Radically different
Cancer drugs that can find and kill tumor cells with molecular precision have reshaped oncology—but their power fades when tumors evolve, diversify, or simply stop presenting the right molecular targets. Now, researchers at Washington University (WashU) School of Medicine in St. Louis have unveiled a modular “click‑to‑assemble” strategy that supercharges these therapies inside the body, allowing them to hit multiple tumor targets at once and reverse drug resistance in mice.
The study, published in Nature, is titled “Modular in vivo antibody–ADC click to reverse drug resistance in tumors,” and introduces a bioorthogonal ligation strategy that forms a dual‑targeting antibody–drug conjugate (ADC) with improved tumor uptake and therapeutic efficacy. In pancreatic, gastric, and breast cancer models, the approach slowed or halted tumor progression—even in tumors with low, ultralow, or heterogeneous HER2 expression, where conventional HER2‑directed ADCs typically fail.
“We’ve shown that when two cancer‑targeting antibodies bind together inside the body, they accumulate at the tumor more effectively and improve treatment response,” said senior author Patrícia M. Ribeiro Pereira, PhD, assistant professor of radiology at WashU Medicine’s Mallinckrodt Institute of Radiology. “There is a lot of excitement here because we have shown that it isn’t necessary to create a whole new drug platform for each therapeutic target. We can repurpose antibodies that already exist to improve treatments.”
The team’s strategy—called antibody–ADC click—relies on the rapid ligation between trans‑cyclooctene (TCO) and tetrazine moieties. In the study, one antibody (such as panitumumab, targeting EGFR) was modified with TCO, while a second antibody or ADC (such as trastuzumab‑deruxtecan, T‑DXd) carried tetrazine. When administered sequentially, the two components “clicked” together, forming a higher‑order complex that internalized more efficiently and delivered more cytotoxic payload.
The paper described the problem bluntly: “ADC efficacy remains constrained by its dependence on a single target antigen, which limits tumor targeting and promotes resistance in heterogeneous tumors with variable and low antigen expression.” The click strategy, the authors wrote, “provides a modular and translatable approach for enhanced targeted drug delivery in heterogeneous tumors.”
In mice bearing tumors with mismatched HER2 and EGFR expression, the clicked ADCs accumulated at levels up to 3.2‑fold higher than standard ADCs.
The modularity is the point. “The approach is flexible enough to be adapted to new cancer targets as we learn more about what drives treatment resistance,” Ribeiro Pereira added.
Next steps include further development and optimization of the click-enabled ADC platform prior to future clinical translation, along with expanding the platform to notoriously hard‑to‑treat cancers. “We’re trying to optimize this tool to help antibodies reach tumors that are normally very difficult to treat, such as brain tumors,” Ribeiro Pereira said.
The post Modular Antibody–ADC Click Chemistry Overcomes Tumor Drug Resistance in Mice appeared first on GEN – Genetic Engineering and Biotechnology News.
Background: Completion of homework, defined as therapeutic activities assigned between sessions to reinforce skills and promote behavior change, is strongly linked to therapy outcomes. Yet, homework compliance remains low, potentially due to outdated delivery methods such as paper or email. Mobile health technologies may improve engagement by digitizing therapy tasks and tracking progress. Yosa is a mobile health app designed to facilitate homework delivery and enhance engagement between sessions for patients in therapy. Objective: The primary aim of this study was to evaluate the perceived acceptability of Yosa among licensed therapists and individuals currently receiving therapy. A secondary aim was to examine whether key Technology Acceptance Model (TAM) constructs predicted attitudes toward and intention to use Yosa. Qualitative feedback was also collected to inform iterative development and future deployment. Methods: Two cross-sectional surveys were conducted: study 1 with licensed therapists (N=45) and study 2 with current therapy patients (N=96). Participants viewed video demonstrations of Yosa, learned about Yosa’s features, and rated the app on TAM constructs, including perceived usefulness, perceived ease of use, perceived risk, attitude toward, and intention to use Yosa, using 0‐100 scales. For most constructs, higher scores reflected more favorable evaluations, whereas lower perceived risk scores reflected more favorable evaluations. Descriptive statistics and 95% CIs were generated for each construct in both samples, with scores interpreted relative to the neutral midpoint (50). Multiple regression analyses were conducted to examine predictors of attitude and intention to use. Qualitative feedback from the surveys was analyzed thematically. Results: Therapists and patients reported generally favorable perceptions of Yosa across TAM domains. Among therapists and patients, ratings of the perceived usefulness of the homework feature, therapy journal, and overall app; perceived ease of use; attitudes toward Yosa; and intention to use were all above the midpoint. Perceived risk scores were mild to moderate in patients and moderate in therapists, respectively. Regression analyses indicated that perceived usefulness was a positive predictor of both attitude toward and intention to use Yosa across therapists and patients, while perceived risk was negatively associated with these outcomes in several models. Qualitative themes included requests for additional features, usability enhancements, and data privacy concerns. Conclusions: Therapists and patients reported generally favorable perceptions of Yosa after reviewing descriptions and video demonstrations of the platform, particularly in terms of usefulness and ease of use, supporting favorable perceptions of its potential acceptability as a digital tool for between-session therapy support. Qualitative feedback informed refinements aimed at reducing perceived risks and enhancing the intention to use.
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Trial Registration: ClinicalTrials.gov NCT05264740; https://clinicaltrials.gov/study/NCT05264740 International Registered Report Identifier (IRRID): RR2-10.1186/s40814-023-01385-0
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Background: Temporal fluctuations in distress and suicidal ideation across daily, weekly, and seasonal cycles may influence the use and effectiveness of digital suicide prevention tools. Understanding patterns of app engagement, perceived suffering, and affective expression can inform the design of proactive, personalized digital interventions, thereby impacting adherence and efficacy. Objective: This study aimed to examine temporal patterns of engagement with 2 core components of the suicide prevention app SERO (Suicide Prevention: a Uniform Effort, Resource-Oriented; BFH, Lucerne Psychiatry), specifically the safety plan and the PRISM-S (Pictorial Representation of Illness and Self-Measure—Suicidality) self-assessment, using 3 years of interaction log data, assessing variations across circadian, weekly, and seasonal cycles, and evaluating the sentiment of free-text responses submitted immediately after PRISM-S self-assessments. Methods: We analyzed anonymized interaction logs from the SERO app collected over 3 years (November 2022 to December 2025). Engagement metrics included the frequency of use of the safety planning functionality and PRISM-S self-assessment entries. Free-text responses provided after PRISM-S assessments were analyzed using automated sentiment classification. Temporal analyses examined variations by the hour of the day, day of the week, and season. One-way ANOVAs, post hoc tests, and Pearson correlations were used to examine patterns and associations between perceived suffering and sentiment. Results: A total of 1076 users engaged with the safety planning functionality of the SERO app, generating 3502 entries, with coping strategies and warning signs showing the highest mean interactions and personal beliefs the lowest. Separately, 1212 app users accessed the PRISM-S self-assessment, producing 2329 entries (mean distance 12.91, 95% CI 12.39‐13.42 cm), with most app users recording only 1 or 2 registrations. Safety planning engagement showed clear diurnal patterns, peaking in the afternoon (2 PM to 3 PM) and being lowest at night (midnight to 3 AM), whereas PRISM-S scores were stable across time. Sentiment analysis revealed predominantly negative affect (mean score of −0.41, SD 0.51, 95% CI −0.44 to −0.39), correlated with PRISM-S distance, and was most negative at night (specifically at 11 PM) and during the afternoon (2 PM to 5 PM). Seasonal effects were small but significant for PRISM-S, with the lowest perceived suffering in summer. Conclusions: Digital suicide prevention tools can support routine patterns of coping behavior, but periods of increased reported distress, particularly at night, may be underaddressed. Integrating automated sentiment analysis alongside self-assessments could potentially enable personalized, time-adaptive interventions that detect changes in emotional state and deliver timely, tailored support, thereby strengthening proactive engagement and resilience.
