The SLIT2-ROBO signaling axis plays a context-dependent role in cancer, functioning as either a tumor suppressor or oncogenic driver. This bidirectionality creates both therapeutic opportunity and significant challenges for drug development and patent strategy. This review analyzes patents targeting SLIT2-ROBO axis inhibition in cancer from 2020-2026. Patent families were retrieved from Google Patents, Espacenet, and WIPO PATENTSCOPE, consolidated by INPADOC family, and evaluated for mechanistic relevance and experimental enablement. Therapeutic modalities include antagonistic antibodies, ligand traps, small molecule and macrocyclic PPI disruptors, nucleic-acid approaches, and bispecific constructs. Each family was assessed using an enablement framework and a directionality-risk checklist, with emphasis on biomarker gating and translational feasibility. The current patent landscape is limited by lack of biomarker-driven stratification and incomplete enablement. Future progress will depend on integrating robust assay-to-asset pipelines with biomarker-guided deployment strategies to ensure both clinical efficacy and durable intellectual property.
Disruptive technologies can reconfigure innovation trajectories and create new market opportunities, yet their early detection remains difficult because disruptive impact is uncertain and often becomes visible only years after invention. Building on the CD disruptiveness measure derived from citation-network dynamics, this study develops an interpretable machine-learning framework to screen and prioritize potentially disruptive patent candidates ex ante. Using IncoPat patent records in the artificial intelligence domain, we construct a multidimensional indicator system spanning technological, market, and legal signals. To ensure conceptual consistency with the CD framework, the main disruption label is defined as patents falling within the top 5% of the empirical CD distribution among patents with at least one backward citation. This definition allows disruptiveness to be assessed relative to identifiable prior art and reduces reliance on extreme CD values that may be sensitive to incomplete reference information. We train models on a time-split learning set covering patents filed from 2007 to 2021 and evaluate their ability to predict this stricter disruption label using early observable patent metadata. Among benchmarked classifiers, AdaBoost provides the most competitive screening performance after feature selection, reducing the feature space from 17 to 12 indicators. Under the main top-5% specification, the model achieves an accuracy of 0.914, a precision of 0.271, a recall of 0.431, and an F1 score of 0.333, indicating modest but nontrivial early-screening ability. Feature importance analysis highlights the predictive relevance of citation- and disclosure-related signals, including family citation activity, backward citations, and document length. The framework is best interpreted as a scalable candidate-generation tool for monitoring and expert review within the patented segment of AI innovation, rather than as a definitive classifier of realized disruptive impact.
This research presents a comprehensive review of the regulatory framework for pharmaceutical patents in Japan by analyzing the foundational legal structures governing the pharmaceutical sector, with a focus on the marketing authorization and reimbursement pricing mechanism. Through an in-depth assessment of patent legislation and its pharmaceutical applications, the paper also highlights ongoing challenges within existing legislative and enforcement mechanisms, referencing key judicial decisions and prevailing industry practices. Furthermore, the study offers practical suggestions to address such challenges with reference to other countries' experiences and practices, aiming to enhance the protection of stakeholders' rights and promote the advancement of the healthcare sector, which ultimately contributes to innovation development and improved medical access in Japan.
Liver transplantation (LT) provides the best long-term survival outcomes for patients with liver cancer. As a result, the field of transplant oncology has grown greatly over the past few decades, and many centers have expanded their criteria to allow increased access to LT for liver malignancies. Center-level guidelines and practices in transplant oncology significantly vary across the world, leading to debate regarding the best course of treatment for this patient population. An international consensus conference was convened by the International Liver Transplantation Society and the International Liver Cancer Association on February 1-2, 2024, in Valencia, Spain, to establish a more universal consensus regarding LT for oncologic indications. The conference followed the Delphi process, followed by external expert review. Consensus statements were accepted regarding patient assessment and waitlisting criteria, pretransplant treatment (including immunotherapy) and downstaging, living donor LT, post-LT patient management, and patient- and caregiver-related outcomes. The multidisciplinary participants in the consensus conference provided up-to-date recommendations regarding the selection and management of patients with liver cancer being considered for LT. Although participants deferred to center protocols in many cases, there was great interest in safely expanding access to LT for patients with larger tumor burden and biologically amenable lesions.
