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Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2- BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10%) ER+/HER2- primary BC. In total, 510 patients were randomized to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo (24.5% versus 13.8%; P = 0.0021), with greater benefit observed in patients with programmed death ligand 1-positive tumors (VENTANA SP142 ≥1%: 44.3% versus 20.2% respectively). There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm. Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2- BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066., Competing Interests: Competing interests: S.L. reports institutional research funding from AstraZeneca/Daiichi Sankyo, Bristol Myers Squibb, Novartis, Puma Biotechnology, Roche-Genentech and Seattle Genetics; consulting fees from Amaroq Therapeutics, Astra Zeneca/Daiichi Sankyo, Bristol Myers Squibb, Domain Therapeutics Gilead, Lilly, Mersana Therapeutics, MSD, Roche-Genentech and Novartis; honoraria from Amaroq Therapeutics, AstraZeneca/Daiichi Sankyo, BioNTech, Bristol Myers Squibb, Domain Therapeutics, Gilead Sciences, Lilly, Mersana Therapeutics, MSD, Novartis and Roche-Genentech; meeting/ travel support from Bristol Myers Squibb and Lilly. R.S. reports consulting fees from Owkin; honoraria from AstraZeneca, Daiichi Sankyo and Exact Sciences; meeting/travel support from AstraZeneca and Daichii Sankyo; leadership position at The International Immuno-Oncology Biomarker Working Group; research support from Bristol Myers Squibb and providing unpaid advice to Case 45. G.C. reports participation on advisory boards for AstraZeneca, Bristol Myers Squibb, Daichii Sankyo, Celcuity, Ellipsis, Exact Science, Gilead, Lilly, Menarini, Merck, Novartis, Pfizer, Roche, Sanofi and Veracyte. S.D. reports institutional research funding from Amgen, AstraZeneca, Bristol Myers Squibb, European Commission, the French government, Lilly, Novartis, Orion, Pierre Fabre, Pfizer, Roche-Genentech, Sanofi and Taiho; meeting/travel support from Novartis, Roche and Seagen; participation on advisory boards for AstraZeneca, Besins, Decibio, Elsan, Gilead and Sanofi; participation on independent data monitoring committee activity for Breast International Group and Pfizer. C.I.R.G. reports honoraria from AstraZeneca, Bristol Myers Squibb, Knight, MSD, Pfizer, Roche and Tecnofarma; participation on data safety monitoring/advisory boards for Bristol Myers Squibb, Pfizer and Sanofi. M.K. reports institutional research funding from AstraZeneca, Bristol Myers Squibb and Roche; honoraria from Bristol Myers Squibb and Gilead; participation on advisory boards for AstraZeneca, BioNTech, Bristol Myers Squibb, MSD and Roche. C.S. reports research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Byondis BV, Daiichi Sankyo, Eisai, Genentech, Gilead, Glaxo, Menarini, Merus, MSD, Novartis, Pfizer, Philips Healthcare, Piere Fabre, Puma Biotechnology, Roche, Sanofi Aventis, Seagen, Synthon and Zymeworks; consulting fees from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MediTech, Novartis, Pfizer, Philips Healthcare, Pharmalex, Piere Fabre, Puma Biotechnology, Roche, Seagen, Synthon and Zymeworks; honoraria from AstraZeneca, Daiichi Sankyo, Exeter Pharmaceuticals, Lilly, Pfizer, Pierre Fabre, Puma Biotechnology and Seagen; payment for expert testimony from AX’s Consulting SARL, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Innoup, MSD España, Novartis and Sanofi; meeting/travel support from AstraZeneca, Daiichi Sankyo, Eisai Europe, Gilead, Lilly, Novartis, Pfizer, Pierre Fabre, Puma Biotechnology, Roche and Seagen; participation on data safety monitoring/advisory boards for AstraZeneca, Daiichi Sankyo, Eisai Europe, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Philips, Pierre Fabre, Roche and Seagen. N.H. reports consulting fees from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Seagen and Viatris; honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Viatris and Zuelligpharma; participation on data safety monitoring/advisory boards for Gilead, Roche and Seagen; leadership position at the West German Study Group. E.A.M. reports research funding from Genentech, Gilead and Roche; consulting fees from AstraZeneca, BioNTech, Moderna and MSD; honoraria from MSD; meeting/travel support from MSD; leadership positions at the American Society of Clinical Oncology Board of Directors 2019–2023 and Scientific Advisor for Susan G. Komen. D.A.Y. reports institutional research funding from AbbVie, Ambrx, AstraZeneca, Dana Farber Cancer Institute, Lilly, Roche-Genentech, G1 Therapeutics, Gilead, Incyte, Innocrin Pharmaceuticals, Merck, Novartis, Polyphor, Stemline Therapeutics, US Oncology and UT Southwestern; and consulting fees paid to institution from AstraZeneca, Daiichi Sankyo, Gilead, Integra Connect, Novartis and Stemline Therapeutics. V.G. reports honoraria from AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, GlaxoSmithKline, Lilly, Menarini Stemline, Novartis, Roche, and Zentiva; payment for expert testimony from Lilly; meeting/travel support from AstraZeneca and Gilead; institutional patent for Her2DX; and participation on data safety monitoring/advisory boards for AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Novartis, Olema Oncology, Pierre Fabre, Pfizer-Seagen and Roche. D.E. reports consulting fees from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, Seagen and Sirius Medical; honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, Seagen and Sirius Medical; meeting/travel support from Daiichi Sankyo and Pfizer; and receipt of medical writing support from Sirius Medical. F.A. reports being an employee of Bristol Myers Squibb. M.P. reports being an employee and shareholder of Bristol Myers Squibb. A.C. reports being an employee of Bristol Myers Squibb and shareholder of Merck. R.C. reports being an employee of Bristol Myers Squibb. R.N. reports being an employee and shareholder of Bristol Myers Squibb. T.S. reports being an employee and shareholder of Bristol Myers Squibb. J.Q.W. reports being an employee and shareholder of Bristol Myers Squibb. L.P. reports institutional research funding from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck, Pfizer and Seagen; consulting fees from AstraZeneca, Bristol Myers Squibb, Daiichi, Exact Sciences, Genentech-Roche, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Pfizer and Stemline-Menarini; and honoraria for advisory board participation from AstraZeneca, Bristol Myers Squibb, Daiichi, Exact Sciences, Genentech-Roche, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Pfizer and Stemline-Menarini. H.M. reports consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Calithera, Celgene, Crown Bioscience Daiichi Sankyo, Lilly, Genentech-Roche, Gilead, Immunomedics, Merck, OBI Pharma, Peregrine, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Seattle Genetics and TapImmune; and research funding from Bristol Myers Squibb, BTG, LLC/AstraZeneca, MedImmune and Merck. R.I.R.D., A.S.Z., F.R.C., A.U. and J.G.R.-T. declare no competing interests., (© 2025. Crown.)

