Synergism between copper and silver nanoclusters induces fascinating structural modifications, properties, and applications.

Among the group 11 transition metal elements, Cu and Ag are widely studied due to their cost effectiveness and easy availability. However, the synergism between copper and silver is also very promising, exhibiting intriguing structures, properties, and applications. Nanoclusters, which are missing links between atoms and nanoparticles, are highly fluorescent due to their discrete energy levels. Their fluorescence can be efficiently tuned because of the synergistic behaviour of copper and silver. Furthermore, their fluorescence can be selectively altered in the presence of various analytes and sensing platforms, as reported by various groups. Moreover, copper clusters can be utilized for sensing silver while silver nanoclusters can be utilized for sensing ionic copper due to the strong interaction between copper and silver. Furthermore, DFT studies have been performed to understand the structural modification due to CuAg synergism. A concise summary of the synergism between copper and silver can open a new window of research for young scientists venturing into the field of environmental nanoscience.

Intestinal stearoyl-CoA desaturase-1 regulates energy balance via alterations in bile acid homeostasis.

BACKGROUND AND AIMS: Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid assimilation and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance. METHODS: To interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine- specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analyses of bile acid content and composition, metabolic phenotyping including body composition, indirect calorimetry, glucose tolerance analyses, quantification of the composition of the gut microbiome, and assessment of bile acid signaling pathways. RESULTS: IKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt. In addition, the alpha and beta diversity of the gut microbiome was reduced in iKO mice, with several alterations in microbe species being associated with the observed increases in plasma bile acids. These increases in plasma bile acids were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and elevated plasma glucagon-like peptide-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice. CONCLUSION: Our results indicate that deletion of intestinal SCD1 has significant impacts on bile acid homeostasis and whole-body energy balance, likely via activation of TGR5.

Comparative evaluation of microleakage and penetration depth of ACP containing pit and fissure sealant and flowable composite - An in-vitro study.

Background: The present in vitro study evaluated and compared the microleakage and penetration depth of ACP containing pit and fissure sealant with flowable composite. Material and Methods: Sixty extracted non-carious premolars were categorized into four groups of 15 samples each. Sealant was applied after the Occlusal surfaces of the sample teeth were prophylactically treated with pumice slurry. Later, the teeth were thermocycled and immersed in methylene blue for a period of 24 hours. The samples were buccolingually sectioned and analysed under a stereomicroscope. Statistical analysis was carried out to compare the microleakage and depth of penetration. Results: Flowable nanocomposite gave comparable results with that of the sealant in terms of microleakage. Nano-hybrid flowable composite performed better with respect to depth of penetration between tested materials with the difference being statistically significant. Conclusions: Flowable nanocomposite can be considered as a promising substitute for sealing fissures and thus can be endorsed to caries susceptible pediatric patients. Key words:Depth of Penetration, Sealants, Microleakage.

Recent applications of coinage metal nanoparticles passivated with salicylaldehyde and salicylaldehyde-based Schiff bases.

Salicylaldehyde (SD) and its derivatives are effective precursors for generating coinage metal (gold, silver, and copper) nanoparticles (NPs). These NPs have a variety of potential environmental applications, such as in water purification and sensing, and those arising from their antibacterial activity. The use of SD and its derivatives for synthesizing coinage NPs is attractive due to several factors. First, SD is a relatively inexpensive and readily available starting material. Second, the synthetic procedures are typically simple and can be carried out under mild conditions. Finally, the resulting NPs can be tailored to have specific properties, such as size, shape, and surface functionality, by varying the reaction conditions. In an alkaline solution, the phenolate form of SD was converted to its quinone form, while ionic coinage metal salts were converted to zero-valent nanoparticles. The capping in situ produced quinone of coinage metal nanoparticles generated metal-enhanced fluorescence under suitable experimental conditions. The formation of iminic bonds during the formation of Schiff bases altered the properties (especially metal-enhanced fluorescence) and applications.

Understanding the landscape of the SARS-CoV-2-specific T cells post-omicron surge.

