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The selective estrogen-receptor degrader imlunestrant plus abemaciclib led to a median progression-free survival of 9.4 months among patients with ER-positive, HER2-negative breast cancer (vs. 5.5 months with imlunestrant alone).

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5–8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554–555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference −1·2 mm Hg, 95% CI −2·3 to −0·1; p=0·030) and valsartan 320 mg/day (−4·4 mm Hg, −5·4 to −3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30–36% of participants in each group. Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. Forest Research Institute.

High-resolution, multiplexed experiments are a staple in cellular imaging. Analogous experiments in animals are challenging, however, due to substantial scattering and autofluorescence in tissue at visible (350–700 nm) and near-infrared (700–1,000 nm) wavelengths. Here, we enable real-time, non-invasive multicolour imaging experiments in animals through the design of optical contrast agents for the shortwave infrared (SWIR, 1,000–2,000 nm) region and complementary advances in imaging technologies. We developed tunable, SWIR-emissive flavylium polymethine dyes and established relationships between structure and photophysical properties for this class of bright SWIR contrast agents. In parallel, we designed an imaging system with variable near-infrared/SWIR excitation and single-channel detection, facilitating video-rate multicolour SWIR imaging for optically guided surgery and imaging of awake and moving mice with multiplexed detection. Optimized dyes matched to 980 nm and 1,064 nm lasers, combined with the clinically approved indocyanine green, enabled real-time, three-colour imaging with high temporal and spatial resolutions.Conducting high-resolution, multiplexed imaging in living mammals is challenging because of considerable scattering and autofluorescence in tissue at visible and near-infrared wavelengths. Now, real-time, non-invasive multicolour imaging experiments in live animals have been achieved through the design of optical contrast agents for the shortwave infrared (SWIR, 1,000–2,000 nm) region and the introduction of excitation multiplexing with single-channel SWIR detection.

Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (∼90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)—a clinically approved NIR-I dye—in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ∼4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery. A renally cleared, water-soluble dye emitting in the near-infrared-imaging (NIR)-II window outperforms a clinically approved NIR-I dye in the in vivo imaging of tumours and their nearby blood and lymphatic vasculatures.

Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies. ER stress and UPR are implicated in various cancers. Here, the authors show that one of the canonical UPR pathways, IRE1α-XBP1 regulates c-MYC signaling to promote prostate tumorigenesis, and pharmacological inhibition of IRE1α with MKC8866 inhibits prostate cancer growth and synergizes with clinically used prostate cancer drugs.

MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.

A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene[3,4- ]pyrroles in 63-94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or 2-phenyl-2-(trifluoromethyl)-3-nitro-2 -chromenes and ethyl isocyanoacetate through the Barton-Zard reaction in ethanol at reflux for 0.5 h, using K CO as a base, has been developed.

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12. Estrogen receptor alpha (ERα) plays critical roles in the etiology and treatment of breast cancer. Here the authors synthesize benzopyrans with variable side chains to identify antiestrogenic compounds and characterize OP-1074, a compound that exhibits pure antiestrogenic activity by inducing the degradation of ERα and possesses greater potency than tamoxifen or fulvestrant in a xenograft model.

Etamicastat is a dopamine β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension. This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM). The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat Tmax was 1 hour postdose, and mean t½ was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine—30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, –11.66 mm Hg [–21.57 to –1.76; P < 0.05]; 100 mg, –14.92 mm Hg [–24.98 to –4.87; P < 0.01]; and 200 mg, –13.62 mm Hg [–22.29 to –3.95; P < 0.01]). Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09.

Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy (DCM). This study was designed to determine the effect of an antioxidant butin (BUT) on ischemia/reperfusion-induced myocardial injury in diabetic mice. Myocardial ischemia/reperfusion (MI/R) was induced in C57/BL6J diabetes mice. Infarct size and cardiac function were detected. For in vitro study, H9c2 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Proteins levels were investigated by Western blotting. In diabetes MI/R model, BUT significantly alleviated myocardial infarction and improved heart function, together with prevented diabetes-induced cardiac oxidative damage. The expression of Nrf2, AMPK, AKT and GSK-3β were significantly increased by BUT. Furthermore, in cultured H9c2 cardiac cells silencing Nrf2 gene with its siRNA abolished the BUT’s prevention of I/R-induced myocardial injury. Inhibition of AMPK and AKT signaling by relative inhibitor or specific siRNA decreased the level of BUT-induced Nrf2 expression, and diminished the protective effects of BUT. The interplay relationship between GSK-3β and Nrf2 was also verified with relative overexpression and inhibitors. Our findings indicated that BUT protected against I/R-induced ROS-mediated apoptosis by upregulating the AMPK/Akt/GSK-3β pathway, which further activated Nrf2-regulated antioxidant enzymes in diabetic cardiomyocytes exposed to I/R.