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Porcine epidemic diarrhea virus (PEDV) is one of the main pathogens causing severe diarrhea in piglets. Infection of the host induces apoptosis, causing huge economic losses to the pig industry. At present, the preventive and therapeutic effects of commercial vaccines are not satisfactory, and it is necessary to develop new anti-PEDV drugs. In this study, we screened the PEDV-inhibiting drug Buddlejasaponin IVb from the natural product library, and determined the inhibitory effect of Buddlejasaponin IVb on PEDV proliferation in a dose-dependent manner. By exploring the effect of Buddlejasaponin IVb on the life cycle of PEDV, it was found that Buddlejasaponin IVb mainly inhibits the replication and release stages of PEDV, but there is no report at home and abroad. In addition, Buddlejasaponin IVb can inhibit PEDV-activated NF-κB signaling pathway by downregulating PEDV or LPS induced elevation of cytokine levels (IL-6, IL-8, IL-1β, TNF-α). Finally, we returned to in vivo experiments to explore the antiviral effects of the drug in pigs. The results show that Buddlejasaponin IVb can effectively relieve the clinical symptoms and intestinal damage caused by PEDV infection in pigs. Therefore, this study will provide an important basis for the research on antiviral drugs of PEDV and its members, and at the same time provide guidance for the actual production, which has important application prospects.

In the phase 3 APOLLO trial, daratumumab in combination with pomalidomide and dexamethasone (D-Pd) significantly reduced the rate of disease progression or death by 37% relative to Pd alone in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor. Here, we present patient-reported outcomes (PROs) from APOLLO. Median treatment duration was 11.5 months with D-Pd and 6.6 months with Pd. PRO compliance rates were high and similar in both groups. No changes from baseline were observed for EORTC QLQ-C30 global health status scores in either group, while physical and emotional functioning, disease symptoms, and adverse effects of treatment remained at baseline levels with D-Pd but worsened with Pd. Reductions (p, The APOLLO study was sponsored by the European Myeloma Network (EMN) in collaboration with Janssen Research & Development, LLC. Medical writing and editorial support were provided by Justine Lempart, PhD, and Linda V. Wychowski, PhD, of Eloquent Scientific Solutions and were funded by Janssen Global Services, LLC

Sulfomycins are sulfur-rich, ribosomally synthesized, and post-translationally modified peptides (RiPPs) that are characterized by a 35-membered macrocyclic ring system with a pyridine domain central to five azoles and additional dehydroamino acids. The pathway through which these large thiopeptide antibiotics are formed in

Regression analysis of heterogeneous samples with subgroup structure is essential to the development of precision medicine. In practice, this task is often challenging owing to the lack of prior knowledge of subgroup labels. Therefore, detecting the subgroups with similar characteristics becomes critical, which often controls the accuracy of regression analysis. In this article, we investigate a new framework for detecting the subgroups that have similar characters in feature space and similar treatment effects. The key idea is that we incorporate K-means clustering into the regression framework of concave pairwise fusion, so that the regression and subgroup detection tasks can be performed simultaneously. Our method is specifically tailored for handling the situations where the sample is not homogeneous in the sense that the response variables in different domains of feature space are generated through different mechanisms.

Organic light-emitting materials, especially those with two-phase high emission, have attracted considerable attention for applications in bioimaging agents, sensors, optoelectronic devices, etc. Many fluorophores applied in such fields either emit brightly in dilute solution or in aggregate state, with the former often suffering from aggregation-caused quenching effect, and the latter falling dark at low concentrations. Herein, we overcame the dilemma by balancing the planar and distorted structures with various side units and achieved bright emission in both dilute solution (e.g., the absolute quantum yields (ФPL) = 90.2% in THF) and in aggregate states (e.g., ФPL=92.7% in powder state, ФPL = 95.3% in crystal). These luminescent mate-rials are demonstrated as promising guests embedded into host matrix to achieve efficient room temperature phosphores-cence, and these host-guest systems could be applied in the information encryption. Moreover, these luminogens could also be used as single-component emitting layers to construct non-doped organic light-emitting diodes, from which a maximum external quantum efficiency up to 4.75% with Commission International de L’Eclairge (CIE) coordinates of (0.15, 0.05), which is neatest to next generation ultra-high definition television (UHDTV) display standard, was realized. This work pro-vides a feasible strategy of balancing the planar and distorted structure of a luminogen toward highly efficient emission in both solution and solid states.