Emerging evidence shows increased humoral response post-omicron surge, but research on T cell responses is limited. This study investigated the durability, magnitude, and breadth of SARS-CoV-2-spike-specific T cell responses in 216 two-dose vaccinated individuals pre- and post-omicron surge. Post-surge samples showed enhanced T cell responses, indicating widespread asymptomatic exposure to omicron. Further analysis of 105 individuals with multiple exposures to SARS-CoV-2 through boosters or infections showed that post-omicron, two-dose vaccinated individuals had T cell responses comparable to those of COVID-19 convalescents or boosted individuals. Additionally, we report cross-reactive T cell responses against omicron sub-variants, including BA2.86, remained strong, with preserved frequencies of spike-specific stem-cell-like memory T cells. In silico prediction indicates that mutated epitopes of JN.1 and KP.2 retain over 95.6% of their HLA binding capability. Overall, our data suggests that T cell responses are sustained, enhanced, and cross-reactive against emerging SARS-CoV-2 variants following symptomatic or asymptomatic omicron infection.

Demographic analysis and biotic potential of Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) on pea.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) is a highly destructive polyphagous pest that primarily damages maize. Maize is considered a most versatile crop for growing intercrops due to the wide row it needs. Maize-pea intercropping is preferred by small and marginal farmers worldwide due to various advantages including higher yield and improved economic benefits. However, the success of this intercropping system may be hampered if pea could sustain the FAW population. Thus, to clarify the fitness and potential effect of S. frugiperda on pea, we analysed the survival and development of S. frugiperda fed on pea leaves in the laboratory and constructed age-stage and two-sex life tables. Results showed that FAW successfully completed its life cycle when fed on pea and produced fertile offspring. The pre-adult duration was significantly higher on pea than maize. The net reproductive rate, intrinsic and finite rate of population increase on pea (135.06 offspring per individual, 0.12 offspring per individual per day and 1.13 times per day) were all significantly different from those on maize (417.64 offspring per individual, 0.19 offspring per individual per day and 1.21 times per day). The probability of survival of S. frugiperda at each stage was lower when fed on pea leaves than that of maize-fed larvae. Due to the overlapping growth periods of the maize and pea, S. frugiperda can easily proliferate throughout the year by shifting between adjacent crops. Thus, this study revealed the adaptability of S. frugiperda for pea and provides the foundation for further assessment of FAW risk to other inter-crops.

Role of silver nanoparticles and silver nanoclusters for the detection and removal of Hg(ii).

Silver metal, being a 3d transition metal in group 11 in the periodic table, is widely used in material science for its distinguished plasmonic properties. Nanoparticles (NPs) and nanoclusters (NCs) are widely used in sensing applications having a surface plasmon band and emissive properties, respectively. Mercury is one of the detrimental toxins and threats to various ecosystems. The distinction between nanoparticles and nanoclusters, the utility and toxicity of heavy metal mercury, fluorometric and colorimetric approaches to the recognition of mercury ions with NPs and NCs, the mechanism of detection, spot detection, and natural water sample analyses were illustrated in detail in this review article. Moreover, the sensing platform and analyte (Hg2+) fate were described for substantiating the mechanism. It was observed that NCs are mostly utilized for fluorometric approaches, while NPs are mostly employed for colorimetric approaches. Fluorometric detection is mainly quenching-based. However, sensing with enhancement was found in a few reports. Adulteration of other metals with silver particles often modifies the sensing platform.

Analytical developments in the synergism of copper particles and cysteine: a review.

Cysteine, a sulfur-containing amino acid, is a vital candidate for physiology. Coinage metal particles (both clusters and nanoparticles) are highly interesting for their spectacular plasmonic properties. In this case, copper is the most important candidate for its cost-effectiveness and abundance. However, rapid oxidation destroys the stability of copper particles, warranting the necessity of suitable capping agents and experimental conditions. Cysteine can efficiently carry out such a role. On the contrary, cysteine sensing is a vital step for biomedical science. This review article is based on a comparative account of copper particles with cysteine passivation and copper particles for cysteine sensing. For the deep understanding of readers, we discuss nanoparticles and nanoclusters, properties of cysteine, and importance of capping agents, along with various synthetic protocols and applications (sensing and bioimaging) of cysteine-capped copper particles (cysteine-capped copper nanoparticles and cysteine-capped copper nanoclusters). We also include copper nanoparticles and copper nanoclusters for cysteine sensing. As copper is a plasmonic material, fluorometric and colorimetric methods are mostly used for sensing. Real sample analysis for both copper particles with cysteine and copper particles for cysteine sensing are also incorporated in this review to demonstrate their practical applications. Both cysteine-capped copper particles and copper particles for cysteine sensing are the main essence of this review. The aspect of the synergism of copper and cysteine (unlike other amino acids) is quite promising for future researchers.