Cardiovascular-kidney-metabolic syndrome is driven by inflammatory mechanisms that propagate injury across organ boundaries, yet the molecular mediators converting systemic inflammation into end-organ damage remain incompletely defined. Across multiple prospective cohorts, suPAR (soluble urokinase plasminogen activator receptor) is associated with incident cardiovascular events, heart failure, diabetes, and kidney disease progression, and genetic and experimental studies support a causal role. How a glycosylphosphatidylinositol-anchored receptor without a transmembrane domain initiates intracellular signaling has remained a fundamental paradox. A membrane-tethered receptor, uPAR, addresses this paradox by assembling lateral signalosomes with coreceptors including αvβ3 integrin, the receptor for advanced glycation end-products, and receptor tyrosine kinases on myeloid, endothelial, and vascular smooth muscle cells, transducing signals that drive atherosclerotic plaque inflammation, vascular remodeling, and maladaptive fibrosis. Proteolytic and lipolytic cleavage of uPAR releases suPAR and its fragments into the circulation; a cleavage/release switch that converts locally scaffolded signaling into diffuse systemic agonist activity and links inflammation in 1 tissue to injury in distant organs. SuPAR activates podocyte αvβ3 integrin and receptor for advanced glycation end-products, now identified as an obligate coreceptor, triggering a Rac1/NOX2-Src-TRPC6 (transient receptor potential canonical channel 6) cascade that produces proteinuria and glomerulosclerosis. The D2D3 cleavage fragment drives insulin-dependent diabetes in transgenic mice through direct β-cell toxicity, an effect reversed by anti-uPAR antibody. This framework reframes the uPAR/suPAR axis not as a single biomarker but as a compartmentalized signaling system operating in distinct modes across cardiovascular-kidney-metabolic-relevant cell types. We map pharmacologically tractable intervention nodes spanning transcriptional suppression, suPAR neutralization, receptor interface disruption, and downstream kinase and channel inhibition, and propose that matching therapeutic strategy to the predominant signaling mode may enable disease-context-dependent precision approaches to cardiovascular-kidney-metabolic syndrome.
Increased radiation exposure during congenital heart disease procedures may have a detrimental effect on patients, especially in the pediatric population. Advances in imaging systems and adherence to the ALARA (As Low As Reasonably Achievable) principle are paramount in minimizing radiation exposure. This is a single center, retrospective study designed to understand the degree of radiation reduction achievable with a novel ultra-low dose fluoroscopy protocol (ULDFP). Patients were included in the study if they underwent any one of the following procedures between 12/1/2021 and 12/31/2023: atrial septal defect (ASD) device closure, coarctation balloon or stent angioplasty, patent ductus arteriosus (PDA) closure, pulmonary valvuloplasty, and aortic valvuloplasty. Our radiation doses were compared to published benchmarks and current registry data. Phantom studies were done to evaluate the radiation reduction achieved by using the novel ULDFP as compared to our standard protocol. We report significant reduction in radiation exposure for pediatric patients undergoing interventional cardiac catheterization procedures achieved predominantly by near-complete elimination of cine angiography and use of ULDFP. Values reported in this study represent a dose reduction of greater than 90% compared to current benchmark doses by Cevallos [1] et al. and Lamers [2] et al., and greater than 85% compared to current CRISP registry data. Use of an ULDFP and the near elimination of cine angiography drastically reduces radiation dose in pediatric patients undergoing cardiac catheterization procedures even when compared to current registry data. Reducing radiation exposure in this vulnerable cohort may potentially play a significant role in lowering morbidity associated with cardiac catheterization.
Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterised by recurrent abdominal pain or discomfort that is often related to defaecation or associated with a change in stool frequency or form. IBS is common in Australia and affects women more than men. The exact pathophysiology remains unclear, though it can be multifactorial and relate to gastrointestinal dysmotility, post-infection and microbial changes, and a patient's psychosocial background. A positive clinical diagnosis can be made when the Rome V criteria are met, alarm features are absent and simple screening tests (full blood count, C-reactive protein, coeliac serology) are negative. If alarm features are present, further examination, laboratory testing or imaging may be helpful in assessing for organic pathology. Management involves lifestyle and dietary modifications, and psychological and pharmacological therapies. Pharmacological therapy should be individualised to the patient's IBS subtype and symptoms. Examples of drug classes that are used include antispasmodics, osmotic laxatives, antidiarrhoeal drugs and neuromodulators (tricyclic antidepressants). There is insufficient evidence to support the use of therapies such as probiotics, faecal microbiota transplantation, and mesalamine.
