The occurrence and bioaccumulation of new and legacy persistent organic pollutants (POPs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), hexabromocyclododecanes (HBCDs), and Dechlorane Plus (DPs) and their related compounds (Dechloranes) in an ecosystem on King George Island, Antarctica are investigated. The new and legacy POPs were widely detected in the animal samples collected from Antarctica, which included Limpet, Antarctic cod, Amphipods, Antarctic icefish, Gentoo and Chinstrap penguins, Kelp gull, and South polar skua. The trophic magnification factors indicated that the levels of PCNs and HBCDs, as well as the legacy POPs, were magnified through the food web, whereas DPs might be diluted through the trophic levels contradicting the classification of Dechloranes as POPs. This is one of the first extensive surveys on PCNs, HBCDs, and Dechloranes, which provides unique information on the distribution and trophic biomagnification potential of the new and legacy POPs in the Antarctic region.

• MeSH
• bioakumulace MeSH
• chemické látky znečišťující vodu * analýza   MeSH
• ekosystém MeSH
• monitorování životního prostředí MeSH
• perzistentní organické znečišťující látky MeSH
• polychlorované bifenyly * analýza   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Antarktida MeSH

The present study was performed to evaluate the antibacterial activities of an antimicrobial peptide (CSpK14) and the synergies thereof with β-lactams against vancomycin-resistant Staphylococcus aureus (VRSA) and Enterococci (VRE). Our strain was isolated from fermented food (kimchi), which is 99.79 % homologous with Bacillus amyloliquefaciens subsp. plantarum FZB42(T). CSpK14 was purified to homogeneity by diammonium sulfate precipitation, concentration, dialysis, and followed by two-stage chromatographic separation, i.e., Sepharose Cl-6B and Sephadex G-25 chromatography, and had a molar mass of ~4.6 kDa via Tricine SDS-PAGE and in situ examination. It was stable at pH 6.0-11.5 and temperature up to 80 °C. In addition, it was also stable with various metal ions, solvents, and proteases. The N-terminal amino acid sequence was H-Y-D-P-G-D-D-S-G-N-T-G and did not show any significant homology with reported peptides. However, it shows some degrees of identity with alpha-2-macroglobulin and ligand-gated channel protein from different microorganisms. CSpK14 significantly reduced the minimum inhibitory concentrations (MICs) of β-lactams and had no effect on non-β-lactams against VRSA and VRE. MICs of CSpK14/oxacillin and CSpK14/ampicillin were reduced by 8- to 64-fold and 2- to 16-fold, respectively. The time killing assay between CSpK14/oxacillin (2.29-2.37 Δlog10CFU/mL at 24 h) and CSpK14/ampicillin (2.30-2.38 Δlog10CFU/mL at 24 h) being >2-fold and fractional inhibitory concentration index ˂0.5 revealed synergy. Furthermore, the biofilms formed by VRSA and VRE were reduced completely. CSpK14 was simple to purify, had low molecular mass, was stable over a wide pH range or tested chemicals, had broad inhibitory spectrum, and possessed potent synergistic antimicrobial-antibiofilm properties. CSpK14 synergistically enhanced the efficacy of β-lactams and is therefore suitable for combination therapy.

• MeSH
• ampicilin farmakologie   MeSH
• antibakteriální látky biosyntéza   izolace a purifikace   farmakologie   MeSH
• Bacillus amyloliquefaciens klasifikace   imunologie   metabolismus   MeSH
• biofilmy účinky léků   růst a vývoj   MeSH
• chromatografie iontoměničová MeSH
• enterokoky rezistentní vůči vankomycinu účinky léků   růst a vývoj   MeSH
• fylogeneze MeSH
• kationické antimikrobiální peptidy biosyntéza   izolace a purifikace   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• mikrobiální testy citlivosti MeSH
• oxacilin farmakologie   MeSH
• rezistence na vankomycin účinky léků   MeSH
• sekvence aminokyselin MeSH
• stabilita proteinů MeSH
• Staphylococcus aureus účinky léků   růst a vývoj   MeSH
• synergismus léků MeSH
• Publikační typ
• časopisecké články MeSH

CANDOR compared the safety/efficacy of carfilzomib with dexamethasone and daratumumab (KdD) to carfilzomib with dexamethasone (Kd) in adults with relapsed/refractory multiple myeloma (RRMM). This CANDOR subgroup analysis evaluated outcomes based on cytogenetic risk. Overall response rates (KdD vs. Kd) were 81% versus 56% in high-risk and 87% versus 79% in standard-risk groups. Median progression-free survival was 11.2 versus 7.4 months in high-risk (hazard ratio, 0.56 [95% CI, 0.34, 0.93]) and not reached versus 16.6 months in standard-risk groups (0.56 [95% CI, 0.39, 0.80]). These data support the efficacy of KdD in RRMM treatment, including in patients with high-risk cytogenetics.

