). The kinetic models derived from the 5 L bioreactor data showed good agreement with experimental results, with R2 values exceeding 0.95. When being applied to validation data from three independent 40 L bioreactor batches, the models consistently achieved R2 values above 0.95. Offline cell densities measured by digestion at 96 h and 120 h showed no significant differences from the model predictions (P=0.48, P=0.92). The results indicated that the kinetic models developed with 5 L bioreactor data could accurately predict the growth and metabolic behavior of MDCK cells in the 40 L system. In addition, the results demonstrated that the operational performance of the 40 L bioreactor was comparable to that of the 5 L system. This confirmed the reliability of the established models for scale-up applications. By quantifying key parameters, including the specific growth rate, glucose consumption rate, and lactate production rate, the models provide a sound theoretical basis for optimizing basket bioreactor processes. Moreover, they offer strong technical support for improving production efficiency and quality control in industrial-scale manufacturing. 为解决工业化生产中篮式生物反应器取样受限的问题，本研究通过建立犬肾(Madin-Darby canine kidney, MDCK)贴壁细胞生长代谢动力学模型，预测篮式生物反应器生产过程中细胞数量、营养物和代谢产物浓度。分析了前期实验收集的MDCK贴壁细胞在5 L篮式生物反应器培养不同时间点细胞密度、葡萄糖和乳酸浓度数据，使用MATLAB软件进行非线性拟合。本文模型以Logistic方程和Luedeking-Piret方程为基础建立，并额外添加了灌流稀释项以适应灌流培养模式。通过拟合优度计算、回归分析和误差分布分析评价模型预测能力，并在40 L篮式生物反应器中对该模型的跨规模预测性能进行了检验。结果显示，MDCK细胞在5 L篮式生物反应器培养至96-108 h达到平台期，最大细胞密度为(795.13±16.22)×104 cells/mL。细胞比生长速率在36 h时达到最大，为1.01/d。平台期葡萄糖的最大消耗速率是1.71 mmol/(L·h)，乳酸的最大生成速率是2.21 mmol/(L·h)。使用5 L反应器培养数据构建的MDCK细胞生长代谢动力学模型拟合优度良好，R2均大于0.95。在40 L篮式生物反应器的3批验证培养中，模型预测曲线与取样离线检测数据吻合度高，R2均大于0.95。在培养第96、120小时取样离线消化读细胞数，离线检测数值与模型预测数值没有显著差异(P=0.48, P=0.92)。结果表明基于5 L反应器建立的动力学模型可以有效地跨规模预测40 L反应器中MDCK细胞的生长和代谢状态，同时证明了5 L和40 L反应器的培养效果相似。本研究的动力学模型能够量化细胞生长、葡萄糖消耗和乳酸生成的速率，为篮式生物反应器培养工艺优化和生产操作提供理论依据，同时为疫苗企业产品质量控制提供辅助。.
Oncology drug development has increasingly shifted toward determining optimal biological doses rather than maximum tolerated doses (MTDs), particularly for targeted therapies and immunotherapies that exhibit complex dose-efficacy relationships. Concurrently, basket trials have emerged as an efficient approach for evaluating investigational treatments across multiple cancer types sharing common molecular targets. We propose the BOIN-ETB design, a model-assisted dose-finding design that addresses optimal dose (OD) identification in phase I/II basket trials by incorporating both toxicity and efficacy endpoints. The proposed approach employs common toxicity boundaries across cancer types while implementing cancer-specific efficacy boundaries to account for differential efficacy responses between baskets. OD selection utilizes utility functions that quantify efficacy-toxicity trade-offs. Through comprehensive simulation studies across Fourteen realistic scenarios, the BOIN-ETB design demonstrates robust performance in identifying true ODs while maintaining acceptable safety profiles across diverse cancer populations. The design provides superior consistency compared to alternative approaches, particularly in scenarios with heterogeneous dose-efficacy relationships between cancer types, making it well-suited for contemporary oncology dose-finding basket trials.