To evaluate the short-term effects of professional scaling and polishing on nine oral health and dental aesthetic outcomes in current smokers and never smokers. A total of 371 participants from the SMILE Study Cohort (305 smokers and 66 never smokers) were assessed at baseline (V0) and 14 days after scaling and polishing (V1). Outcomes included Modified Gingival Index (MGI), quantitative light-induced fluorescence parameters (ΔR30, reflecting the percentage of tooth surface covered by mature plaque, and ΔR120, reflecting the percentage covered by thicker deposits including calculus), MacPherson-modified Lobene Stain Index (MLSI) for buccal and lingual surfaces, Whitening Index for Dentistry (WID), Simple Oral Hygiene score (SOH), oral health-related quality of life (OHRQoL), and general health perception (EQ-VAS). Linear mixed model analysis was used for between-group comparisons of V0-V1 changes. At baseline, smokers exhibited significantly worse values across all objective indices. Following intervention, significant improvements were observed in MGI, MLSI, ΔR30, ΔR120, and SOH in both groups (p<0.0001). MGI improved by a median of -0.5 units in smokers (IQR: -0.8/-0.2) and -0.08 units in never smokers (IQR: -0.3/-0.02); the magnitude of improvement was significantly greater in smokers (p<0.0001). Similarly, greater reductions in buccal MLSI (p<0.0001), lingual MLSI (p<0.0001), and ΔR120 (p=0.010) were observed in smokers compared to never smokers. WID showed no significant changes in either group. OHRQoL improved slightly without between-group differences; EQ-VAS did not change significantly. Professional scaling and polishing produced consistent short-term improvements in objective oral health indicators in both smokers and never smokers, with greater gains among smokers reflecting their higher baseline burden. Regular professional mechanical plaque removal is clinically beneficial for smokers, producing measurable short-term improvements in gingival and aesthetic parameters even in the presence of ongoing tobacco exposure, although smoking cessation remains essential for long-term oral health.
The Functional Liver Imaging Score (FLIS; range 0-6, with higher scores indicating better liver function), derived from gadoxetic acid-enhanced MRI, is a prognostic imaging biomarker in advanced chronic liver disease (ACLD). Our aim was to investigate whether semiquantitative FLIS and quantitative imaging parameters, namely relative liver enhancement (RLE), relative enhancement ratio of the biliary system (REB), and liver-to-portal vein contrast ratio (LPC), predict acute-on-chronic liver failure (ACLF; a syndrome defined by extrahepatic organ failure and high short-term mortality)/liver-related mortality in acute decompensation (AD), the main at-risk population. We included 210 patients with ACLD with GA-MRI-derived, semi-quantitative FLIS, in whom the RLE, REB, and LPC were also computed by two independent, experienced radiologists. Patients were stratified into clinically stable ACLD (including compensated or non-acutely decompensated) and AD. The prognostic value of semi-quantitative FLIS and quantitative GA-MRI parameters for ACLF/liver-related death was evaluated using competing risk regression analyses, considering liver transplantation as a competing event. The FLIS was lower in AD (vs. clinically stable ACLD). Furthermore, low FLIS was an independent risk factor for ACLF development/liver-related death in AD (adjusted subdistribution hazard ratio [aSHR]: 2.37 [95%CI: 1.08-5.17], p=0.031; accounting for MELD-Na, albumin, and aetiological cure), but not in clinically stable ACLD (aSHR: 1.58 [95%CI: 0.73-3.45], p=0.250). Conversely, while RLE, REB, and LPC could distinguish between AD and clinically stable ACLD (p<0.001), they failed to predict ACLF/liver-related death. The Functional Liver Imaging Score (FLIS) is a simple prognostic imaging biomarker in acute decompensation that predicts acute-on-chronic liver failure and liver-related mortality. FLIS-based risk stratification may help identify patients who could benefit from intensified monitoring or timely liver transplant evaluation. The visual, semi-quantitative Functional Liver Imaging Score (FLIS), derived from gadoxetic acid-enhanced MRI, assesses liver function. We found that FLIS predicts acute-on-chronic liver failure/liver-related mortality in patients with acutely decompensated cirrhosis, independent of established risk scores. Conversely, quantitative MRI parameters did not add prognostic value.
