Calibration Unit Design for High-Resolution Infrared Spectrograph for Exoplanet Characterization (HISPEC)

The latest generation of high-resolution spectrograph instruments on 10m-class telescopes continue to pursue challenging science cases. Consequently, ever more precise calibration methods are necessary to enable trail-blazing science methodology. We present the High-resolution Infrared SPectrograph for Exoplanet Characterization (HISPEC) Calibration Unit (CAL), designed to facilitate challenging science cases such as Doppler imaging of exoplanet atmospheres, precision radial velocity, and high-contrast high-resolution spectroscopy of nearby exoplanets. CAL builds upon the heritage from the pathfinder instrument Keck Planet Imager and Characterizer (KPIC) and utilizes four near-infrared (NIR) light sources encoded with wavelength information that are coupled into single-mode fibers. They can be used synchronously during science observations or asynchronously during daytime calibrations. A hollow cathode lamp (HCL) and a series of gas absorption cells provide absolute calibration from 0.98 {\mu}m to 2.5 {\mu}m. A laser frequency comb (LFC) provides stable, time-independent wavelength information during observation and CAL implements a lower finesse astro-etalon as a backup for the LFC. Design lessons from instrumentation like HISPEC will serve to inform the requirements for similar instruments for the ELTs in the future.Comment: 16 pages, 14 figure

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis

Long-lasting successful dissemination of resistance to oxazolidinones in MDR Staphylococcus epidermidis clinical isolates in a tertiary care hospital in France.

Objectives: Patient- and procedure-related changes in modern medicine have turned CoNS into one of the major nosocomial pathogens. Treatments of CoNS infections are challenging owing to the large proportion of MDR strains and oxazolidinones often remain the last active antimicrobial molecules. Here, we have investigated a long-lasting outbreak (2010-13) due to methicillin- and linezolid-resistant (LR) CoNS (n = 168), involving 72 carriers and 49 infected patients. Methods: Antimicrobial susceptibilities were tested by the disc diffusion method and MICs were determined by broth microdilution or Etest. The clonal relationship of LR Staphylococcus epidermidis (LRSE) was first determined using a semi-automated repetitive element palindromic PCR (rep-PCR) method. Then, WGS was performed on all cfr-positive LRSE (n = 30) and LRSE isolates representative of each rep-PCR-defined clone (n = 17). Self-transferability of cfr-carrying plasmids was analysed by filter-mating experiments. Results: This outbreak was caused by the dissemination of three clones (ST2, ST5 and ST22) of LRSE. In these clones, linezolid resistance was caused by (i) mutations in the chromosome-located genes encoding the 23S RNA and L3 and L4 ribosomal proteins, but also by (ii) the dissemination of two different self-conjugative plasmids carrying the cfr gene encoding a 23S RNA methylase. By monitoring linezolid prescriptions in two neighbouring hospitals, we highlighted that the spread of LR-CoNS was strongly associated with linezolid use. Conclusions: Physicians should be aware that plasmid-encoded linezolid resistance has started to disseminate among CoNS and that rational use of oxazolidinones is critical to preserve these molecules as efficient treatment options for MDR Gram-positive pathogens

Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND: The efficacy and safety of lenalidomide as maintenance therapy after chemotherapy-based second-line therapy in patients with chronic lymphocytic leukaemia is unknown. Although kinase inhibitors can improve outcomes for some patients with relapsed and refractory disease, not all patients have access to these novel drugs. In this study, we aimed to assess the efficacy and safety of lenalidomide as maintenance therapy in patients with previously treated chronic lymphocytic leukaemia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (CONTINUUM) was done at 111 hospitals, medical centres, and clinics in 21 countries. Patients were eligible if they had chronic lymphocytic leukaemia; were aged 18 years or older; had been treated with two lines of therapy (with at least a partial response after second-line therapy); had received a purine analogue, bendamustine, anti-CD20 antibody, chlorambucil, or alemtuzumab as first-line or second-line treatment; and had an Eastern Cooperative Oncology Group performance score of 0-2. Eligible patients were randomly assigned (1:1) by an interactive voice-response system to receive either oral lenalidomide (2·5 mg/day) or matching oral placebo capsules (2·5 mg/day) for 28-day cycles, until disease progression or unacceptable toxicity. Lenalidomide dose escalation (to 5 mg or 10 mg per day) was permitted if the drug was well tolerated. Patients, investigators, and those completing data analyses were masked to treatment allocation. Randomisation was stratified by age, response to second-line therapy, and prognostic factors. Co-primary endpoints were progression-free survival and overall survival; the primary endpoint was later changed to overall survival after the data cutoff for this analysis. Secondary endpoints were time from randomisation to second disease progression or death (PFS2),32 tumour response (improvement in response and duration of response), safety, and health-related quality of life (HRQoL). Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00774345, and is closed to accrual, but follow-up is ongoing. FINDINGS: Between Feb 16, 2009 and Sept 29, 2015, 314 patients with chronic lymphocytic leukaemia were enrolled and randomly assigned to receive either lenalidomide (n=160) or placebo (n=154). With a median follow-up of 31·5 months (IQR 18·9-50·8), there was no significant difference in overall survival between the lenalidomide and the placebo groups (median 70·4 months, 95% CI 57·5-not estimable [NE] vs NE, 95% CI 62·8-NE; hazard ratio [HR] 0·96, 95% CI 0·63-1·48; p=0·86). Progression-free survival was significantly longer in the lenalidomide group (median 33·9 months, 95% CI 25·5-52·5) than in the placebo group (9·2 months, 7·4-13·6; HR 0·40, 95% CI 0·29-0·55; p<0·0001). PFS2 was significantly longer in the lenalidomide group than in the placebo group (median 57·5 months [47·7-NE] vs 32·7 months [26·4-49·0]; HR 0·46, 95% CI 0·29-0·70; p<0·01). Improved responses from baseline were observed in ten (6%) of 160 lenalidomide-treated patients versus four (3%) of 154 placebo-treated patients (p=0·12). Median time to improved response was 12·2 weeks (IQR 7·2-22·5) in the lenalidomide group versus 76·3 weeks (20·2-182·6) in the placebo group. Duration of improved response was not estimable in either group (95% CI 22·9-NE in the lenalidomide group vs NE-NE for placebo). There were no clinically meaningful differences in HRQoL between lenalidomide-treated patients and placebo-treated patients, as measured by FACT-Leu and EQ-5D, during maintenance treatment. In the safety population, the most common grade 3 or 4 adverse events included neutropenia (94 [60%] of 157 patients in the lenalidomide group vs 35 [23%] of 154 patients in the placebo group), thrombocytopenia (26 [17%] vs ten [6%]), and diarrhoea (13 [8%] vs one [<1%]). There were five fatal adverse events (three [2%] patients in the lenalidomide group and two [1%] patients in the placebo group). INTERPRETATION: Lenalidomide might delay time to subsequent therapy and does not adversely affect response to subsequent therapy. Chemoimmunotherapy followed by lenalidomide maintenance could be an effective treatment option for patients with chronic lymphocytic leukaemia who do not have access to kinase inhibitors

Long-lasting successful dissemination of resistance to oxazolidinones in MDR Staphylococcus epidermidis clinical isolates in a tertiary care hospital in France

International audienceObjectives: Patient-and procedure-related changes in modern medicine have turned CoNS into one of the major nosocomial pathogens. Treatments of CoNS infections are challenging owing to the large proportion of MDR strains and oxazolidinones often remain the last active antimicrobial molecules. Here, we have investigated a long-lasting outbreak (2010-13) due to methicillin-and linezolid-resistant (LR) CoNS (n " 168), involving 72 carriers and 49 infected patients. Methods: Antimicrobial susceptibilities were tested by the disc diffusion method and MICs were determined by broth microdilution or Etest. The clonal relationship of LR Staphylococcus epidermidis (LRSE) was first determined using a semi-automated repetitive element palindromic PCR (rep-PCR) method. Then, WGS was performed on all cfr-positive LRSE (n " 30) and LRSE isolates representative of each rep-PCR-defined clone (n " 17). Self-transferability of cfr-carrying plasmids was analysed by filter-mating experiments. Results: This outbreak was caused by the dissemination of three clones (ST2, ST5 and ST22) of LRSE. In these clones, linezolid resistance was caused by (i) mutations in the chromosome-located genes encoding the 23S RNA and L3 and L4 ribosomal proteins, but also by (ii) the dissemination of two different self-conjugative plasmids carrying the cfr gene encoding a 23S RNA methylase. By monitoring linezolid prescriptions in two neighbouring hospitals, we highlighted that the spread of LR-CoNS was strongly associated with linezolid use. Conclusions: Physicians should be aware that plasmid-encoded linezolid resistance has started to disseminate among CoNS and that rational use of oxazolidinones is critical to preserve these molecules as efficient treatment options for MDR Gram-positive pathogens