By combining aggregation-induced emission (AIE) effect and a triplet–triplet upconversion (TTU) process, a blue emitter with excellent photoluminescence quantum efficiency and high upconversion efficiency in the film state is developed, from which a highly efficient non-doped blue TTU organic light-emitting diode (TTU-OLED) was realized.

Underwater acoustic stealth is of significance for hiding targets. Since perfect cloaking achieved by carpet cloaks or metasurface carpet cloaks may only be suitable for static targets, here we propose a broadband 2-bit coding metasurface to reduce the scattering cross section (SCS) of an object by the destructive interferences among waves scattered by different coding elements. A simple and easy fabricated design is developed by drilling square holes into a steel plate. Utilizing the antiresonance induced by couplings among four square holes of the unit cell, we achieve an approximate $95.62\mathrm{%}$ fractional bandwidth of acoustic stealth with the SCS reduction below $\ensuremath{-}10\phantom{\rule{0.2em}{0ex}}\mathrm{dB}$, which has been confirmed by both the theoretical prediction and experimental measurement. Compared with the previously proposed underwater acoustic carpet cloaks by the transformation acoustics, the bandwidth of SCS reduction is greatly expanded by the destructive interferences. In addition, simulations have demonstrated that the proposed metasurface may also be suitable for an object with a nonplanar surface.

New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0–∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0–∞ and Cmax of 2.06 (90% confidence interval 1.86–2.30) and 1.95 (90% confidence interval 1.65–2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.

AIM Phase III, randomized, double-blind study evaluating the efficacy and safety of ertugliflozin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin, including evaluation in the China subpopulation. MATERIALS AND METHODS A 26-week, double-blind study of 506 Asian patients (80.2% from mainland China), randomized 1:1:1 to placebo, ertugliflozin 5- or 15 mg, was performed. Primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight (BW), systolic/diastolic blood pressure (SBP/DBP), and proportion of patients with HbA1c

Silkworm silk is a promising natural biopolymer for textile and biomedical applications for its remarkable flexibility, excellent biocompatibility and controllable biodegradability. The functionalization of silks makes them more versatile for flexible displays and visible bioscaffolds. However, fluorescent silks are normally fabricated through unstable physical absorption or complicated chemical reactions under harsh conditions. Herein, we developed a simple strategy for preparing fluorescent silks. Five aggregation-induced emission luminogens (AIEgens) with activated alkynes were synthesized by rational molecular design, and then reacted with silk fibers through facile metal-free click bioconjugation. The resulting conjugates show bright full-color emissions and high stability. A white light-emitting silk was fabricated by simultaneous bioconjugation with red-, green- and blue-emissive AIEgens. The red-emissive AIEgen-functionalized silks were successfully applied for long-term cell tracking and two-photon bioimaging, demonstrating great potential for tissue engineering and bioscaffold monitoring.

Triplet-triplet upconversion (TTU), where two low-energy triplet excitons are converted to one higher energy singlet exciton, is excellent approach to break through the theoretical limit of the pure fluorescent organic light-emitting diodes (OLEDs) by 5%. To data, however, the reported emitters with high emission efficiency and efficiently TTU in film state are rare. Herein, we design the blue aggregation-induced emission luminogens (AIEgens) and investigate their upconversion efficiency. TPA-An-mPhCz can not only achieve high emission efficiency in the film state, but also show high upconversion efficiency of close to 50% even though the calculated energy level of the triplet excitons (T2) is lower than 2T1. A possible upconversion mechanism is proposed according to the transient electroluminescence spectra and theoretical calculation. This strategy may provide a new platform for the construction of highly efficient non-doped blue OLEDs based on TTU and AIEgens.

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development., European Myeloma Network and Janssen Research and Development.