• MeSH
• cytogenetické vyšetření MeSH
• dexamethason terapeutické užití   MeSH
• dospělí MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   genetika   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• Publikační typ
• abstrakt z konference MeSH

INTRODUCTION: This double-blind, parallel-group, active-controlled phase III trial (NCT02260804) assessed CT-P10 and rituximab safety and efficacy in patients with previously untreated low-tumor-burden follicular lymphoma (LTBFL), including after a single switch from rituximab to CT-P10. PATIENTS AND METHODS: LTBFL patients were randomized (1:1) to receive CT-P10 or rituximab (375 mg/m2 intravenously; day 1 of 4 7-day cycles). Patients achieving disease control entered a 2-year maintenance period. CT-P10 or rituximab were administered every 8 weeks (6 cycles) in year 1; all patients could receive CT-P10 (every 8 weeks; 6 cycles) in year 2. Secondary endpoints (reported here) were overall response rate (ORR) during the study period, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Safety and immunogenicity were evaluated. RESULTS: Between November 9, 2015 and January 4, 2018, 258 patients were randomized (130 for CT-P10; 128 for rituximab). ORR was similar between groups over the study period (CT-P10: 88%; rituximab: 87%). After 29.2 months' median follow-up, median PFS, TTP, and OS were not estimable; 24-month Kaplan-Meier estimates suggested similarity between groups. Overall, 114 (CT-P10: 88%), and 104 (rituximab: 81%) patients experienced treatment-emergent adverse events. The single switch was well tolerated. CONCLUSION: These updated data support therapeutic similarity of CT-P10 and rituximab and support the use of CT-P10 monotherapy for previously untreated LTBFL.

• MeSH
• biosimilární léčivé přípravky MeSH
• folikulární lymfom * farmakoterapie   patologie   MeSH
• lidé MeSH
• myší monoklonální protilátky * škodlivé účinky   MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• rituximab škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: In the phase III, open-label, randomised HannaH study, fixed-dose neoadjuvant-adjuvant subcutaneous trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer was non-inferior to standard weight-based intravenous infusion in terms of serum trough concentration and pathological complete response (pCR). Evidence suggests that pCR, particularly total pCR (tpCR), is likely to predict clinical benefit. We report associations between tpCR and event-free survival (EFS) from HannaH (the largest population from a single study of patients presenting with newly diagnosed HER2-positive breast cancer treated with neoadjuvant-adjuvant trastuzumab to date) plus long-term efficacy and safety. METHODS: Eligible patients received four cycles of neoadjuvant docetaxel followed by four cycles of fluorouracil/epirubicin/cyclophosphamide administered concurrently with 3-weekly subcutaneous (600 mg fixed dose) or intravenous trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses). Post-surgery, patients received adjuvant trastuzumab as randomised to complete 1 year of standard treatment. In exploratory analyses, we used Cox regression to assess associations between tpCR and EFS. EFS rates per subgroup were estimated using the Kaplan-Meier method. FINDINGS: Three-year EFS rates were 76% for subcutaneous and 73% for intravenous trastuzumab (unstratified hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.69-1.30; intention-to-treat population). Three-year overall survival rates were 92% for subcutaneous and 90% for intravenous trastuzumab (unstratified HR 0.76, 95% CI 0.44-1.32). tpCR was associated with a reduced risk of an EFS event: subcutaneous arm HR 0.38 (95% CI 0.22-0.65); intravenous arm HR 0.32 (95% CI 0.18-0.60). Results were similar for subgroups, including oestrogen receptor status. The few additional adverse events occurring during treatment-free follow-up were balanced between arms. INTERPRETATION: Long-term efficacy supports the established non-inferiority of subcutaneous trastuzumab, and its safety profile remains consistent with the known intravenous profile. In each of HannaH's treatment arms, tpCR was associated with improved EFS, adding to evidence that tpCR is associated with clinical benefit in HER2-positive early breast cancer.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• dospělí MeSH
• injekce subkutánní MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• následné studie MeSH
• neoadjuvantní terapie MeSH
• přežití po terapii bez příznaků nemoci MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• trastuzumab terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma. METHODS: In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. FINDINGS: Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI -6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. INTERPRETATION: CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. FUNDING: Celltrion, Inc.

• MeSH
• bezpečnost * MeSH
• biosimilární léčivé přípravky škodlivé účinky   farmakokinetika   farmakologie   terapeutické užití   MeSH
• dvojitá slepá metoda MeSH
• folikulární lymfom farmakoterapie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myší monoklonální protilátky škodlivé účinky   farmakokinetika   farmakologie   terapeutické užití   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• rituximab škodlivé účinky   farmakokinetika   farmakologie   terapeutické užití   MeSH
• tumor burden * účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

• MeSH
• adenin aplikace a dávkování   analogy a deriváty   MeSH
• analýza přežití MeSH
• bendamustin hydrochlorid aplikace a dávkování   škodlivé účinky   MeSH
• indukce remise MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• lymfom z plášťových buněk * farmakoterapie   mortalita   MeSH
• piperidiny aplikace a dávkování   škodlivé účinky   MeSH
• progrese nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie * škodlivé účinky   terapeutické užití   MeSH
• pyrazoly aplikace a dávkování   škodlivé účinky   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   MeSH
• rituximab aplikace a dávkování   škodlivé účinky   MeSH
• senioři MeSH
• udržovací chemoterapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

• MeSH
• autofagie * fyziologie   MeSH
• biotest metody   normy   MeSH
• lidé MeSH
• počítačová simulace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• směrnice MeSH

BACKGROUND: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. METHODS: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. RESULTS: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. CONCLUSIONS: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

• MeSH
• celosvětové zdraví * MeSH
• globální zátěž nemocemi * MeSH
• incidence MeSH
• kvalitativně upravené roky života MeSH
• lidé MeSH
• morbidita MeSH
• naděje dožití MeSH
• rány a poranění * mortalita   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH