Late-Stage C(sp2)-C(sp3) Diversification via Nickel Oxidative Addition Complexes.

Herein, we describe nickel oxidative addition complexes (Ni-OACs) of drug-like molecules as a platform to rapidly generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed not only in C(sp2)-C(sp3) couplings but also in additional bond formations without recourse to specialized ligands and with improved generality when compared to Ni-catalyzed reactions. The development of an automated diversification process further illustrates the robustness of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery.

Metaproteomic Analysis of Microbial Communities Affecting Fishery Products.

Fishery products are one of the main human nutritional sources, and due to the consumption increase, the quality of the derived products may be modified, during catching, technological processing, and storage. Detection and identification of pathogenic and spoilage microorganisms in fishery products is needed because the first may be involved in human diseases, while the second is responsible of significant economic losses. In this sense, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method and computational analysis of MS data are useful tools for characterizing and identifying different microorganisms and to develop promising strategies for food science investigations. Moreover, in the past decade, metaproteomic methodologies have progressed for the study of microorganisms isolated from their natural samples and independently of the culture restrictions. Metaproteomics enables assessment of proteins and pathways from individual members of the consortium. Metaproteomics can provide a detailed understanding of which organisms occupy specific metabolic niches, how they interact, and how they utilize nutrients, and these insights can be obtained directly from environmental samples.According to that, the sample preparation of the fishery product, the LC-ESI-MS/MS dedicated method, and the MS data analysis were described in the present chapter to obtain the metaproteomic analysis of the respective microbiomes or microbial communities.

On the Determination of Elastic Properties of Single-Walled Nitride Nanotubes Using Numerical Simulation.

In recent years, tubular nanostructures have been related to immense advances in various fields of science and technology. Considerable research efforts have been centred on the theoretical prediction and manufacturing of non-carbon nanotubes (NTs), which meet modern requirements for the development of novel devices and systems. In this context, diatomic inorganic nanotubes formed by atoms of elements from the 13th group of the periodic table (B, Al, Ga, In, Tl) and nitrogen (N) have received much research attention. In this study, the elastic properties of single-walled boron nitride, aluminium nitride, gallium nitride, indium nitride, and thallium nitride nanotubes were assessed numerically using the nanoscale continuum modelling approach (also called molecular structural mechanics). The elastic properties (rigidities, surface Young's and shear moduli, and Poisson's ratio) of nitride nanotubes are discussed with respect to the bond length of the corresponding diatomic hexagonal lattice. The results obtained contribute to a better understanding of the mechanical response of nitride compound-based nanotubes, covering a broad range, from the well-studied boron nitride NTs to the hypothetical thallium nitride NTs.

A hydrophobic groove in secretagogin allows for alternate interactions with SNAP-25 and syntaxin-4 in endocrine tissues.

Vesicular release of neurotransmitters and hormones relies on the dynamic assembly of the exocytosis/trans-SNARE complex through sequential interactions of synaptobrevins, syntaxins, and SNAP-25. Despite SNARE-mediated release being fundamental for intercellular communication in all excitable tissues, the role of auxiliary proteins modulating the import of reserve vesicles to the active zone, and thus, scaling repetitive exocytosis remains less explored. Secretagogin is a Ca2+-sensor protein with SNAP-25 being its only known interacting partner. SNAP-25 anchors readily releasable vesicles within the active zone, thus being instrumental for 1st phase release. However, genetic deletion of secretagogin impedes 2nd phase release instead, calling for the existence of alternative protein-protein interactions. Here, we screened the secretagogin interactome in the brain and pancreas, and found syntaxin-4 grossly overrepresented. Ca2+-loaded secretagogin interacted with syntaxin-4 at nanomolar affinity and 1:1 stoichiometry. Crystal structures of the protein complexes revealed a hydrophobic groove in secretagogin for the binding of syntaxin-4. This groove was also used to bind SNAP-25. In mixtures of equimolar recombinant proteins, SNAP-25 was sequestered by secretagogin in competition with syntaxin-4. Kd differences suggested that secretagogin could shape unidirectional vesicle movement by sequential interactions, a hypothesis supported by in vitro biological data. This mechanism could facilitate the movement of transport vesicles toward release sites, particularly in the endocrine pancreas where secretagogin, SNAP-25, and syntaxin-4 coexist in both α- and ß-cells. Thus, secretagogin could modulate the pace and fidelity of vesicular hormone release by differential protein interactions.