2-Aminovinyl-cysteine (AviCys) is a thioether amino acid shared by a variety of ribosomally synthesized and posttranslationally modified peptides (RiPPs). Based on investigations into the biosynthesis of thioviridamide RiPPs in Streptomyces sp. NRRL S-87, we here report a path for the formation of this unusual thioether residue. This path relies on four dedicated proteins: phosphotransferase TvaCS-87, Lyase TvaDS-87, kinase homolog TvaES-87, and LanD-like flavoprotein TvaFS-87. TvaES-87 plays a critical role in effective AviCys formation. During the posttranslational modifications of the precursor peptide, it works with TvaFS-87 to form a minimum AviCys synthetase complex, which follows the combined activity of TvaCDS-87 for Thr dehydration and catalyzes Cys oxidative decarboxylation and subsequent Michael addition of the resulting enethiol nucleophile onto the newly formed dehydroamino acid residue for cyclization. With TvaES-87, TvaFS-87 activity for Cys processing can be coordinated with TvaCDS-87 activity for minimizing competitive or unexpected spontaneous reactions and forming AviCys effectively.

2-Aminovinyl-cysteine (AviCys) is an unusual thioether amino acid shared by a variety of ribosomally synthesized and posttranslationally modified peptides (RiPPs), as part of a macrocyclic ring system that contains theC-terminal 4 or 6 residues of a precursor peptide. This amino acid is nonproteinogenic and arises from processing theC-terminal Cys residue and an internal Ser/Thr residue to form an unsaturated thioether linkage. Enzyme activities for forming lanthionine (Lan), a distinct saturated thioether residue characteristic of lanthipeptide-related RiPPs, has long been speculated to be necessary for AviCys formation. Based on investigations into the biosynthesis of thioviridamide non-lanthipeptdes inStreptomyces sp. NRRL S-87, we here report an alternative path for AviCys formation that is independent of known Lan synthetase activity. This path relies on four dedicated enzymes for posttranslational modifications of the precursor peptide, in which TvaES-87, a phosphotransferase homolog, plays a critical role. It works with LanD-like flavoprotein TvaFS-87to form a minimum AviCys synthetase complex that follows the combined activity of TvaCDS-87for Thr dehydration and catalyzes Cys oxidative decarboxylation and subsequent Michael addition of the resulting enethiol nucleophile onto the newly formed dehydrobutyrine residue for cyclization. With TvaES-87, TvaFS-87activity for Cys processing can be coordinated with TvaCDS-87activity for minimizing competitive or unexpected spontaneous reactions and forming AviCys effectively.

This study characterized the multidose pharmacokinetic (PK) characteristics of posaconazole tablets used as prophylactic antifungal therapy in Chinese patients with acute myelogenous leukemia (AML) at risk for invasive fungal infection (IFI). Participants in this open-label, single-arm, phase 1b study received posaconazole 300 mg twice daily on day 1 and then once daily for up to 28 days. In the intensive PK sampling subgroup, posaconazole was administered under fasting conditions on days 1 and 8, and blood samples were regularly collected over 24 h. Trough PK sampling was conducted in all participants on days 1, 2, 3, 8, 14, 21, and 28 without regard for food intake. Population PK characteristics were predicted using PK modeling. Primary endpoints were steady-state average concentration (Cavg) and percentage of participants with steady-state Cavg (predicted and observed) > 500 ng/ml. Treatment safety and efficacy were secondary endpoints. Sixty-five adult Chinese participants were enrolled. On day 8, steady-state arithmetic mean Cavg was 1610 ng/ml (% coefficient of variation [%CV] 42.8%) in the intensive PK subgroup (n = 20). All participants achieved a steady-state Cavg > 500 ng/ml. Predicted Cavg (pCavg) was 1770 ng/ml (%CV 33.7%) in the total population (n = 64); 92.2% of participants had pCavg values ≥ 500 ng/ml (n = 59). The posaconazole tablet safety profile was consistent with that of the oral formulation, and the IFI rate was 3%. In Chinese AML patients, the posaconazole 300-mg tablet provided PK data comparable with those of previous studies and was generally well tolerated and efficacious. ClinicalTrials.gov, NCT02387983.