Monoclonal antibodies (mAbs) have revolutionized therapeutic treatments by their ability to target specific antigens, leading to enhanced clinical outcomes over other drugs. They are one of the largest modalities within the growing biotherapeutics space and are indicated for a range of diseases. Though transformative, mAbs are still not readily accessible to many patients globally because of their high costs. An increasing number of mAbs are losing patent exclusivity, which has opened the door for the development of biosimilars that could drive down costs and ensure increased access to these life-saving drugs. Regulators approve biosimilars after conducting a rigorous evaluation similar to any other biologic medicine to ensure the safety, quality, and efficacy of these products. To establish biosimilarity, extensive comparative analytical and clinical studies of the biosimilar product with the approved reference product is a regulatory expectation. Growing acceptance from regulators to potentially waive clinical efficacy studies when robust evidence for similarity with reference product is established from analytical, functional, and pharmacokinetic/pharmacodynamic studies will have a major impact on reducing the time and cost of developing biosimilars. Comparative analytical assessment includes side-by-side analysis of the biosimilar with the reference product to demonstrate similarity regarding their physicochemical and functional characteristics. This is usually achieved by identifying product quality attributes (PQAs) that could impact clinical safety and efficacy and applying orthogonal analytical methods to characterize these attributes to identify any differences between the products. This review identifies the common PQAs studied for approved mAb biosimilars in the United States and the European Union through to the end of 2024. We have also compiled the data for the analytical methods used to characterize these attributes and identified a subset of methods universally used among biosimilar applicants. Finally, a brief overview of the risk-based analysis of attributes is summarized from the regulatory submissions.
Sonobiopsy is a promising new technique that employs focused ultrasound (FUS) to noninvasively enrich brain tumor-derived biomarkers from spatially targeted brain location into the bloodstream. Building upon our recent first-in-human sonobiopsy trial demonstrating enrichment of circulating tumor DNA (ctDNA), here we investigated whether sonobiopsy can enhance the release and detection of tumor-derived microRNAs (miRNAs). Eleven patients with glioma underwent FUS sonication immediately prior to surgical resection. Peripheral blood samples were collected 5 min before and 5, 10, and 30 min after sonication. Plasma and brain tissue miRNA levels were quantified through small RNA sequencing and compared among different time points. Plasma miRNAs that were below the detection threshold [reads per million (RPM) <10] showed significant enrichment at all post-FUS time points across all patients, with a maximal increase of 8.7-fold at 30 min. In contrast, miRNAs above the detection threshold (RPM ≥10) exhibited no significant change following FUS. Among the miRNAs that were initially below the detection threshold but increased to detectable levels following sonobiopsy, miR-29c-5p, miR-125b-1-3p, miR-129-5p, miR-132-3p, miR-143-5p, miR-149-5p, miR-195-5p, miR-218-5p, miR-329-3p, and miR-1271-5p were associated with cancer- and glioma-related biological pathways. These findings extend our prior work and support sonobiopsy as a spatially targeted, noninvasive multimodal liquid biopsy platform. By increasing the detectability of otherwise difficult-to-detect tumor-derived signals, sonobiopsy has the potential to advance the development of sensitive molecular diagnostics for glioma without surgery.
The androgen receptor (AR) is expressed in 75% of estrogen receptor-positive (ER+) breast cancers (BC). Selective AR modulators (SARMs), like EP0062, present a promising therapeutic strategy for ER + BC, particularly in patients who cannot tolerate endocrine therapy (ET) or whose tumors have developed resistance. We aimed to study the antitumor activity of EP0062 in ER+ patient-derived xenograft (PDX) models. EP0062 displayed comparable antitumor efficacy to selective ER degraders (SERDs), including in PDXs with ESR1, PIK3CA, or PTEN mutations. Tumors sensitive to SARMs were enriched in GATA3 mutations. EP0062 treatment induced AR-target genes across all models tested. A transcriptional signature associated with SARM sensitivity was identified, primarily driven by proliferation-related processes, consistent with a significant decrease in S-phase cell cycle proteins upon treatment in EP0062-sensitive models. In some EP0062-resistant tumors, the combination with palbociclib enhanced the antitumor effect of EP0062, suggesting a potential strategy for metastatic patients with acquired ET resistance.