Shotgun proteomic analyses of Pseudomonas species isolated from fish products.

Numerous Pseudomonas species can infect aquatic animals, such as farmed rainbow trout, sea trout, sea bass, and sea bream, by causing disease or stress reactions. In aquaculture facilities, a number of Pseudomonas species have been isolated and identified as the main pathogens. The present study describes the characterization of 18 Pseudomonas strains, isolated from fish products using shotgun proteomics. The bacterial proteomes obtained were further analyzed to identify the main functional pathway proteins involved. In addition, this study revealed the presence of 1015 non-redundant peptides related to virulence factors. An additional 25 species-specific peptides were identified as putative Pseudomonas spp. biomarkers. The results constitute the largest dataset, described thus far for the rapid identification and characterization of Pseudomonas species present in edible fish; furthermore, these data can provide the basis for further research into the development of new therapies against these harmful pathogens.

Clinical Outcomes Among Immunotherapy-Treated Patients With Primary Cardiac Soft Tissue Sarcomas: A Multicenter Retrospective Study.

Background: Primary cardiac soft tissue sarcomas (CSTS) affect young adults, with dismal outcomes. Objectives: The aim of this study was to investigate the clinical outcomes of patients with CSTS receiving immune checkpoint inhibitors (ICIs). Methods: A retrospective, multi-institutional cohort study was conducted among patients with CSTS between 2015 and 2022. The patients were treated with ICI-based regimens. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events version 5.0. Results: Among 24 patients with CSTS, 17 (70.8%) were White, and 13 (54.2%) were male. Eight patients (33.3%) had angiosarcoma. At the time of ICI treatment, 18 patients (75.0%) had metastatic CSTS, and 4 (16.7%) had locally advanced disease. ICIs were administered as the first-line therapy in 6 patients (25.0%) and as the second-line therapy or beyond in 18 patients (75.0%). For the 18 patients with available response data, objective response rate was 11.1% (n = 2 of 18). The median PFS and median OS in advanced and metastatic CSTS (n = 22) were 5.7 months (95% CI: 2.8-13.3 months) and 14.9 months (95% CI: 5.7-23.7 months), respectively. The median PFS and OS were significantly shorter in patients with cardiac angiosarcomas than in those with nonangiosarcoma CSTS: median PFS was 1.7 vs 11 months, respectively (P < 0.0001), and median OS was 3.0 vs 24.0 months, respectively (P = 0.008). Any grade treatment-related adverse events occurred exclusively in the 15 patients with nonangiosarcoma CSTS (n = 7 [46.7%]), of which 6 (40.0%) were grade ≥3. Conclusions: Although ICIs demonstrate modest activity in CSTS, durable benefit was observed in a subset of patients with nonangiosarcoma, albeit with higher toxicity.

Profile of serum microRNAs in heart failure with reduced and preserved ejection fraction: Correlation with myocardial remodeling.

Background and aims: Cardiomyocyte hypertrophy and interstitial fibrosis are key components of myocardial remodeling in Heart Failure (HF) with preserved (HFpEF) or reduced ejection fraction (HFrEF). MicroRNAs (miRNAs) are non-coding, evolutionarily conserved RNA molecules that may offer novel insights into myocardial remodeling. This study aimed to characterize miRNA expression in HFpEF (LVEF ≥ 45%) and HFrEF (LVEF < 45%) and its association with myocardial remodeling. Methods: Prospectively enrolled symptomatic HF patients (HFpEF:n = 36; HFrEF:n = 31) and controls (n = 23) underwent cardiac magnetic resonance imaging with T1-mapping and circulating miRNA expression (OpenArray system). Results: 13 of 188 miRNAs were differentially expressed between HF groups (11 downregulated in HFpEF). Myocardial extracellular volume (ECV) was increased in both HF groups (HFpEF 30 ± 5%; HFrEF 30 ± 3%; controls 26 ± 2%, p < 0.001). miR-128a-3p, linked to cardiac hypertrophy, fibrosis, and dysfunction, correlated positively with ECV in HFpEF (r = 0.60, p = 0.01) and negatively in HFrEF (r = -0.51, p = 0.04). miR-423-5p overexpression, previously associated HF mortality, was inversely associated with LVEF (r = - 0.29, p = 0.04) and intracellular water lifetime (τic) (r = -0.45, p < 0.05) in both HF groups, and with NT-proBNP in HFpEF (r = -0.63, p < 0.01). Conclusions: miRNA expression profiles differed between HF phenotypes. The differential expression and association of miR-128a-3p with ECV may reflect the distinct vascular, interstitial, and cellular etiologies of HF phenotypes.

Comprehensive shotgun proteomic characterization and virulence factors of seafood spoilage bacteria.

This article summarizes the characterization, by shotgun proteomics, of 11 bacterial strains identified as responsible for seafood spoilage. A total of 4455 peptide spectrum matches, corresponding to 4299 peptides and 3817 proteins were identified. Analyses of data determined the functional pathways they are involved in. The proteins identified were integrated into a protein-protein network that involves 371 nodes and 3016 edges. Those proteins are implicated in energy pathways, peptidoglycan biosynthesis, spermidine/putrescine metabolism. An additional 773 peptides were characterized as virulence factors, that participates in bacterial pathogenesis; while 14 peptides were defined as biomarkers, as they can be used to differentiate the bacterial species present. This report represents the most extensive proteomic repository available in the field of seafood spoilage bacteria; the data substantially advances the understanding of seafood decay, as well as provides fundamental bases for the recognition of the bacteria existent in seafood that cause spoilage during food processing/storage.

Effect of atorvastatin versus placebo on efficacy in patients with diffuse large B-cell lymphoma receiving R-CHOP.

STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n = 55) or placebo (n = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p = .18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.

Encoding of Predictive Associations in Human Prefrontal and Medial Temporal Neurons During Pavlovian Appetitive Conditioning.

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-value and stimulus-stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

Numerical Evaluation of the Elastic Moduli of AlN and GaN Nanosheets.

Two-dimensional (2D) nanostructures of aluminum nitride (AlN) and gallium nitride (GaN), called nanosheets, have a graphene-like atomic arrangement and represent novel materials with important upcoming applications in the fields of flexible electronics, optoelectronics, and strain engineering, among others. Knowledge of their mechanical behavior is key to the correct design and enhanced functioning of advanced 2D devices and systems based on aluminum nitride and gallium nitride nanosheets. With this background, the surface Young's and shear moduli of AlN and GaN nanosheets over a wide range of aspect ratios were assessed using the nanoscale continuum model (NCM), also known as the molecular structural mechanics (MSM) approach. The NCM/MSM approach uses elastic beam elements to represent interatomic bonds and allows the elastic moduli of nanosheets to be evaluated in a simple way. The surface Young's and shear moduli calculated in the current study contribute to building a reference for the evaluation of the elastic moduli of AlN and GaN nanosheets using the theoretical method. The results show that an analytical methodology can be used to assess the Young's and shear moduli of aluminum nitride and gallium nitride nanosheets without the need for numerical simulation. An exploratory study was performed to adjust the input parameters of the numerical simulation, which led to good agreement with the results of elastic moduli available in the literature. The limitations of this method are also discussed.

High-Resolution Comparative and Quantitative Proteomics of Biogenic-Amine-Producing Bacteria and Virulence Factors Present in Seafood.

The presence of biogenic amines (histamine, tyramine, putrescine, and cadaverine) in seafood is a significant concern for food safety. This review describes for the first time a shotgun quantitative proteomics strategy to evaluate and compare foodborne strains of bacteria that produce biogenic amines in seafoods. This approach recognized 35,621 peptide spectrum matches, belonging to 20,792 peptides, and 4621 proteins. It allowed the determination of functional pathways and the classification of the strains into hierarchical clusters. The study identified a protein-protein interaction network involving 1160 nodes/10,318 edges. Proteins were related to energy pathways, spermidine biosynthesis, and putrescine metabolism. Label-free quantitative proteomics allowed the identification of differentially regulated proteins in specific strains such as putrescine aminotransferase, arginine decarboxylase, and l-histidine-binding protein. Additionally, 123 peptides were characterized as virulence factors and 299 peptide biomarkers were selected to identify bacterial species in fish products. This study presents the most extensive proteomic repository and progress in the science of food biogenic bacteria and could be applied in the food industry for the detection of bacterial contamination that produces histamine and other biogenic amines during food processing/storage.

Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure.

Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure.

Long-term outcomes of cardioneuroablation with and without extra-cardiac vagal stimulation confirmation in severe cardioinhibitory neurocardiogenic syncope.

