BackgroundDespite recent advances in T-cell engager based multiple myeloma therapies, high rate of cytokine release syndrome (CRS) and severe neurotoxicity remains a challenge in clinic. EMB-06 is a ...novel 2+2 BCMA×CD3 T-Cell engaging bispecific antibody developed based on the EpimAb’s proprietary Fabs-In-Tandem-Immunoglobulin (FIT-Ig®) platform. Differentiated from existing T-cell engagers, EMB-06 comprises tetravalent binding domains in cis-configuration and proprietary anti-CD3 arms with optimized affinity. It induced modest levels of cytokine release yet retained robust anti-tumor activity in preclinical studies. Here we report the initial results from an ongoing multicenter, first-in-human, Phase I study of EMB-06 in relapsed or refractory multiple myeloma (RRMM).MethodsThe Phase I study evaluates escalating doses of once weekly IV administrations of EMB-06 in patients (pts) with RRMM who have failed or are intolerant to standard therapies. Dose escalation was guided by the Bayesian optimal interval (BOIN) design. Primary objectives were to assess safety, tolerability, and determine the MTD and/or RP2Ds. Secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activities.ResultsAs of Aug 28, 2023, 33 pts had been treated with EMB-06 at 0.2mg to 200mg. Median age was 66 y (46–82). Median prior lines of therapies were 3 (2–6) and 26 (79%) pts were refractory to the most recent line of therapy. Treatment-related AEs (TRAEs) were reported in 20 (61%) pts, with Gr ≥3 occurring in 7 (21%) pts. The most common TRAEs include ALT increase (18%), leukopenia (18%), ALP increase (15%), neutropenia (15%), anemia (12%), AST increase (12%), GGT increase (12%), lymphopenia (12%) and CRS (12%). All CRS were Grade 1. Only 1 patient experienced treatment related neurotoxicity (Gr.1 paresthesia). One DLT (pneumonia, cardiac failure, creatinine increased and hepatic insufficiency) was observed at 60mg cohort. EMB-06 shows dose proportional increase in PK exposure across 0.2–120 mg, and the median half-life after single dosing is 4.4 days. PD activity (T cell redistribution and activation along with transient release of low-level cytokines) was observed at doses ≥0.6mg. The ORR was 29% (9/31) among 31 response evaluable pts. Of the 5 evaluable pts treated with doses ≥120mg, the ORR was 100% (1 CR, 2 VGPR, 2 PR).ConclusionsEMB-06 demonstrated a differentiated safety profile in RRMM pts with exceptionally low CRS and neurotoxicity rates so far. An initial ORR of 100% has been observed at doses ≥120mg. Updated data will be shared at the meeting.Trial RegistrationThe clinical trial was registered with www.clinicaltrials.gov (NCT04735575).Ethics ApprovalThe trial was done according to Good Clinical Practice and the Declaration of Helsinki. The protocol and amendments were approved by the institutional review board or ethics committee at each site. And all participants gave informed consent before taking part in the trial. The name of the ethics committee(s) or institutional review board(s), the number/ID of the approval(s) are as follow:Epworth health – No. 2020-12-1350Sunshine Coast Haematology and Oncology Clinic- No. 2020-12-1350-AAOne Clinical Research - No. 2020-12-1350-AB Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiaotong University School Of Medicine-No. 2021- 73 Henan Cancer Hospital Medical Science Research Ethics Committee-No. 2021-381-002Clinical Trial Ethics Committee of Huazhong University of Science and Technology-No. 2021-218Ethics Committee of the First Affiliated Hospital, School Of Medicine, Zhejiang University-No. 2021-627 Ethics Committee of Beijing Jishuitan Hospital-No. 20210902-01Peking University Third Hospital Medical Science Research Ethics Committee-No.2022-220-02Ethics Committee of Guangdong Provincial People’s Hospital-No. YW2023-011-02ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single- and ...multiple-ascending-dose study in 70 healthy male volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg, including one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n = 4; 11.1%), diarrhea (n = 3; 8.3%), dizziness (n = 3; 8.3%), and abdominal pain (n = 2; 5.6%) were the most common adverse events. Headache (n = 4; 16.7%), nausea (n = 3; 12.5%), upper respiratory tract infection (n = 3; 12.5%), and dizziness (n = 2; 8.3%) were the most common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0 h. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally in both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while mean Cmax decreased from 778 ng/ml to 627 ng/ml and Tmax was delayed from a median of 3.0 h under fasting conditions to 6.0 h under fed conditions. Renal elimination is a minor route.