Mutations in Plasmodium falciparum Kelch13 (PfK13) dysregulates PI3K/AKT signalling pathway in artemisinin resistance.

BACKGROUND: PfK13 protein mutations are associated with the emergence of artemisinin resistance in Plasmodium falciparum. PfK13 protein is essential for mediating ubiquitination and controlling the PI3K/AKT pathway. Mutant PfK13 variations can interfere with substrate binding, especially with PfPI3K, which raises PfPI3K levels. METHODS: DUET, DynaMut2, mCSM, iStable 2.0, I-Mutant 2.0, and MuPro were utilized to study the protein stability and protein-substrate binding was studied using HADDOCK 2.4 docking algorithm between Wild-type and mutant PfK13 with the helical and catalytic domain of PfPI3K. RESULTS: i-Stable server analysis predicted that seven, out of the nine mutations associated with artemisinin resistance (F446I, Y493H, R539T, I543T, P553L, R561H, C580Y) reduced the protein stability. HADDOCK scores of the catalytic domain underscores the significant impact of the reported mutations on the binding affinity of the PfK13 protein. Further validation through the MM_GBSA technique, the binding free energy (DDG) between the wild-type and the mutant PfK13 protein analysis revealed a loss of interactions resulting from mutations in PfK13. CONCLUSION: The study finding suggest that mutations in the PfK13 cause destabilization in the protein structure and affects the binding of PfPI3K. Although the findings remain preliminary and require further validation, it provides the basis for further research considering the importance of the interaction of PfK13 and PfPI3K to overcome the impact of artemisinin resistance.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

PURPOSE: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. METHODS: Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. RESULTS: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Aluminum-Crosslinked Nanocellulose Scaffolds for Fluoride Removal.

Anionic carboxylated cellulose nanofibers (CNF) are effective media to remove cationic contaminants from water. In this study, sustainable cationic CNF-based adsorbents capable of removing anionic contaminants were demonstrated using a simple approach. Specifically, the zero-waste nitro-oxidization process was used to produce carboxylated CNF (NOCNF), which was subsequently converted into a cationic scaffold by crosslinking with aluminum ions. The system, termed Al-CNF, is found to be effective for the removal of fluoride ions from water. Using the Langmuir isotherm model, the fluoride adsorption study indicates that Al-CNF has a maximum adsorption capacity of 43.3 mg/g, which is significantly higher than that of alumina-based adsorbents such as activated alumina (16.3 mg/g). The selectivity of fluoride adsorption in the presence of other anionic species (nitrate or sulfate) by Al-CNF at different pH values was also evaluated. The results indicate that Al-CNF can maintain a relatively high selectivity towards the adsorption of fluoride. Finally, the sequential applicability of using spent Al-CNF after the fluoride adsorption to further remove cationic contaminant such as Basic Red 2 dye was demonstrated. The low cost and relatively high adsorption capacity of Al-CNF make it suitable for practical applications in fluoride removal from water.

BODIPY directed one-dimensional self-assembly of gold nanorods.

The assembly of anisotropic nanomaterials into ordered structures is challenging. Nevertheless, such self-assembled systems are known to have novel physicochemical properties and the presence of a chromophore within the nanoparticle ensemble can enhance the optical properties through plasmon-molecule electronic coupling. Here, we report the end-to-end assembly of gold nanorods into micrometer-long chains using a linear diamino BODIPY derivative. The preferential binding affinity of the amino group and the steric bulkiness of BODIPY directed the longitudinal assembly of gold nanorods. As a result of the linear assembly, the BODIPY chromophores positioned themselves in the plasmonic hotspots, which resulted in efficient plasmon-molecule coupling, thereby imparting photothermal properties to the assembled nanorods. This work thus demonstrates a new approach for the linear assembly of gold nanorods resulting in a plasmon-molecule coupled system, and the synergy between self-assembly and electronic coupling resulted in an efficient system having potential biomedical applications.

Experiences from a COVID-19 vaccination center at a tertiary care teaching hospital in Delhi, India: Challenges and solutions.