Aminovinyl-cysteine residues arise from processing the C-terminal l-Cys and an internal l-Ser/l-Thr or l-Cys of a peptide. Formation of these nonproteinogenic amino acids, which occur in a macrocyclic ring of diverse ribosomally synthesized lanthipeptides and non-lanthipeptides, remains poorly understood. Here, we report that LanD-like flavoproteins in the biosynthesis of distinct non-lanthipeptides share an unexpected dual activity for aminovinyl-cysteine formation. Each flavoprotein catalyzes oxidative decarboxylation of the C-terminal l-Cys and couples the resulting enethiol nucleophile with the internal residue to afford a thioether linkage for peptide cyclization. The cyclization step, which largely depends on proximity effect by positioning the enethiol intermediate with a bent conformation at the active site, can be substrate-dependent, proceeding inefficiently through nucleophilic substitution for an unmodified peptide or efficiently through Michael addition for a dehydrated/dethiolated peptide. Uncovering this unusual flavin-dependent paradigm for thioether residue formation advances the understanding in the biosynthesis of aminovinyl-cysteine-containing RiPPs and renews interest in flavoproteins, particularly those involved in non-redox transformations. LanD-like flavoproteins activity, which is flexible in peptide substrate and amenable for evolution by engineering, can be combined with different post-translational modifications for structural diversity, thereby holding promise for peptide macrocyclization/functionalization in drug development by chemoenzymatic or synthetic biology approaches.

Large cohort studies are commonly launched to study the risk effect of genetic variants or other risk factors on a chronic disorder. In these studies, family data are often collected to provide add...

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved as monotherapy or in combination with standard-of-care regimens for the treatment of relapsed or refractory multiple myeloma (RRMM). In the primary analysis (median follow-up, 16.9 months) of the phase 3 APOLLO study (NCT03180736), the addition of DARA to pomalidomide and dexamethasone (D-Pd) showed a significant progression-free survival (PFS) improvement over pomalidomide and dexamethasone (Pd) alone in patients (pts) with RRMM (Dimopoulos MA, et al. Lancet Oncol. 2021;22[6]:801-812). Here, we report results from the APOLLO study, including outcomes of pts refractory to lenalidomide based on the last dose of lenalidomide received. Methods: Eligible pts were ≥18 years of age, had RRMM, had received ≥1 prior line of therapy (including both a proteosome inhibitor and lenalidomide), and had responded to prior treatment; pts with only 1 prior line of therapy were required to be refractory to lenalidomide. Pts were randomized 1:1 to Pd ± DARA, stratified via International Staging System disease stage (I vs II vs III) and number of lines of prior therapy (1 vs 2-3 vs ≥4). All pts received 28-day cycles of pomalidomide (4 mg PO daily on Days 1-21) and dexamethasone (40 mg [20 mg for pts ≥75 years of age], PO daily on Days 1, 8, 15, and 22). Pts in the D-Pd group received DARA subcutaneously (DARA SC; 1,800 mg; co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; ENHANZE ® drug delivery technology, Halozyme, Inc.]) or, prior to a protocol amendment, intravenously (DARA IV; 16 mg/kg; n=7) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Pts receiving DARA IV were allowed to switch to DARA SC starting on Day 1 of Cycle 3 or later. All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Results: In total, 304 pts were randomized (D-Pd, n=151; Pd, n=153). At the time of randomization, 120 (79.5%) pts in the D-Pd group and 122 (79.7%) pts in the Pd group were refractory to lenalidomide. Among pts refractory to lenalidomide, the last dose of lenalidomide received was 5-10 mg in 30 (25.0%) pts in the D-Pd group and 31 (25.4%) pts in the Pd group and was 15-25 mg in 86 (71.7%) pts in the D-Pd group and 89 (73.0%) pts in the Pd group. With a median follow-up of 16.9 months, the median PFS in the overall population was 12.4 months in the D-Pd group versus 6.9 months in the Pd group (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.85; P=0.0018); the estimated 18-month PFS rate was 42.1% for the D-Pd group and 25.5% for the Pd group. Among pts refractory to lenalidomide, the median PFS was 9.9 months in the D-Pd group and 6.5 months in the Pd group (HR, 0.66; 95% CI, 0.49-0.90). For lenalidomide-refractory pts who last received a dose of 5-10 mg lenalidomide, the median PFS was 10.3 months for the D-Pd group and 8.5 months for the Pd group (HR, 0.75; 95% CI, 0.41-1.36); for lenalidomide-refractory pts who last received a dose of 15-25 mg lenalidomide, the median PFS was 10.7 months for the D-Pd group and 6.1 months for the Pd group (HR, 0.61; 95% CI, 0.42-0.88) (Figure). Grade 3/4 treatment-emergent adverse events occurred in 130 (87.3%) pts in the D-Pd group and 123 (82.0%) pts in the Pd group; the most frequently reported (≥15% in both groups) were neutropenia (67.8% vs 50.7%), thrombocytopenia (17.5% vs 18.0%), and anemia (16.8% vs 21.3%). Grade 3/4 pneumonia occurred in 20 (13.4%) pts in the D-Pd group and 10 (6.7%) of pts in the Pd group. Serious adverse events occurred in 75 (50.3%) pts in the D-Pd group and 59 (39.3%) pts in the Pd group. Conclusion: The addition of DARA to Pd provided a PFS benefit in the overall pt population and among pts refractory to lenalidomide. The safety profile observed in the APOLLO trial was consistent with previous reports for DARA SC and Pd. Additional analyses for lenalidomide-refractory pts, as well as efficacy and safety data for the overall population at longer follow up, will be presented. Figure 1 Figure 1. Disclosures Sonneveld: Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Symeonidis: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bila: Janssen, Takeda, AMGEN: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Orfanidis: Health Data Specialists: Current holder of individual stocks in a privately-held company. Kampfenkel: Janssen: Current Employment. Qiu: Janssen: Current Employment. Amin: Janssen: Current Employment, Current equity holder in publicly-traded company. Kosh: Janssen: Current Employment. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; BMS: Honoraria. OffLabel Disclosure: The regimen is approved for patients who have received at least two prior therapies, whereas the APOLLO study included patients who have received at least 1 prior therapy.

