PURPOSE: Napabucasin is an investigational, orally administered reactive oxygen species generator bioactivated by intracellular antioxidant NAD(P)H:quinone oxidoreductase 1 that has been evaluated in various solid tumors, including metastatic colorectal cancer (mCRC). Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is hypothesized to predict response in napabucasin-treated patients with mCRC. PATIENT AND METHODS: In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, adults with histologically confirmed mCRC that progressed on first-line fluoropyrimidine plus oxaliplatin ± bevacizumab were randomized to twice-daily napabucasin plus FOLFIRI (napabucasin) or FOLFIRI alone (control). The primary endpoint was overall survival (OS) in the general study population and in patients with pSTAT3-positive tumors (biomarker-positive). RESULTS: In the general study population (napabucasin, n = 624; control, n = 629), median OS was 14.3 months for napabucasin and 13.8 months for control (hazard ratio [HR], 0.976, one-sided P = .74). Overall, 44% of patients were biomarker-positive (napabucasin, n = 275; control, n = 272). In the biomarker-positive population, median OS was 13.2 months for napabucasin and 12.1 months for control (HR, 0.969; one-sided P > .99). In the control arm, median OS was shorter for biomarker-positive versus biomarker negative patients (12.1 vs. 18.5 months; HR, 1.518; nominal 2-sided P = .0002). The most common treatment-emergent adverse events (TEAEs) were diarrhea (napabucasin, 84.6%; control, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs occurred in 73.8% of napabucasin-treated and 66.7% of control-treated patients, most commonly diarrhea (21.2%, 7.0%), neutrophil count decreased (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). Safety was similar in biomarker-positive patients. CONCLUSION: In patients with previously treated mCRC, adding napabucasin to FOLFIRI did not improve OS. Results from the control arm indicate that pSTAT3 is an adverse prognostic factor in mCRC.

• Klíčová slova
• Clinical trial, Colon cancer, FOLFIRI, pSTAT3, phase 3,
• MeSH
• bevacizumab MeSH
• dospělí MeSH
• fluorouracil MeSH
• kamptothecin MeSH
• kolorektální nádory * patologie   MeSH
• leukovorin MeSH
• lidé MeSH
• nádory rekta * MeSH
• nádory tračníku * chemicky indukované   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• bevacizumab MeSH
• fluorouracil MeSH
• kamptothecin MeSH
• leukovorin MeSH
• napabucasin MeSH Prohlížeč

AIMS: Consensus is lacking regarding the best treatment for coronary in-stent restenosis (ISR). The two most effective treatments are angioplasty with paclitaxel-coated balloon (PCB) and repeat stenting with drug-eluting stent (DES) but individual trials were not statistically powered for clinical endpoints, results were heterogeneous, and evidence about comparative efficacy and safety in relevant subsets was limited. METHODS AND RESULTS: The Difference in Anti-restenotic Effectiveness of Drug-eluting stent and drug-coated balloon AngiopLasty for the occUrrence of coronary in-Stent restenosis (DAEDALUS) study was a comprehensive, investigator-initiated, collaborative, individual patient data meta-analysis comparing angioplasty with PCB alone vs. repeat stenting with DES alone for the treatment of coronary ISR. The protocol was registered with PROSPERO (CRD42017075007). All 10 available randomized clinical trials were included with 1976 patients enrolled, 1033 assigned to PCB and 943 to DES. At 3-year follow-up, PCB was associated with a significant increase in the risk of target lesion revascularization (TLR) compared with DES [hazard ratio (HR) 1.32, 95% CI 1.02–1.70, P = 0.035; number-needed-to-harm 28.5]. There was a significant interaction between treatment effect and type of restenosed stent (P = 0.029) with a more marked difference in patients with DES-ISR and comparable effects in patients with bare-metal stent-ISR. At 3-year follow-up, the primary safety endpoint of all-cause death, myocardial infarction, or target lesion thrombosis was comparable between treatments (HR 0.80, 95% CI 0.58–1.09, P = 0.152). A pre-specified subgroup analysis indicated a significant interaction between treatment effect and type of DES used to treat ISR (P = 0.033), with a lower incidence of events associated with PCB compared with first-generation DES and similar effect between PCB and second-generation DES (HR 1.06, 95% CI 0.71–1.60, P = 0.764). Long-term all-cause mortality was similar between PCB and DES (HR 0.81, 95% CI 0.53–1.22, P = 0.310); results were consistent comparing PCB and non-paclitaxel-based DES (HR 1.42, 95% CI 0.80–2.54, P = 0.235). Myocardial infarction and target lesion thrombosis were comparable between treatments. CONCLUSIONS: In patients with coronary ISR, repeat stenting with DES is moderately more effective than angioplasty with PCB at reducing the need for TLR at 3 years. The incidence of a composite of all-cause death, myocardial infarction, or target lesion thrombosis was similar between groups. The rates of individual endpoints, including all-cause mortality, were not significantly different between groups.