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Turmoil at the American Diabetes Association has taken a fresh turn, with leaders blocking editors at its flagship journal from publishing an opinion piece and first-person accounts detailing a high-profile controversy at the group’s own annual meeting just last month.
Nearly five weeks after five diabetes specialists were escorted out of a convention center in New Orleans for handing out reprints of an editorial expressing concern over cuts to federal research, the ADA’s flagship journal, Diabetes Care, was preparing to publish an editorial and several accounts detailing the episode, which drew national attention and prompted the ADA to both apologize for the evictions and pledge a formal review. But the organization says it delayed publication pending the outcome of that review — even as there is disagreement about how it is being carried out.
In the spiked editorial and personal accounts, now available on an open-access website, the diabetes specialists who were ejected in early June detail their treatment. Prominent ADA members, including past leaders and one who resigned in the wake of the confrontation, also express dismay over how the events were handled initially and afterward. All voice disappointment over the decision to suppress views opposing policies of the Trump administration while also disagreeing with how ADA’s leadership handled the episode and its aftermath.
Response to cancer therapies is highly variable. While some cancers that have genomic defects, including microsatellite instability (MSI) and deficient DMA mismatch repair (dMMR) are understood to be more likely to activate the immune system, the mechanism underlying this response is still unclear.
Researchers from the Keck School of Medicine of USC have identified a genetic feedback loop in colorectal cancers that may explain one such mechanism. They recently published their work in Gastroenterology.
The team, led by Lin Zhang, PhD, professor and chair of oncology at the Keck School of Medicine, and Heinz-Josef Lenz, MD, associate director for clinical research at the USC Norris Comprehensive Cancer Center, focused on identifying the “role and mechanism of MSI-induced antitumor immunity and immunogenic cell death response.”
To do this, they used a combination of methods including createing a mouse model with transplanted tumor cells, immune cell assays and organoid data to elucidate the mechanism of action for the dMMR derived antitumor immune response.
Mice injected with tumor cells lacking a functional Mlh1, a gene that is involved with DNA repair, showed increased immune response that was tracked for cell signaling, behavior, and gene activity. Researchers identified Death Receptor 5 (DR5) and Ligase 3 (Lig3) as immune response mediators.
“We found that inactivating Mlh1 causes endoplasmic reticulum stress and Dr5–mediated apoptosis in syngeneic colorectal tumors,” the authors wrote. “Sustained immune response against Mlh1-deficient tumors requires nuclear Lig3–mediated release of extrachromosomal circular DNAs from apoptotic cells. A feedback Dr5/Lig3 amplification loop perpetuates apoptosis and immune cell activation in Mlh1-deficient syngeneic tumors.”
This continued immune response to dying tumor cells is critical for effective response to immune checkpoint inhibitor therapy, but it is not the complete story.
“We’ve gathered enough evidence to suggest that this feedback loop is an important piece of the puzzle,” said co-lead author Zhang. “Our hope is that these findings can someday help make cancers more visible to the immune system and more responsive to immunotherapy treatment.”
Validation of these results in humans is a necessary next step to get closer to the clinic. The team analyzed data from human patients, examining gene expression in colorectal cancers. They found that in patients with higher levels of DR5 and Lig3 activity, immune checkpoint inhibitor therapies were move effective at treating the cancer, and those patients were more likely to respond better to treatment.
“One of the most encouraging parts of the study was seeing that the same signals showed up in patient tumors,” Zhang said. “That suggests we’re uncovering a mechanism that could be clinically relevant.”
Moving forward, the team plans to explore the effectiveness of drugs that activate the DR5 pathway and investigate alternative methods for how to incorporate DR5 and Lig3 into personalized colorectal cancer therapies. They also note that, “Our results reveal a functional link between dMMR and antitumor immunity, which may be useful for improving immune checkpoint inhibitor therapy in tumors with different MMR statuses.”
The post Immunotherapy More Effective in Colorectal Tumors with Active DR5 Pathway appeared first on Inside Precision Medicine.