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC 50 for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (K d ) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC 50 by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro K d . The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2-3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein., Competing Interests: All authors are current or former employees of Bristol Myers Squibb and own or previously owned the company’s stocks., (Copyright © 2022 Yang, Loy, Poirson, Dai, Rajendran, Xu, Spires, Gururajan, Lin, Arbanas, Carl, Pace, Wang, Mehl, Vasudevan, Spires, Novosiadly, Coker, Perez, Covello, Morin, Graziano, Broz and Lehman-McKeeman.)

Little data are available regarding the determinants and prognostic significance of serum albumin in Heart Failure with Preserved Ejection Fraction (HFpEF). We sought to examine the phenotypic correlates of albumin and its independent prognostic implications in HFpEF. We analyzed data from 3,254 subjects enrolled the TOPCAT trial. We stratified subjects according to tertiles of albumin and examined differences in various phenotypic traits between these strata, including 8 protein biomarkers selected ad hoc and measured from frozen samples available in a subset of participants (n = 372). We also assessed the relationship between albumin and the trial primary endpoint. Lower albumin was associated with older age, black race, and greater prevalence of NYHA class III-IV, peripheral arterial disease, atrial fibrillation and diabetes mellitus. Lower albumin was also associated with increased levels of several inflammatory biomarkers, markers of liver fibrosis, albuminuria, and greater arterial stiffness, diastolic dysfunction and pulmonary hypertension. Albumin was a strong predictor of the primary trial endpoint, even after adjustment for the MAGGIC risk score (hazard ratio [HR] 0.72, confidence interval [CI] 0.67 to 0.78; p <0.0001) and prespecified traditional risk factors (HR 0.78, CI 0.71 to 0.85; p <0.0001). Lower albumin was strongly associated with a worse prognosis even well within normal ranges (>3.5 g/dL), with a sharp increase in risk between 4.6 and 3.6 g/dL. In conclusion, albumin is an integrated marker of various adverse processes in HFpEF, including inflammation, subclinical liver disease, arterial stiffness, and renal disease. Albumin is a powerful risk predictor independent of traditional risk prediction models, even within normal ranges., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy., Experimental Design: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response., Results: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8 + and NK cells populations measured by granzyme B expression with upregulation of CD8 + CD103 + tissue-resident memory cells (T RM ) within the abscopal tumor microenvironment relative to radiation only., Conclusions: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of T RM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients., (©2019 American Association for Cancer Research.)

This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Extremely large carbon tubes, some exceeding 5 microm in diameter, were produced with both laser and electric arc techniques using graphite, a transition metal catalyst, and a reactive third-body gas. We have named these structures carbon megatubes. They are the first carbonaceous tubes large enough to observe using optical microscopy. We also report the synthesis of what we believe to be the first self-assembled branched nanotubes. In addition to their extreme diameters and unique morphologies, X-ray photoelectron spectroscopy has shown that these tubes also contain a significant amount of nitrogen atom incorporation into the graphite lattice. Subsequently, these nitrogen functionalities were shown to interact with rhenium pentacarbonyl bromide and serve as anchor points to tether molecules to the surface of the tubules.