• Klíčová slova
• Clinical Trials, Drug-coated balloon, Drug-eluting stent, In-stent restenosis, Meta-analysis, Mortality, Paclitaxel, Percutaneous coronary intervention,
• MeSH
• balónková angioplastika * MeSH
• koronární angiografie MeSH
• koronární restenóza * terapie   MeSH
• léčivé přípravky * MeSH
• lidé MeSH
• paclitaxel MeSH
• protézy - design MeSH
• randomizované kontrolované studie jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Názvy látek
• léčivé přípravky * MeSH
• paclitaxel MeSH

BACKGROUND: In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES). OBJECTIVES: This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR. METHODS: The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses. RESULTS: A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types. CONCLUSIONS: At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.

• Klíčová slova
• drug-coated balloon, drug-eluting stent, in-stent restenosis, individual patient data, percutaneous coronary intervention, randomized clinical trial, restenosis,
• MeSH
• balónková koronární angioplastika mortalita   MeSH
• koronární restenóza terapie   MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• stenty uvolňující léky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

A glycoside hydrolase family 5 β-mannanase-encoding gene was cloned from Bacillus sp. HJ14 isolated from saline soil in Heijing town. Coding sequence of mature protein (without the predicted signal peptide from M1 to A30) was successfully expressed in Escherichia coli BL21 (DE3). Purified recombinant mannanase (rMan5HJ14) exhibited optimal activity at pH 6.5 and 65 °C. The enzyme showed good salt tolerance, retaining more than 56 % β-mannanase activity at 3.0-30.0 % (w/v) NaCl and more than 94 % of the initial activity after incubation with 3.0-30.0 % (w/v) NaCl at 37 °C for 60 min. Almost no mannanase activity was lost after incubation of rMan5HJ14 with trypsin, proteinase K, and Alcalase at 37 °C for 60 min. Surfactants and chelating agents, namely SDS, CTAB, Tween 80, Triton X-100, EDTA, and sodium tripolyphosphate, showed little or no effect (retaining >82.4 % activity) on enzymatic activity. Liquid detergents, namely Tupperware, Walch, Bluemoon, Tide, and OMO, also showed little or no effect (retaining >72.4 % activity) on enzymatic activity at 0.5-2.0 % (v/v). The enzyme further presents a high proportion (11.97 %) of acidic amino acid residues (D and E), which may affect the SDS and NaCl tolerance of the enzyme. Together, the mannanase may be an alternative for potential use in liquid detergent industry.

• MeSH
• aktivace enzymů účinky léků   MeSH
• Bacillus účinky léků   genetika   metabolismus   MeSH
• beta-mannosidasa chemie   genetika   izolace a purifikace   metabolismus   MeSH
• chlorid sodný farmakologie   MeSH
• detergenty farmakologie   MeSH
• endopeptidasy metabolismus   MeSH
• exprese genu MeSH
• genom bakteriální MeSH
• hydrolýza MeSH
• ionty MeSH
• kovy MeSH
• povrchově aktivní látky farmakologie   MeSH
• rekombinantní proteiny MeSH
• sekvence aminokyselin MeSH
• sekvenční analýza DNA MeSH
• stabilita enzymů účinky léků   MeSH
• tolerance k soli * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• beta-mannosidasa MeSH
• chlorid sodný MeSH
• detergenty MeSH
• endopeptidasy MeSH
• ionty MeSH
• kovy MeSH
• povrchově aktivní látky MeSH
• rekombinantní proteiny MeSH

A mannanase-coding gene was cloned from Sphingobacterium sp. GN25 isolated from the feces of Grus nigricollis. The gene encodes a 371-residue polypeptide (ManAGN25) showing less than 74 % identity with a number of hypothetical proteins and putative glucanases and mannanases. Before experiment's performance, ManAGN25 was predicted to be a low-temperature active mannanase based on the molecular characterization, including (1) ManAGN25 shared the highest identity of 41.1 % with the experimentally verified low-temperature active mannanase (ManAJB13) from Sphingomonas sp. JB13; (2) compared with their mesophilic and thermophilic counterparts, ManAGN25 and ManAJB13 had increased number of amino acid residues around their catalytic sites; (3) these increased number of amino acid residues built longer loops, more α-helices, and larger total accessible surface area and packing volume. Then the experiments of biochemical characterization verified that the purified recombinant ManAGN25 is a low-temperature active mannanase: the enzyme showed apparently optimal activity at 35-40 °C and retained 78.2, 44.8, and 15.0 % of its maximum activity when assayed at 30, 20, and 10 °C, respectively; the half-life of the enzyme was approximately 60 min at 37 °C; the enzyme presented a K m of 4.2 mg/ml and a k cat of 0.4/s in McIlvaine buffer (pH 7.0) at 35 °C using locust bean gum as the substrate; and the activation energy for hydrolysis of locust bean gum by the enzyme was 36.0 kJ/mol. This study is the first to report the molecular and biochemical characterizations of a mannanase from a strain.