Introduction Immunomodulatory drug (IMiD)-based regimens are a standard of care (SOC) for RRMM. Daratumumab (DARA) is a CD38-targeted mAb approved for treatment of pts with RRMM. The subcutaneous (SC) formulation of DARA has a similar safety profile as intravenous DARA, with a statistically significant reduction in infusion-related reaction (IRR) rates and a considerably shorter administration duration of 5 mins. DARA SC is approved for use in the US, EU, Canada, and Korea. In the phase 1b study of DARA plus the IMiD pomalidomide, D-Pd induced deep responses and was well tolerated in pts with heavily pretreated RRMM, including those with prior lenalidomide (len) treatment. D-Pd is approved in the US for RRMM pts with ≥2 prior lines of therapy, including len and a proteasome inhibitor (PI). APOLLO (NCT03180736) is a phase 3 study conducted in collaboration between European Myeloma Network investigators and Janssen to evaluate DARA SC plus Pd vs Pd alone in RRMM pts who had received ≥1 prior line of therapy including len and a PI. We report the primary analysis of APOLLO. Methods In this open-label, multicenter study, eligible pts had RRMM and received ≥1 prior line of therapy including len and a PI, had responded to prior treatment and progressed on or after their last regimen; pts with only 1 prior line of therapy (1PL) were required to be refractory to len. Prior anti-CD38 or pomalidomide was not permitted. Pts were randomized 1:1 to Pd ± DARA SC. Stratification was based on International Staging System (ISS) disease stage (I, II, III) and number of lines of prior therapy (1, 2-3, ≥4). All pts received 28-day treatment cycles (C). P: 4 mg (PO) QD on Days 1-21; d: 40 mg (PO) on Days 1, 8, 15 and 22 (20 mg for pts ≥75 years of age). For D-Pd pts, DARA was given QW for C 1-2, Q2W for C 3-6, and Q4W thereafter. Prior to protocol amendment, pts received DARA IV 16 mg/kg (n=7); after protocol amendment, all pts received DARA SC 1,800 mg co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.). All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Major secondary endpoints included overall response rate, rates of very good partial response or better and complete response or better, MRD-negativity rate, overall survival (OS), and safety. Results A total of 304 pts from 12 European countries were randomized (151 D-Pd; 153 Pd). The median (range) age was 67 (35-90) years, and 45%/33%/22% pts were ISS stage I/II/III. 35% had high cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). 11% of pts had received 1PL (median [range] prior lines of therapy = 2 [1-5]). 82% of pts were refractory to len, 68% of pts were refractory to a PI, and 63% of pts were refractory to both. Median duration of treatment was 11.5 months with D-Pd vs 6.6 months with Pd. The primary analysis was performed after 190 PFS events. The study met its primary endpoint of improved PFS; the hazard ratio (HR) was 0.63 (95% CI, 0.47-0.85; P=0.0018), representing a 37% reduction in the risk of progression or death in pts treated with D-Pd. The median PFS for the D-Pd vs Pd arms was 12.4 vs 6.9 months, respectively. With a median follow-up of 16.9 months, 99 pts (33%) have died; the HR for OS was 0.91 (95% CI, 0.61-1.35); survival data are immature and follow-up is ongoing. ≥CR rates for D-Pd vs Pd were 24.5% vs 3.9%; ≥VGPR rates were 51.0% vs 19.6%. The most common grade 3/4 adverse events with a >5% difference between D-Pd vs Pd were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), and pneumonia (13% vs 7%). The rate of IRRs with DARA SC was low (6%, all grade 1/2), and 2% of pts had local injection-site reactions (all grade 1). Median duration of injection was 5 mins. Rates of study treatment discontinuation due to TEAEs were similar for D-Pd vs Pd (2% vs 3%). The safety profile of D-Pd is consistent with known profiles of DARA SC and Pd. Conclusion In this phase 3 study evaluating DARA SC plus Pd, D-Pd significantly reduced the risk of progression or death by 37% in pts with RRMM who had received ≥1 prior line of therapy vs Pd alone. No new safety concerns were observed. The IRR rate was very low and administration duration short, thus increasing convenience for pts and decreasing treatment burden. Collectively, these data show that D-Pd is an effective and convenient treatment for pts with RRMM who received ≥1 prior therapy, including len and a PI. Disclosures Dimopoulos: Beigene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Terpos:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Beksac:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou:Theagenion Cancer Hospital: Current Employment; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Symeonidis:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Celgene/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Mateos:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Orfanidis:Health Data Specialists: Current Employment, Current equity holder in private company. Ahmadi:Genmab: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Kampfenkel:Janssen: Current Employment. Schecter:Janssen: Current Employment, Current equity holder in publicly-traded company. Qiu:Janssen: Current Employment. Amin:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Sonneveld:Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding.