Objectives　The average daily vegetable intake of adults in Japan remains below recommended levels. As foods are primarily purchased at supermarkets (SMs), this study examined whether nudge interventions implemented in SMs are associated with increased vegetable purchases, using a quasi-experimental design.Methods　Among SMs operated by the same company within a single city, three medium-sized stores with similar customer numbers and vegetable sales trends that were located at least 3-km apart were non-randomly assigned to the intervention (stores A and B) or control (store C) condition. In the intervention stores, shopping baskets were equipped with flyers recommending vegetable purchases (Easy-Attractive nudge). Furthermore, Store B displayed a poster that visually presented 70-g portions of popular seasonal vegetables in the produce section (Attractive-Social-Timely nudge). Store C served as the control and received no intervention. The 1-month observation and intervention periods were October and November 2024, respectively. By comparing point-of-sale (POS) data from October to November 2024 with data from the corresponding period in the previous year, we calculated the year-on-year increase rates for daily vegetable sales (primary outcome) as well as non-vegetable and total sales (secondary outcomes), adjusted for relative changes in customer volume. During the final 2 days of the intervention, 50 customers per store were surveyed to obtain their basic demographics, socioeconomic status, awareness of the intervention materials, and impressions. Average treatment effects (ATEs) were estimated using a difference-in-differences approach that modeled outcomes, intervention status, and store and time indicators for the first and second halves of October and November. Store-specific analyses (A versus B) were also performed.Results　No significant differences were observed between stores regarding basic customer characteristics or socioeconomic status. The ATE for vegetable sales was ＋4.0 percentage points (95% confidence interval: 0.6-7.5), indicating a statistically significant increase. In contrast, no significant ATE was observed for non-vegetable sales (－4.4 percentage points: －14.2 to 5.5) or total sales (－3.6 percentage points: －13.0 to 5.9). Store-specific analyses revealed no additional differences between stores B and A. Awareness of shopping basket flyers was 95%. Among those aware, 24% reported purchasing vegetables, 51% expressed positive opinions, and 8% expressed negative opinions. The corresponding figures for the produce-section poster were 36%, 28%, 61%, and 0%, respectively.Conclusions　Easy-Attractive nudge flyers in shopping baskets were associated with increased vegetable purchases. This intervention potentially represents an effective strategy for promoting vegetable selection without increasing the overall customer spending.
Balloon-in-basket pulsed field ablation (BiB-PFA) enables atrial fibrillation (AF) ablation under conscious sedation (CS). While augmented reality (AR) has been proposed to improve patient comfort during invasive procedures, its benefit in an already well-tolerated awake ablation setting remains uncertain. To evaluate the impact of adjunctive AR glasses on sedation requirements and patient comfort during BiB-PFA performed under CS. In this prospective, single-center study, 50 patients undergoing AF ablation with BiB-PFA were treated under a standardized CS protocol. Patients were allocated to either ablation without AR (n = 25) or ablation with adjunctive AR glasses (n = 25). Sedation requirements and patient-reported outcomes were assessed during ablation, as well as at 1-hour and 1-day post-procedure. Baseline characteristics were comparable. All procedures were completed without conversion to deep sedation. Fentanyl requirements were lower in AR-group (1.1 vs. 1.4 µg/kg; p = 0.015), while other sedatives were similar. Intraprocedural pain was moderate and comparable. AR enhanced perceived calming effect (10.0 vs. 8.5; p = 0.015). Satisfaction was high in both groups. Recommendation scores were high overall, with higher values without AR (90(90,100) vs. 90 (70,90); p = 0.023). Retrospective anxiety at day 1 remained low but was higher with AR (2.0(0.0,5.0) vs. 0.0 (0.0,0.0); p = 0.002). Pain decreased over time in both (p < 0.001). CS for BiB-PFA is feasible and well tolerated. Intraprocedural pain was low, while satisfaction and recommendation were high in both groups, with slightly higher values without AR support. AR use was associated with modest reduced opioid requirements, suggesting a potential role in selected patients. Slightly higher retrospectively reported anxiety at 1 day in AR-group, while overall low, warrants further investigation.