Background: Type 1 diabetes remains an underrecognized and challenging condition across Southeast Asia, where many countries face limited health care infrastructure, shortages of trained health care professionals, inconsistent access to diabetes education, and a lack of culturally appropriate resources in local languages. These barriers contribute to delayed diagnosis, suboptimal self-management, high rates of diabetic ketoacidosis, and inequities in care. During the COVID-19 pandemic, Action4Diabetes, a nonprofit organization working with local health care professionals and diabetes associations across Southeast Asia, developed HelloType1, a multilingual digital educational platform designed to improve awareness, education, and access to credible type 1 diabetes information. The platform was launched sequentially in Cambodia in 2021, Vietnam and Thailand in 2022, and Malaysia in 2023 through formal memorandums of understanding with local partners. Objective: This study aimed to evaluate the reach, platform usage, and online engagement of the HelloType1 digital educational platform across Southeast Asia between 2021 and 2024. Methods: Website analytics from Google Analytics 4 and Meta Business Suite metrics were descriptively analyzed to assess digital reach and engagement across countries. Metrics were compared over time and by country to examine patterns of platform uptake and user engagement. Results: HelloType1 demonstrated substantial growth between 2021 and 2024. Total unique website users increased from 1178 in 2021 to 40,361 in 2024, representing a marked expansion in regional reach. Pageviews rose from 4644 in 2021 to 83,689 in 2024, suggesting increasing content use and user platform engagement. By 2024, most website visits originated from organic search engines. Platform use was predominantly mobile-based, particularly in Vietnam, Thailand, and Malaysia, with the strongest engagement among adults aged 25 to 54 years. Facebook followers increased from 940 to 4553, and average engagement rates rose between 2022 and 2024. Cambodia achieved the highest number of Facebook interactions, whereas Thailand demonstrated the highest engagement rate. Content-level analysis showed that practical self-management topics, including blood glucose monitoring, insulin treatment, nutrition and exercise, complications, and emotional support, generated high levels of reach and interaction. Conclusions: HelloType1 demonstrates strong growth, mobile-first use, search-driven visibility, and engagement with practical self-management content. These findings support the feasibility and potential utility of a low-cost, multilingual digital education model, while future studies should evaluate its effects on knowledge, behavior, and clinical outcomes.
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Background: AI is an increasingly prominent feature of contemporary health care, with medical AI systems beginning to support diagnostic and therapeutic processes in many clinical domains. Alongside the anticipated benefits of these technologies, their introduction also raises broader questions about how clinical work and professional roles may change. In particular, medical AI systems may affect physician autonomy, a key factor influencing the acceptance and long-term implementation of new medical technologies. Objective: The aim of this study was to develop and pretest a semistructured interview guide concerning the potential effects of medical AI systems on physician autonomy. Methods: The interview guide was theoretically grounded in a 7-component model of physician autonomy proposed by Schulz and Harrison. Semistructured qualitative interviews were conducted with a sample of 7 hospital physicians. Interview recordings were transcribed and analyzed using a hybrid inductive-deductive thematic approach: themes were first identified inductively from participant responses and subsequently mapped onto the 7-component model of physician autonomy proposed by Schulz and Harrison. Data were analyzed to assess both the potential effects of medical AI systems on physician autonomy and the methodological adequacy of the interview guide. Results: Most participants did not express strong concerns about losing clinical autonomy through the introduction of AI systems. However, several autonomy-related risks were identified, including potential deskilling, automation bias, limited system explainability, and increasing economic or cost-related pressures. Participants emphasized that AI should serve as a supportive tool rather than a substitute for physician judgment. All physicians agreed that AI systems should not replace clinicians as primary clinical decision-makers. Conclusions: Medical AI was largely viewed as compatible with physician autonomy; however, participants highlighted important risks that warrant attention in future research and system design. Our preliminary findings suggest that autonomy-related concerns extend beyond the direct loss of decision-making authority and include broader professional, cognitive, and organizational dimensions. However, our inductively identified themes and subthemes did not fully reflect all components of physician autonomy, indicating the need for further refinement of how to assess physician autonomy in qualitative research.
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