8046 Background: APOLLO (NCT03180736) is a phase 3 trial of pomalidomide and dexamethasone (Pd) ± subcutaneous daratumumab (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) in patients with RRMM and ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor. After 16.9 months (mo) median follow-up, D-Pd significantly reduced the rate of progression or death by 37% relative to Pd. Patients with RRMM have reduced HRQoL compared with age- and sex-matched populations. Here, we present PROs from the APOLLO trial. Methods: Patients were randomized 1:1 to D-Pd or Pd and treated in 28-day cycles until disease progression/unacceptable toxicity. PROs were assessed on Day 1 of each cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), EORTC QLQ Multiple Myeloma Module 20-item (MY20), and EuroQol 5-dimensional descriptive system. PRO analyses were performed on patients from the intent-to-treat population with a baseline (BL) and ≥1 post-BL assessment. Treatment effect was assessed by a mixed effects model with repeated measures. Time to worsening was estimated using the Kaplan-Meier method. Results: A total of 304 patients were included (151 D-Pd, 153 Pd). Median treatment duration was 11.5 mo with D-Pd vs 6.6 mo with Pd. At Cycle 16 (Cyc 16), 63 and 40 patients remained on treatment in the D-Pd and Pd groups, respectively. Compliance rates for PRO instruments were high and comparable between groups. Patients treated with D-Pd had a reduction in pain (maximum improvement: 6.8 points at Cyc 12) measured with the EORTC QLQ-C30 and no mean change in disease symptoms or the treatment side effects subscales of the EORTC QLQ-MY20. Group mean physical and emotional functioning were unchanged from BL with D-Pd but worsened in the Pd group (maximum worsening: 6.4 at Cyc 4 and 9.1 points at Cyc 14). The proportion of patients with a meaningful improvement from BL was 55.0% vs 49.0% for disease symptoms, 43.0% vs 35.3% for physical functioning, and 41.7% vs 31.4% for emotional functioning with D-Pd vs Pd, respectively. Median time to worsening was ̃4 mo, except for the disease symptoms subscale (̃10 mo); there were no differences between groups. Conclusions: When daratumumab was added to Pd, patients did not experience any decrements in HRQoL while on treatment, but some patients experienced reductions in pain as well as clinically meaningful improvements in symptoms and emotional/physical function. These findings complement the clinical benefits of D-Pd in RRMM patients and further support its use in this RRMM population. Clinical trial information: NCT03180736.