Trypanosoma brucei, a divergent eukaryote parasite, is responsible for neglected tropical diseases in humans and animals, specifically sleeping sickness or human African trypanosomiasis and nagana. Beyond its scientific significance, a comprehensive understanding of its biology has substantial medical and economical implications. Nuclear pore complexes (NPCs) are large multiprotein channels embedded in the nuclear envelope that regulate nucleocytoplasmic transport. In addition to this critical function, NPCs are involved in essential nuclear processes such as chromosome segregation, transcription, and cytokinesis. This study demonstrates that Myosin-like protein-1 (MLP1) localizes to the nuclear basket of NPCs in T. brucei. Silencing of TbMLP1 by RNA interference in T. brucei procyclic cells resulted in severe growth, significant impairment of messenger RNA export, disorganization of nuclear structure, and marked genomic instability. Flow cytometry and fluorescence in situ hybridization (FISH) analyses revealed abnormal DNA content and a reduction in disomic cells, alongside an increase in monosomic, trisomic, and polysomic cells, indicating intolerable aneuploidy detrimental to cell viability. Together, these findings demonstrate that TbMLP1 links NPC function to multiple key cellular pathways. This research provides new insights into the mechanisms that maintain nuclear architecture, preserve nuclear envelope morphology, ensure genome stability, and faithful chromosome segregation, and support appropriat kinetochore distribution and mitotic spindle organization.
Single-shot pulsed field ablation (PFA) is increasingly used for pulmonary vein isolation (PVI) in atrial fibrillation (AF). Although balloon-in-basket (BiB)-PFA system integrates ablation and mapping into a single catheter, standardized procedural workflows remain limited. This study aimed to describe a standardized, step-by-step workflow for AF ablation using the BiB-PFA system and evaluate procedural performance, acute safety, and the learning curve in clinical practice. This prospective, single-center study included 40 consecutive patients undergoing index PVI using the BiB-PFA system at a tertiary high-volume electrophysiology center. Procedures followed standardized protocol including balloon preparation, ultrasound-guided access, fluoroscopy-guided transseptal puncture, selective pulmonary vein (PV) angiography, and a structured 2-step ablation approach for each vein. Posterior wall ablation (PWA) was performed in selected patients. Procedural metrics and acute complications were analyzed descriptively. Patients were 64.5 years old (56.5, 73.3); 41% were female, and 57.5% had nonparoxysmal AF. The median procedural duration was 41.5 minutes (35.0, 59.0), left atrial dwell time 27.5 minutes (25.0, 36.0), and BiB dwell time 23.0 minutes (20.0, 25.8). A median of 4 applications per PV was used. Reduced-energy delivery was required in 30% of right inferior and 25% of right superior PV. PWA was performed in 35% of patients using a median of 5 applications. No major intraprocedural complication occurred. The mean procedural duration decreased from 50.0 minutes (38.0, 60.5) in the first 10 cases to 34.5 minutes (31.5, 52.0) in the last 10 cases (P = .059). A standardized BiB-PFA workflow enables efficient, safe, and reproducible PVI with optional PWA and can be rapidly implemented during early operator experience.
Myocardial Infarction with No Obstructive Coronary Arteries (MINOCA) or Nonischemic Myocardial Injury affects approximately 1 in 9 patients presenting with acute coronary syndrome, yet evidence-based therapies are lacking. Coronary microvascular dysfunction is implicated in the pathogenesis of suspected MINOCA, but its prevalence, prognostic implications and treatment are uncertain. The objectives are, first, to assess the prevalence of coronary microvascular dysfunction in patients with suspected MINOCA and, second, to implement endotype-informed stratified medicine involving patients with coronary microvascular dysfunction to treatment with eplerenone, a cardio- and vasculo-protective mineralocorticoid receptor antagonist. This is a prospective, registry-based, multicenter, diagnostic study and nested, randomized, controlled, open-label, blinded-endpoint (PROBE) basket trial. Up to 400 patients with clinically suspected MINOCA and one or more cardiovascular risk factors will be enrolled into a registry-based diagnostic study. Coronary microvascular function will be assessed during invasive angiography using thermodilution. Patients with an index of coronary microvascular resistance (IMR) ≥ 25 will be randomized 1:1 to eplerenone (25-50 mg daily for 6 months) or standard care without eplerenone (control group) (n = 150 randomized). Final endotypes will be centrally adjudicated by a panel of blinded cardiologists. The primary outcome of the diagnostic study is the proportion of patients with IMR ≥ 25 during index coronary angiography. Secondary outcomes include coronary flow reserve, cardiovascular MRI parameters, patient-reported outcome measures, biomarkers of myocardial fibrosis and vascular inflammation, health outcomes and health economic assessments. The primary outcome of the randomized trial is the within-individual change in NT-proBNP at baseline, 1 month, and 6 months, based on intention-to-treat. Secondary outcomes include mechanistic blood biomarkers and patient-reported outcome measures. This registry-based randomized trial will provide novel evidence on endotype-informed secondary prevention therapy with eplerenone for suspected MINOCA.
