Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant

Background The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. Methods Postmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). Results At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. Conclusions This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.This work was supported by Novartis Pharmaceuticals Corporation. The funder of this study, in agreement with the authors and the study steering committee members, designed this study. Representatives of the trial sponsor performed data collection and the subsequent analysis

Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system

Author Manuscript 2010 August 1Hepatitis C virus (HCV), which infects 2–3% of the world population, is a causative agent of chronic hepatitis and the leading indication for liver transplantation1. The ability to propagate HCV in cell culture (HCVcc) is a relatively recent breakthrough and a key tool in the quest for specific antiviral therapeutics. Monitoring HCV infection in culture generally involves bulk population assays, use of genetically modified viruses and/or terminal processing of potentially precious samples. Here we develop a cell-based fluorescent reporter system that allows sensitive distinction of individual HCV-infected cells in live or fixed samples. We demonstrate use of this technology for several previously intractable applications, including live-cell imaging of viral propagation and host response, as well as visualizing infection of primary hepatocyte cultures. Integration of this reporter with modern image-based analysis methods could open new doors for HCV research.New York (State). Dept. of Health (Empire State Stem Cell Fund Contract C023046)United States. Public Health Service (Grant R01 DK56966)National Institutes of Health (U.S.) (Roadmap for Medical Research Grant 1 R01 DK085713-01)Howard Hughes Medical Institute (Investigator

Stability of Yellow Fever Virus under Recombinatory Pressure as Compared with Chikungunya Virus

Recombination is a mechanism whereby positive sense single stranded RNA viruses exchange segments of genetic information. Recent phylogenetic analyses of naturally occurring recombinant flaviviruses have raised concerns regarding the potential for the emergence of virulent recombinants either post-vaccination or following co-infection with two distinct wild-type viruses. To characterize the conditions and sequences that favor RNA arthropod-borne virus recombination we constructed yellow fever virus (YFV) 17D recombinant crosses containing complementary deletions in the envelope protein coding sequence. These constructs were designed to strongly favor recombination, and the detection conditions were optimized to achieve high sensitivity recovery of putative recombinants. Full length recombinant YFV 17D virus was never detected under any of the experimental conditions examined, despite achieving estimated YFV replicon co-infection levels of ∼2.4×106 in BHK-21 (vertebrate) cells and ∼1.05×105 in C710 (arthropod) cells. Additionally YFV 17D superinfection resistance was observed in vertebrate and arthropod cells harboring a primary infection with wild-type YFV Asibi strain. Furthermore recombination potential was also evaluated using similarly designed chikungunya virus (CHIKV) replicons towards validation of this strategy for recombination detection. Non-homologus recombination was observed for CHIKV within the structural gene coding sequence resulting in an in-frame duplication of capsid and E3 gene. Based on these data, it is concluded that even in the unlikely event of a high level acute co-infection of two distinct YFV genomes in an arthropod or vertebrate host, the generation of viable flavivirus recombinants is extremely unlikely

TREATMENT OF ANXIODEPRESSIVE DISORDERS IN PATIENTS WITH CARDIOVASCULAR DISEASES

Sixty patients at the age of 43 to 79 years with anxiodepressive symptoms with comorbid cardiovascular disease have been examined after admission to psychotherapeutic department. Patients have been divided into two groups. The first group including 30 patients were treated by the tricyclic antidepressant amitriptyline with the average daily dose of 34.4 ± 12.9 mg. The 30 patients from the second group were treated by antidepressants of the selective serotonin reuptake inhibitors group. The sociodemographic characteristics in both groups did not differ significantly; the severity of cardiovascular disease, additional somatic and other diseases were certainty lower in the first group than in the second (p < 0.05). Examination of the patients with the use of Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale (HDRS and HARS) was carried out three times: at admission, in 1 week and in 4 weeks. At the time of admission, anxiety and depression in the first group were more expressed (p < 0.05) than in the second due to frequent psychogeny. The treatment scheme included tranquilizers, neuroleptics, neurometabolic drugs, basic cardiotropic therapy and psychotherapy. After 4 weeks anxiodepressive symptoms were more than 50 % reduced in both groups: 61 % in the first group and 50.7 % in the second group by the HDRC scale; 65.9 % in the first group and 59.8 % in the second group by the HARS scale. It has been shown that the small doses of antidepressant including amitriptyline involved in the complex treatment scheme were efficient and did not cause cardiotoxic effect