NosN is a radical S-adenosylmethionine protein observed in the biosynthesis of the bicyclic thiopeptide nosiheptide. Insights are provided in terms of the timing of NosN action, its catalytic mechanism, and its role in side ring formation. Beyond being a methyltransferase, NosN transforms a polythiazolyl peptide intermediate by functionalizing the S-conjugated indolic moiety to selectively build a C1 unit, form an ester linkage to the thiopeptide framework, and establish the side ring system specific for nosiheptide.

Sulfomycins are sulfur-rich, ribosomally synthesized, and post-translationally modified peptides (RiPPs) that are characterized by a 35-membered macrocyclic ring system with a pyridine domain centr...

With the development of the society and the extensive studies of brain sciences, teaching adolescents according to their brain development characteristics has become particularly important to the improvement of their intelligence level and the cultivation of their overall quality. This paper develops inquiry-based teaching programs and conducts inquiry-based teaching in natural science classes for one year, hoping to understand the effects of inquiry-based teaching on the brain development of adolescent students and provide a certain reference for the selection of teaching models in the future. The results show that inquiry-based teaching can significantly improve students’ academic performance and enhance their right-brain tendency; and that at the same time such kind of teaching has positive effects on the students’ imagery thinking and right-brain development. Therefore, in teaching practice, teachers should provide students with a suitable learning environment and pay attention to students’ abilities to observe, think and solve problems. At the same time, considering the importance of the theoretical brain science research, brain science education should also be incorporated into the occupational training of teachers to improve their scientific literacy.

Aim To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. Methods In this study (http://Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. Results At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (−1.5%) and E15/S100 (−1.5%) than with individual agents (−1.0%, −1.1% and −1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c

Ordinary differential equation (ODE) models are widely used to model dynamic processes in many scientific fields. Parameter estimation is usually a challenging problem, especially in nonlinear ODE models. The most popular method, nonlinear least square estimation, is shown to be strongly sensitive to outliers. In this paper, robust estimation of parameters using M-estimators is proposed, and their asymptotic properties are obtained under some regular conditions. The authors also provide a method to adjust Huber parameter automatically according to the observations. Moreover, a method is presented to estimate the initial values of parameters and state variables. The efficiency and robustness are well balanced in Huber estimators, which is demonstrated via numerical simulations and chlorides data analysis.

Ordinary differential equation (ODE) models are quite popular for modelling complex dynamic processes in many scientific fields, and the parameters in these models are usually unknown, and we need to estimate them using statistical methods. When some observations are contaminated, regular estimation methods, such as nonlinear least-square estimation, will bring large bias. In this paper, robust estimations of both constant and time-varying parameters in ODE models using M-estimators are proposed, and their asymptotic properties are obtained under some mild conditions. We focus on Huber M-estimator, and also provide a method to adjust the Huber parameter automatically to the observations. The proposed method is compared to existing methods in numerical simulations and CD8+ T cell data analysis. It is demonstrated that our method gain substantial efficiency as well as robust properties.