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Freshwater clams belonging to the genus Corbicula have been identified as exotic animals in New Zealand. Here, we present the complete mitochondrial genome of C. australis from a sample collected in the North Island of New Zealand.
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Anti-programmed death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 antibodies are efficacious in various malignancies. The potential role of dual checkpoint inhibitors in many rare solid tumors is not established. This study presents the results of ipilimumab-nivolumab in salivary gland neoplasm cohorts of the SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) trial. DART is a prospective, open-label, multicenter (1016 US sites), multi-cohort phase II trial of ipilimumab (1 mg/kg intravenously (IV) every 6 weeks) plus nivolumab (240 mg IV every 2 weeks). We performed a prospective, multicenter phase II clinical trial of ipilimumab (1 mg/kg IV every 6 weeks) plus nivolumab (240 mg IV every 2 weeks) in three salivary gland neoplasm cohorts: major and minor salivary gland and adenoid cystic cancers. Patients with adenoid cystic salivary gland tumors (N = 26) and other salivary gland neoplasms (N = 34) were evaluable. The most common site of origin was the parotid (31%, N = 8 adenoid cystic group; 68%, N = 23 remaining histologies). In the adenoid cystic group, objective response rate (ORR), 4% (complete response (CR) 0%, N = 0; partial response (PR) 4%, N = 1); 6-month progression-free survival (PFS) and overall survival (OS), 32% (95% confidence interval (CI) 18%-57%) and 84% (95% CI 71%-100%), respectively. In the remaining histologic subtypes, the confirmed ORR was 9% (CR, 0%, N = 0; PR, 9%, N = 3); stable disease (SD) >6 months/PR/unconfirmed PR = 35%; 6-month PFS and OS, 34% (95% CI 21%-55%) and 88% (95% CI 78%-100%), respectively. The most common toxicities were fatigue (39%) and diarrhea (26%); diarrhea (8%) was the most common grade 3-4 immune-related adverse event. In salivary gland tumors, combined ipilimumab plus nivolumab resulted in only a 4% ORR in adenoid cystic carcinoma and 9% in all other histologies combined, though the latter showed clinical benefit (included SD >6 months) in 35% of patients.Trial registration: ClinicalTrials.gov registry: NCT02834013. Testing a dual immunotherapy treatment for rare salivary gland cancers Salivary gland cancers are rare, and there are limited treatment options for patients whose cancer has spread or returned after initial treatment. Immunotherapy helps the immune system fight cancer and has been successful in some other types of cancer. This study tested whether a combination of two immunotherapy drugs—one targeting CTLA-4 and the other targeting PD-1—could help treat these rare tumors. Patients with advanced salivary gland cancer took part in a clinical trial called DART. They received the two immunotherapy drugs and were monitored to see if their tumors shrank or stopped growing. Researchers also tracked any side effects caused by the treatment. Some patients responded well to the treatment, where their tumors got smaller or stopped growing for a period of time. However, not all patients benefited. Some experienced side effects, as the immune system can also attack healthy cells. This study shows that dual immunotherapy may be a promising option for some people with rare salivary gland cancers, but more research would be needed to understand who is most likely to benefit and how to manage side effects. The findings could help doctors develop better treatment strategies for these rare cancers in the future.