To evaluate the effectiveness of a novel suspension bending cast (SBC) technique for early-onset scoliosis (EOS) that enables coronal correction through suspension-assisted bending and facilitates derotational molding, and to identify factors associated with curve improvement. A retrospective review was conducted on 49 patients with EOS who underwent SBC between 2011 and 2023. For inclusion, patients had to be < 10 years at casting initiation and have ≥ 2 years of follow-up. Curves were measured before the first cast, after the first cast, at the end of casting, and at final follow-up. We analyzed curve improvement, scoliosis type, rib phase, and rib-vertebral angle difference (RVAD). Median age at initial casting was 44 months (interquartile range [IQR] 25-78). The median number of casts was 3 (IQR 2-6); the median follow-up was 58 months (IQR 35.0-81.6). The median curve was 63° before casting, corrected to 21° in the first cast, and 67° at final follow-up. Of the 49 patients, 30.6% went from casting to definitive fusion, and an additional 30.6% underwent additional surgery before definitive fusion, while the remaining 38.8% were "cured" or remain under non-operative management. Time from first cast application to any surgery was 38.6 months (IQR 21.9-58.5). Curve improvement (from initial to final) was associated with higher initial correction rates. Idiopathic scoliosis demonstrated greater initial correction than non-idiopathic scoliosis. No differences were observed in final curve or correction rate based on rib phase or RVAD. Suspension bending casts showed high initial correction in patients with moderate to severe EOS and contributed to delayed surgical intervention. A higher correction rate after the first cast was associated with long-term curve improvement, indicating that initial correction of casting may be an important prognostic factor.
Organ-on-a-chip (OoC) platforms are microengineered systems that combine microfluidic control with living cells to emulate the physiological functions of human tissues and organs in vitro. OoC has become a transformative tool in pharmaceutical research, offering unprecedented capabilities for predicting drug efficacy, pharmacokinetics, and toxicity with human-relevant precision. This study presents a comprehensive scientometric and patent landscape analysis of OoC studies in pharmaceutical sciences spanning 2008-2025. Using CiteSpace, we mapped 1,786 publications to identify influential authors, landmark works, and temporal shifts in thematic focus. Keyword burst and clustering analyses reveal emerging frontiers in multi-organ integration, disease modeling, and drug screening. Patent data indicate a rapid expansion since 2016, led by China and the United States, underscoring a translational trajectory from fundamental research to applied biotechnology. These findings delineate the evolving intellectual and technological framework of organ-on-a-chip research in drug development and highlight future priorities in multi-organ systems, biomaterials optimization, and clinical translation.
Single chain urokinase (LTI-01) intrapleural enzymatic therapy (IET) was safe and promising in a phase 1 clinical trial to overcome failed drainage in patients with pleural infection. The LTI-01-2001 phase 2a trial was a randomized, double-blind, placebo-controlled, multi-center, dose-ranging study in hospitalized subjects with infected, non-draining pleural effusions. LTI-01, in doses of 400,000, 800,000 or 1,200,000 Units, or placebo was administered intrapleurally once daily for up to 3 days. The primary efficacy endpoint was incidence of treatment failure within 7 days of starting study medication. Treatment failure was defined as requiring alternative pleural therapy irrespective of subsequent treatment. Pleural opacification was a secondary endpoint and was assessed by CT imaging of the change in opacified area expressed as a percentage of the ipsilateral hemithorax (relative change) or absolute change in pleural opacification volume expressed in liters. 40/43 enrolled patients received LTI-01 or placebo due to constraints of the COVID-19 pandemic. There was no significant difference in incidence of treatment failure between the LTI-01 and placebo groups (OR 1.04, 95% CI 0.24,4.44, P = 0.96) while two predetermined sensitivity analyses demonstrated trends of improved efficacy in the 400,000 U group (P = 0.052 and 0.147). The absolute (Liters; L) and relative change from baseline in opacity volume were - 0.28 L (p=0.035) and - 55.8% (P = 0.064) versus placebo in the 800,000 U group, with significant reduction in absolute opacification found in the 400,000 and all LTI-01-treated groups combined (P < 0.03, respectively). There were no safety signals of concern, nor were there any episodes of intrapleural or pulmonary bleeding in LTI-01-treated patients. No statistically significant difference in the incidence of treatment failure was seen, potentially related to low recruitment. Trends towards efficacy were observed in predetermined sensitivity analyses at the 400,000 U dose of intrapleural LTI-01. Pleural opacification appeared most improved by the 800,000 U intrapleural LTI-01. A larger phase 2b trial is required to confirm these results or determine the efficacy of LTI-01 in patients with organizing, nondraining, infected pleural effusions. ClinicalTrials.gov NCT04159831. Registration date: November 12, 2019.