• MeSH
• bakteriální proteiny chemie   genetika   izolace a purifikace   metabolismus   MeSH
• beta-mannosidasa chemie   genetika   izolace a purifikace   metabolismus   MeSH
• kinetika MeSH
• konformace proteinů MeSH
• molekulární sekvence - údaje MeSH
• nízká teplota MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• Sphingobacterium chemie   enzymologie   genetika   MeSH
• stabilita enzymů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bakteriální proteiny MeSH
• beta-mannosidasa MeSH

A glycosyl hydrolase family 10 endoxylanase from Bacillus sp. HJ14 was grouped in a separated cluster with another six Bacillus endoxylanases which have not been characterized. These Bacillus endoxylanases showed less than 52% amino acid sequence identity with other endoxylanases and far distance with endoxylanases from most microorganisms. Signal peptide was not detected in the endoxylanase. The endoxylanase was expressed in Escherichia coli BL21 (DE3), and the purified recombinant enzyme (rXynAHJ14) was characterized. rXynAHJ14 was apparent optimal at 62.5 °C and pH 6.5 and retained more than 55% of the maximum activity when assayed at 40-75 °C, 23% at 20 °C, 16% at 85 °C, and even 8% at 0 °C. Half-lives of the enzyme were more than 60 min, approximately 25 and 4 min at 70, 75, and 80 °C, respectively. The enzyme exhibited more than 62% xylanase activity and stability at the concentration of 3-30% (w/v) NaCl. No xylanase activity was lost after incubation of the purified rXynAHJ14 with trypsin and proteinase K at 37 °C for 60 min. Different components of oligosaccharides were detected in the time-course hydrolysis of beechwood xylan by the enzyme. During the simulated intestinal digestion phase in vitro, 11.5-19.0, 15.3-19.0, 21.9-27.7, and 28.2-31.2 μmol/mL reducing sugar were released by the purified rXynAHJ14 from soybean meal, wheat bran, beechwood xylan, and rapeseed meal, respectively. The endoxylanase might be an alternative for potential applications in the processing of sea food and saline food and in aquaculture as agastric fish feed additive.

• MeSH
• Bacillus enzymologie   genetika   MeSH
• chlorid sodný metabolismus   MeSH
• endo-1,4-beta-xylanasy chemie   genetika   izolace a purifikace   metabolismus   MeSH
• endopeptidasa K metabolismus   MeSH
• Escherichia coli genetika   MeSH
• exprese genu MeSH
• klonování DNA MeSH
• koncentrace vodíkových iontů MeSH
• molekulární sekvence - údaje MeSH
• proteolýza MeSH
• rekombinantní proteiny chemie   genetika   izolace a purifikace   metabolismus   MeSH
• sekvenční analýza DNA MeSH
• sekvenční homologie aminokyselin MeSH
• stabilita enzymů MeSH
• teplota MeSH
• trypsin metabolismus   MeSH
• xylany metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chlorid sodný MeSH
• endo-1,4-beta-xylanasy MeSH
• endopeptidasa K MeSH
• rekombinantní proteiny MeSH
• trypsin MeSH
• xylany MeSH

BACKGROUND: There is medium correlation between the current anthropometric method and the radiography in the angle of hallux valgus (AoH) measurement, so this study aimed at designing a reliable and more accurate approach to measure the AoH (AoH). MATERIALS AND METHODS: Fifteen age, body weight, and height matched male students were included and those with foot disorders, deformities, or injuries were excluded from the study. The dorsal protrusions of the first metatarsal and the hallux were marked by palpating from three experienced observers; then their barefoot model in standing was collected by a three dimensional laser scanning system. The AoH was defined in the X-Y plane by the angle between the line joining the marks of centre of head and centre of base of metatarsal shaft and the one connecting the marks of the centre of metatarsal head and the hallux. The same procedure was repeated a week later. Besides, other measures based on the footprint, outline, and the radiography were also available for comparisons. Paired t-test, linear regression, and reliability analysis were applied for statistical analysis with significant level of 0.05 and 95% confidence interval. RESULTS: There were no significant differences recorded between the new method and the radiographic method (P = 0.069). The AoH was superior to the methods of footprint and outline and it displayed a relative higher correlation with the radiographic method (r = 0.94, r (2) = 0.89). Moreover both the inter and intraobserver reliabilities of this method were proved to be good. CONCLUSION: This new method can be used for hallux valgus inspection and evaluation.

• Klíčová slova
• Hallux valgus, angle of hallux valgus, foot print, radiography, three dimensional laser foot scanning,
• Publikační typ
• časopisecké články MeSH