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Sleep disturbances are a prevalent global health concern with wide-ranging negative consequences. Although physical activity is recognized as a cost-effective strategy to enhance sleep quality, the specific impact of team sports such as football, basketball, handball, and volleyball-remains underexplored. This study systematically examines the effects of team sports on sleep quality. A comprehensive search strategy was used to retrieve all studies indexed in PubMed, Scopus, Embase, and Web of Science databases (up to June 11, 2024) with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. The search strategy incorporated keywords such as "Team sport*" OR "Teamsport*" OR "Handball" OR "Volleyball*" OR "Basketball*" OR "Netball*" OR "Basket ball" OR "football" OR "soccer" AND "Sleep Qualit*". Out of 1,148 initially identified records, 491 studies were screened, and 11 met the inclusion criteria for review. These studies involved 809 participants (367 males, 442 females) aged 13.5-65 years, including adolescents, college students, elite athletes, and untrained individuals. Findings showed that soccer, Zumba, volleyball, and handball interventions significantly improved sleep quality, while results for basketball were inconsistent college players benefited, but elite and wheelchair athletes showed no significant changes. Participation in team sports such as basketball, football, Zumba, handball, and volleyball appears to be associated with improvements in sleep quality. However, given the limited number of included studies and the heterogeneity in study designs, populations, and outcome measures, these findings should be interpreted with caution. Overall, the current evidence suggests a potentially positive relationship between engagement in team sports and sleep outcomes, but further well-designed and large-scale studies are needed to establish the strength and generalizability of this association. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024557907, identifier CRD42024557907.
Price promotions influence food choices and are disproportionately applied to foods high in fat, sugar and salt (HFSS), consumption of which is a known contributor to poor diet and diet-related non-communicable diseases. This study evaluates the effectiveness of (1) restricting price promotions of HFSS products and (2) allowing such promotions but restricting communications regarding them in changing purchasing behaviours. Between-subjects randomised controlled trial with three arms: (1) reduced price, labelled a price promotion ('Usual Practice'); (2) reduced price, not labelled a price promotion ('No Communication') and (3) standard price ('No Promotion'). Participants selected food and drinks for 2 d in a one-off shop, without restrictions on the number of items to purchase or the budget, at a simulated online supermarket. We measured total energy (kcal) in basket, total cost, total number of items, energy density (kcal/100 g) and proportion of the basket that was HFSS. Simulated online supermarket. Adults representative of the UK population (n 9004). There were no significant differences in energy in baskets between groups, after controlling for age, sex, household income, ethnicity and deprivation. No significant differences were found between groups' baskets for total cost, energy density or proportion HFSS. Participants in the 'Usual Practice' group selected significantly more items than the 'No Promotion' group (11·4 v. 11·1; P = 0·003). No significant effects of restricting price promotions, or communications of them, were found for purchasing behaviours in a simulated online supermarket. Further price-based interventions, especially in real-world settings, are needed to provide robust policy recommendations.
OBI-999 is an antibody-drug conjugate consisting of the Globo H-targeting antibody OBI-888 linked to the cytotoxic payload monomethyl auristatin E. In a dose-escalation study, the OBI-999 recommended phase 2 dose (RP2D) was 1.2 mg/kg every 3 weeks. This dose-expansion study evaluated the efficacy and safety of OBI-999 in patients with pancreatic cancer, colorectal cancer (CRC), or other tumor types ("basket cohort") and tumoral Globo-H H-scores ≥100 (NCT04084366). Patients were treated at the RP2D of OBI-999. We assessed response, progression-free survival (PFS), treatment-emergent adverse events (TEAEs), and pharmacokinetics of OBI-999. Of 29 patients treated, 23 were evaluable for response. Eight (34.8%) had stable disease): pancreatic cancer, 4 of 7; CRC, 2 of 8; basket cohort, 2 of 8. No objective response was noted. The median time on treatment was 22 days. No association between H-score and tumor size reduction was noted. Median PFS was 3.3 months, 1.3 months, and 1.4 months in the pancreatic, CRC, and basket cohorts, respectively. One patient (3.4%) experienced a serious TEAE related to OBI-999 (febrile neutropenia) that led to discontinuation of OBI-999; the TEAE resolved 3 days after onset. OBI‑999 showed consistent pharmacokinetics with comparable exposure at the RP2D across cohorts. OBI-999 had a favorable safety profile. Although 34.8% of patients had disease stabilization, no objective response was noted, likely owing to inefficient antigen binding, suboptimal systemic exposure at the tolerated dose, and complex tumor biology.