India began its nationwide coronavirus disease 2019 (COVID-19) vaccination program on January 16, 2021, in a phased manner. In this paper, we have discussed our experience at one of the COVID-19 vaccination centers in the country and have identified a few of the major challenges and their implications. The guidelines for COVID-19 vaccination in the country were changing frequently, leading to ambiguity among the beneficiaries. Co-WIN software, used for program implementation, had some glitches, which caused dissatisfaction among the service providers and beneficiaries. Vaccine hesitancy and eagerness caused low vaccine uptake initially and overcrowding at vaccination centers later. Some of the vaccination centers had the potential to become hot spots for further spread of the virus due to insufficient infrastructure. The disparity in access to vaccines for the homeless and other vulnerable groups was another hurdle for adequate vaccination coverage. These challenges could have been addressed by pretesting the information technology platform, long-term planning with a vision for handling vaccine hesitancy and eagerness, strong communication systems, removing disparities in vaccine access, and maintaining uniformity in messages for frequently updating guidelines.

Photocatalytic degradation of methyl blue dye with H2O2 sensing.

A condensation polymer (urea-formaldehyde resin) passivated ZnO nanoparticles were used as an efficient photocatalyst for methyl blue degradation in the presence of H2O2 involving a Fenton-like reaction. The formation of OH˙ radicals were attributed to the pivotal factor for the degradation process. The method was easy and recyclable. The dose of photocatalyst, initial dye concentration, pH variation, variations of the composition of the photocatalyst, and the effect of scavengers were gauged. The degraded product was highly fluorescent and fluorometric detection of H2O2 was achieved along with a colorimetric recognition pathway. No other dye could be degraded under similar experimental conditions, implying the novel utility of methyl blue for environmental remediation.

Lipidomic Analysis Reveals Systemic Alterations in Servicemen Exposed to Repeated Occupational Low-Level Blast Waves.

INTRODUCTION: Occupational exposure to blast is a prevalent risk experienced by military personnel. While low-level exposure may not manifest immediate signs of illness, prolonged and repetitive exposure may result in neurophysiological dysfunction. Such repeated exposure to occupational blasts has been linked to structural and functional modifications in the brain, adversely affecting the performance of servicemen in the field. These neurological changes can give rise to symptoms resembling concussion and contribute to the development of post-traumatic stress disorder. MATERIALS AND METHODS: To understand long-term effects of blast exposure, the study was conducted to assess memory function, serum circulatory protein and lipid biomarkers, and associated concussive symptomology in servicemen. Concussion-like symptoms were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ) along with memory function using PGI memory scale. The serum protein biomarkers were quantified using a sandwich ELISA assay, and the serum lipid profile was measured using liquid chromatography-mass spectrometer. RESULTS: The findings revealed that repeated low-level blast exposure resulted in impaired memory function, accompanied by elevated levels of serum neurofilament light chain (neuroaxonal injury) and C-reactive protein. Furthermore, alterations in the lipid profile were observed, with an increase in lipid species associated with immune activation. These changes collectively point to systemic inflammation, neuronal injury, and memory dysfunction as pathological characteristics of repeated low-level blast exposure. CONCLUSION: The results of our preliminary investigation offer valuable insights for further large-scale study and provide a guiding principle that necessitates a suitable mitigation approach to safeguard the health of personnel against blast overpressure.

Perceptions regarding second wave of coronavirus disease 2019 (COVID-19) pandemic among Indian adults: A cross-sectional study.

BACKGROUND AND AIMS: A massive surge in coronavirus disease 2019 (COVID-19) cases and deaths occurred in India during March-April 2021, and this was considered as second wave of the pandemic in the country. This study was conducted to find out the perceptions about second wave of the COVID-19 pandemic among Indian adults. METHODS: An online-survey-based cross-sectional study was conducted over 3 weeks from April 21, 2021 to May 11, 2021. Information regarding sociodemographic profile, perceptions about COVID-19 during second wave, perceptions and practices related to COVID-19 vaccination, COVID-19 appropriate behavior, and government's response to the pandemic was collected. Descriptive analysis was performed. RESULTS: A total of 408 study participants were included. Mean age of the study participants was 29.2 ± 10.4 years. Around 92.6 percent (378) of respondents agreed that COVID-19 in 2021 is different from 2020. Perceived reasons for increased severity and cases were change in virus characteristics; social, religious, and political gatherings; and complacent behavior by people. Three-fourth (311, 76.2 percent) of the study participants agreed that vaccines have a positive role against COVID-19. Majority of the study participants (329, 80.6 percent) concurred that lockdown restrictions help in control of the pandemic. About 60.3 percent (246) of respondents had less trust on government post this pandemic compared to pre-COVID-19 times. CONCLUSION: The public perception about reasons for second wave in India acknowledges both human and virus factors and highlights the importance of shared responsibility between citizens and government for controlling the pandemic.

Drought stress in Lens culinaris: effects, tolerance mechanism, and its smart reprogramming by using modern biotechnological approaches.

Among legumes, lentil serves as an imperative source of dietary proteins and are considered an important pillar of global food and nutritional security. The crop is majorly cultivated in arid and semi-arid regions and exposed to different abiotic stresses. Drought stress is a polygenic stress that poses a major threat to the crop productivity of lentils. It negatively influenced the seed emergence, water relations traits, photosynthetic machinery, metabolites, seed development, quality, and yield in lentil. Plants develop several complex physiological and molecular protective mechanisms for tolerance against drought stress. These complicated networks are enabled to enhance the cellular potential to survive under extreme water-scarce conditions. As a result, proper drought stress-mitigating novel and modern approaches are required to improve lentil productivity. The currently existing biotechnological techniques such as transcriptomics, genomics, proteomics, metabolomics, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/cas9), and detection of QTLs (quantitative trait loci), proteins, and genes responsible for drought tolerance have gained appreciation among plant breeders for developing climate-resilient lentil varieties. In this review, we critically elaborate the impact of drought on lentil, mechanisms employed by plants to tolerate drought, and the contribution of omics approaches in lentils for dealing with drought, providing deep insights to enhance lentil productivity and improve resistance against abiotic stresses. We hope this updated review will directly help the lentil breeders to develop resistance against drought stress.

Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation.

Peptidyl arginine deiminases (PADIs) catalyze protein citrullination, a post-translational conversion of arginine to citrulline. The most widely expressed member of this family, PADI2, regulates cellular processes that impact several diseases. We hypothesized that we could gain new insights into PADI2 function through a systematic evolutionary and structural analysis. Here, we identify 20 positively selected PADI2 residues, 16 of which are structurally exposed and maintain PADI2 interactions with cognate proteins. Many of these selected residues reside in non-catalytic regions of PADI2. We validate the importance of a prominent loop in the middle domain that encompasses PADI2 L162, a residue under positive selection. This site is essential for interaction with the transcription elongation factor (P-TEFb) and mediates the active transcription of the oncogenes c-MYC, and CCNB1, as well as impacting cellular proliferation. These insights could be key to understanding and addressing the role of the PADI2 c-MYC axis in cancer progression.

TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.

Background: Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. Objectives: TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Methods and design: Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. Ethics: TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. Discussion: TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. Trial registration: ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

TROPION-Breast03: a clinical trial designed to assess the effectiveness and safety of Dato-DXd, alone or in combination with durvalumab, in patients with triple-negative breast cancer who have cancer cells remaining at the time of surgery after initial systemic therapy Triple-negative breast cancer (TNBC), in which cells do not have estrogen or progesterone receptors or high levels of human epidermal growth factor receptor 2, is the most aggressive breast cancer subtype. TNBC is difficult to treat and associated with high risk of recurrence despite standard systemic therapy (treatment targeting the entire body), which can include chemotherapy alone or in combination with immunotherapy (treatment targeting the immune system). To reduce the risk of recurrence, standard systemic treatment is often followed by surgical removal of the patient's tumors and additional systemic treatment. Dato-DXd is an antibody-drug conjugate, which is an anticancer drug (DXd) connected to an antibody (datopotamab) by a stable linker. Datopotamab binds to TROP2, a protein found on breast cancer cells, and is taken into the tumor cell where the linker breaks, releasing DXd to kill the cell. By delivering DXd directly to cancer cells, Dato-DXd reduces exposure in the rest of the body, reducing the risk of side effects. Since Dato-DXd can recruit immune cells to cancer sites, it may work better combined with durvalumab, a drug that blocks the activity of a protein called PD-L1, making cancer cells more susceptible to being killed by immune cells. The TROPION-Breast03 study will compare Dato-DXd, alone or combined with durvalumab, with standard-of-care therapy in patients with TNBC that has not spread to parts of the body away from the original tumor site(s), but with cancer cells remaining at the time of surgery after initial systemic therapy. It will assess how well each treatment works and describe any side effects. We plan to recruit 1,075 eligible adults who will be randomly assigned in a 2:1:2 ratio to: • Dato-DXd + durvalumab • Dato-DXd alone • Standard-of-care therapy • Patients will receive treatment until they complete the planned course of therapy (8 or 9 cycles), their cancer returns, side effects become unacceptable, or they choose to stop.