Separation of intra- and intergranular magnetotransport properties in nanocrystalline diamond films on the metallic side of the metal-insulator transition

A systematic study on the morphology and electronic properties of thin heavily boron-doped nanocrystalline diamond (NCD) films is presented. The films have nominally the same thickness (≈150 nm) and are grown with a fixed B/C ratio (5000 ppm) but with different C/H ratios (0.5-5%) in the gas phase. The morphology of the films is investigated by x-ray diffraction and atomic force microscopy measurements, which confirm that lower C/H ratios lead to a larger average grain size. Magnetotransport measurements reveal a decrease in resistivity and a large increase in mobility, approaching the values obtained for single-crystal diamond as the average grain size of the films increases. In all films, the temperature dependence of resistivity decreases with larger grains and the charge carrier density and mobility are thermally activated. It is possible © IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.status: publishe

Clinical and angiographic results of precutaneous excimer laser versus balloon angioplasty for coronary intra-stent restenosis

Treatment of in-stent restenosis (ISR) with conventional PTCA causes significant recurrent neointimal tissue growth in 30-85%. Therefore, laser ablation of intra-stent neointimal hyperplasia prior to balloon dilatation can be an attractive alternative. However, the long-term outcomes of such treatment have not been studied thoroughly enough. This prospective case-control study evaluated angiographic and clinical outcomes of PTCA alone and a combination of eximer laser coronary angioplasty (ELCA) and adjunct PTCA in 125 patients with ISR. ELCA was performed prior to balloon dilatation in 67 patients, PTCA alone was performed in 58 patients. Basic demographic and clinical data were comparable in both groups. Lesions included in ELCA group were longer (17.1± 9.9 mm versus 13.6±9.1 mm; p=0.034), more complex (36.5% type-C stenoses versus 14.3%; p=0.006) and more frequently had reduced distal blood flow (TIMI < 3: 18.9% versus 4.8%; p=0.025) compared to lesions in PTCA group. Immediate angiographic results of PTCA and ELCA+PTCA appeared to be comparable. PTCA alone was successful in 57 patients (98.3%), ELCA+PTCA -in 66 patients (98.5%). The rates of hospital complications were comparable (3.0% in ELCA group versus 8.6% in PTCA group). The 1 year-follow-up showed that the rates of MACE were comparable in the two groups (37.3% in ELCA group versus 46.6% in PTCA group). The rates of TVR within 1 year after the intervention were also similar in ELCA and PTCA groups (32.8% versus 34.5%). The data mean that ELCA in patients with complex ISR is efficient and safe. Despite a higher complexity of lesions in ELCA group, no increase in the rate of complications was registered

Plasmacytoid dendritic cells sense hepatitis C virus–infected cells, produce interferon, and inhibit infection

Hepatitis C virus (HCV), a member of the Flaviviridae family, is a single-stranded positive-sense RNA virus that infects >170 million people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Despite its ability to block the innate host response in infected hepatocyte cell lines in vitro, HCV induces a strong type 1 interferon (IFN) response in the infected liver. The source of IFN in vivo and how it is induced are currently undefined. Here we report that HCV-infected cells trigger a robust IFN response in plasmacytoid dendritic cells (pDCs) by a mechanism that requires active viral replication, direct cell-cell contact, and Toll-like receptor 7 signaling, and we show that the activated pDC supernatant inhibits HCV infection in an IFN receptor-dependent manner. Importantly, the same events are triggered by HCV subgenomic replicon cells but not by free virus particles, suggesting the existence of a novel cell-cell RNA transfer process whereby HCV-infected cells can activate pDCs to produce IFN without infecting them. These results may explain how HCV induces IFN production in the liver, and they reveal a heretofore unsuspected aspect of the innate host response to viruses that can subvert the classical sensing machinery in the cells they infect, and do not infect or directly activate pDCs