A major barrier in mucosal vaccine development is achieving localized immunity without systemic toxicity. Here we engineered NanoCF501, a nanoparticulate STING agonist formulated with a 2-ethyl-2-oxazoline polymer. As an adjuvant, NanoCF501 facilitates efficient mucus penetration and localized respiratory retention, minimizing systemic exposure as confirmed by pharmacokinetics in rats. In mice, intranasal co-administration of NanoCF501 (1/20th the systemic dose) with an antigen comprising multivalent fragments derived from different coronaviruses induced robust mucosal and systemic immunity, conferring protection against homologous/heterologous pan-β-coronaviruses. Single-cell transcriptomics reveals STING-dependent reprogramming of lung antigen-presenting cells, enhancing adaptive responses. Our results were further validated in non-human primates and were extended to licensed influenza vaccines, showing that NanoCF501 can be used to repurpose intramuscular antigens for mucosal delivery. By integrating nanoscale rational design with innate targeting, NanoCF501 establishes a universal adjuvant for next-generation vaccines, advancing nanomedicine for pandemic preparedness.
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Cadmium (Cd) is a toxic and carcinogenic heavy metal, and rice, as a staple food, is a major source of dietary Cd intake. Therefore, limiting the transfer of Cd from soil to rice grain without compromising grain yield is a critical issue for human health. In this study, through base-editing-mediated mutagenesis screening targeting OsNramp5, a major transporter gene for manganese (Mn) and Cd uptake, we identified a single amino acid substitution at position 441 (Ile to Thr) that significantly reduced Cd accumulation in both shoots and grains without affecting the accumulation of other essential metals. Functional analysis revealed that this point mutation did not alter gene expression, protein abundance, subcellular localization, or Cd and Mn transport activity in yeast. However, we found that OsNramp5 also transports zinc (Zn), and the point mutation increased its selectivity for Zn. It is likely that elevated Zn levels in root cells competitively inhibit Cd release into the xylem, thereby reducing root-to-shoot Cd translocation. A field trial confirmed that the mutated OsNramp5 did not affect grain yield or essential micronutrient concentration but significantly decreased Cd accumulation in grains. Our findings suggest that precise editing of this key residue in OsNramp5 offers an effective strategy to reduce Cd transfer from soil to rice grain without yield penalty.
Aldehyde dehydrogenase (ALDH) isoforms are crucial for cellular detoxification and metabolic regulation, yet their enzymatic properties with non-canonical substrates remain underexplored. ALDH1A isoforms are overexpressed in several cancer types and contribute to tumor aggressiveness and chemoresistance. In this study, we characterize the esterase activity of ALDH1A isoforms using novel resorufin-derived fluorogenic substrates. Steady-state kinetic analysis reveals distinct catalytic efficiencies (kcat/Km) among isoforms, emphasizing differences in substrate hydrolysis rates and binding affinities. Structural modeling and fluorescence-based assays indicate that NAD+ binding induces conformational rearrangements that modulate esterase activity. Resorufin-derived esters clearly outperformed 4-nitrophenyl acetate and standard aldehyde substrates of ALDH. These findings provide mechanistic insights into ALDH1A isoform selectivity and expand the application of resorufin-based probes for ALDH functional assays. Our study establishes a foundation for developing targeted ALDH assays and potential applications in cancer drug screening and biomarker discovery.
Bees and flowering plants have co-evolved as mutualists. In this relationship, bees facilitate genetic outcrossing for plants, and in return, they collect and eat floral nectar and pollen. Nectar is produced as a reward for pollinators, but pollen is not: it is the plant's male gamete. While we expect bees to have adapted to use pollen as their main source of essential amino acids (EAAs), we know relatively little about nutritional constraints imposed on them by pollinivory. Here, we measured the EAA profiles of pollen, bee bread, honeybees, and royal jelly to understand how natural variation in pollen protein quality impacted bee feeding behavior and performance. Specifically, we tested how mismatches in EAAs relative to bee tissues impacted protein-to-carbohydrate regulation in adult workers. Bees fed diets with an EAA profile that matched their own tissues consumed more food, gained more weight, and ate proportionally more protein relative to carbohydrates, while those fed with pollen sources, including bee bread, ate proportionally less protein and less food overall. Deficiencies found in pollen led us to discover that nutrient balancing for protein and carbohydrate in bees was driven by the inverse relationship between quantities of the branched-chain amino acids relative to histidine in dietary protein. We predict that bees create bee bread, a mixture of pollen, as an adaptation to pollen feeding that reduces the impact of imbalances in the EAA profile of pollen protein.