BACKGROUND: Cardioneuroablation (CNA) is a novel therapeutic approach for functional bradyarrhythmias, specifically neurocardiogenic syncope or atrial fibrillation, achieved through endocardial radiofrequency catheter ablation of vagal innervation, obviating the need for pacemaker implantation. Originating in the nineties, the first series of CNA procedures was published in 2005. Extra-cardiac vagal stimulation (ECVS) is employed as a direct method for stepwise denervation control during CNA. OBJECTIVE: This study aimed to compare the long-term follow-up outcomes of patients with severe cardioinhibitory syncope undergoing CNA with and without denervation confirmation via ECVS. METHOD: A cohort of 48 patients, predominantly female (56.3%), suffering from recurrent syncope (5.1 ± 2.5 episodes annually) that remained unresponsive to clinical and pharmacological interventions, underwent CNA, divided into two groups: ECVS and NoECVS, consisting of 34 and 14 cases, respectively. ECVS procedures were conducted with and without atrial pacing. RESULTS: Demographic characteristics, left atrial size, and ejection fraction displayed no statistically significant differences between the groups. Follow-up duration was comparable, with 29.1 ± 15 months for the ECVS group and 31.9 ± 20 months for the NoECVS group (p = .24). Notably, syncope recurrence was significantly lower in the ECVS group (two cases vs. four cases, Log Rank p = .04). Moreover, the Hazard ratio revealed a fivefold higher risk of syncope recurrence in the NoECVS group. CONCLUSION: This study demonstrates that concluding CNA with denervation confirmation via ECVS yields a higher success rate and a substantially reduced risk of syncope recurrence compared to procedures without ECVS confirmation.

The impact of sodium-glucose cotransporter-2 inhibitors on outcome of patients with diabetes mellitus and colorectal cancer.

BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) have a higher risk of colorectal cancer (CRC), and those with diagnosed CRC have a poorer prognosis compared with individuals with normal glucose levels. The inhibition of sodium-glucose cotransporter 2 (SGLT2) channels has been associated with a reduction in tumor proliferation in preclinical studies. We aimed to investigate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcome of T2DM patients with colorectal cancer. METHODS: We performed a retrospective cohort study comprising adult patients with T2DM and colorectal adenocarcinoma. SGLT2i recipients were matched to non-SGLT2i recipients in a 1:1 ratio based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with SGLT2i. RESULTS: We identified 1347 patients with T2DM and colorectal adenocarcinoma, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of 5-year OS (86.2% [95% CI: 72.0-93.5] vs 62.3% [95% CI: 50.9-71.8], P = 0.013) and 5-year PFS (76.6% [95% CI: 60.7-86.7] vs 57.0% [95% CI: 46.2-66.4], P = 0.021). In Cox proportional hazard analyses, SGLT2i were associated with a 50-70% reduction in all-cause mortality and disease progression. SGLT2i were not associated with an increased risk of serious adverse events. CONCLUSION: SGLT2i were associated with a higher rate of survival in T2DM patients with colorectal cancer.

The side effect registry immuno-oncology (SERIO) - A tool for systematic analysis of immunotherapy-induced side effects.

BACKGROUND: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes. METHODS: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered. RESULTS: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy. CONCLUSIONS: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy.

SGLT2 Inhibitor Use and Risk of Clinical Events in Patients With Cancer Therapy-Related Cardiac Dysfunction.

BACKGROUND: Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF. OBJECTIVES: This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF. METHODS: The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period. RESULTS: The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors. CONCLUSIONS: SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.

Risk of death and readmission among individuals with heart failure and HIV: A systematic review and meta-analysis.

The association between human immunodeficiency virus (HIV) status and readmissions and death outcomes in patients with established heart failure (HF) remains unclear. We conducted a systematic search of PubMed, EMBASE, Cochrane Library, and Web of Science up to March 1st, 2023, for cohort studies of adult patients (≥18 years) diagnosed with HF and recorded HIV status at baseline. Our analysis included 7 studies with 10,328 HF patients living with HIV and 48,757 HF patients without HIV. Compared to HF patients without HIV, those with HIV had a higher risk of all-cause deaths (HR: 1.20, 95% CI: 1.15-1.25). HIV infection was also associated with increased risks of HF-associated readmission (HR: 1.34, 95% CI: 1.03-1.75) and all-cause readmission (HR: 1.27, 95% CI: 1.10-1.46). Our study highlights the independent association between HIV and poor HF outcomes, emphasizing the need for improved management in individuals living with HIV.

Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer.

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.