Abstract Purpose We established a vitamin A–deficient (VAD) model of pregnant rats to evaluate the effect of vitamin A deficiency in maternal rats on tumor formation in filial rats. Methods Ten ...pregnant Wistar rats were divided into 2 groups: (1) VAD group, 6 rats were given nonvitamin A diet from 2 weeks before mating till delivery and (2) normal diet (ND) group, 4 rats were given normal diet. Twenty random neonatal rats from each group were killed on the next day of delivery. The rest neonates were given normal diet for 1 year until killed. Serum levels of vitamin A, morphology of the kidney, incidence of tumor formation, and retinoid X receptor (RXR) α messenger RNA (mRNA) expression in renal tissue were assessed for the filial rats. Results Fifty-six and 49 neonatal rats were born for VAD group and ND group, respectively. The detection rate of nephrogenic rests (NRs) from neonates in VAD group (50%) was significantly higher than that in ND group (20%; P < .05). The incidence of nephroblastoma was 13.9% in filial rats of VAD group and 0% for ND group. The detection rate of NRs for filial rats of VAD group (30.6%) was significantly higher than that of ND group (6.9%; P < .01). The expression of RXR α mRNA in tumor tissue of the filial rats of VAD group (3.17 ± 0.15) was significantly lower than that in kidney tissue of ND group (3.58 ± 0.20; P < .01). Conclusion Deficiency in vitamin A for pregnant rats resulted in renal dysplasia, increased NRs, and higher incidence of nephroblastoma.
The decomposition of a large amount of unexploited macroalgal resource along the coast of China often results in heavy environmental pollution. In order to pave a way of using macroalgae as the ...dietary ingredient of rabbitfish Siganus canaliculatus, one of a few farmed herbivorous marine teleosts in China, its preference （feeding selectivity） for different macroalgae was determined in this study. Seven seaweed species abundantly inhabiting the coast of east Guangdong Province were exposed simultaneously to rab-bitfish juveniles in laboratory （multiple-choice feeding） with their content and absolute intake assayed. It was found that the most preferred algae were Ulva prolifera, Gracilaria lemaneiformis and Chaetomorpha linum, less preferred algae were U. pertusa and Porphyra haitanensis, and least preferred ones were Sargassum fusiforme and Corallina sessilis. Such an order did not change when one to four relatively preferred seaweeds were removed. The preferred seaweeds were richer in protein and soluble sugar thus higher in energy than the least preferred. In addition, this fish was found to favor filamentous and flat algae rather than calcified ones. Ac-cordingly, the richness of nutrients and morphological characteristics determined the preference of S. canaliculatus for tested macro-algae.
Effects of stocking density on nitrogen and energy budget of gibel carp Yao Feng, Anhui Agricultural University, Hefei(China), School of Animal Science and Technology; Zeng Shuqi, Yangtze University, Jingzhou(China), School of Animal Science; Yang Yanou, Anhui Agricultural University, Hefei(China), School of Animal Science and Technology
Anhui nong ye da xue xue bao,
20/Jul., Letnik:
36, Številka:
3
Journal Article
在（28±1）℃、自然光照条件下,设计4种养殖密度饲养异育银鲫（Carassius auratus ...gibelio）。第1种处理为对照组,在体积为70cm×55cm×36cm、水深为18cm的水族箱放入23尾鱼（平均体重6.82g.尾-1）,试验鱼占用1个水箱,折算养殖密度为407g.m-2,第2、3和4种处理中试验鱼分别占用1/2、1/4和1/8水箱（其余空间空置）,养殖密度分别为对照组的2倍、4倍和8倍,4种密度分别以C、D1/2、D1/4和D1/8表示。每天9：00和16：00过量投喂配合饲料2次,2h后回收残饵,同时用虹吸法收集粪便,70℃烘干。试验持续28d。结果显示,随着养殖密度上升,生长氮和生长能的比例显著下降,排泄氮、排泄能和代谢能的比例显著上升;粪氮的比例有所下降,而粪能的比例无显著变化。高密度下鱼体增重的下降与氮及能量的利用效率下降有关。著者文摘
In order to investigate the nitrogen and energy budget of gibel carp （ Carassius auratus gibelio） in different stocking densities, a 28-day growth trial was conducted at four stocking densities in condition of （28 ±1）℃ and the natural photoperiod. In the first group （ control group）, 23 fish with the initial average hody weight of 6.82 g・ind. 1 were cultivated in a whole tank（70 cm ×55 cm ×36 cm,water depth 18 cm） ,and the stocking density was 407 g. m. 2. In the second to fourth groups, the tanks were divided into 2,4 and 8 parts, and the fish occupied 1/2, 1/4 and 1/8 water volume respectively in each. Tank, and other water
Effects of feeding regime on compensatory growth of yellow catfish larvae Yao Feng, Anhui Agricultural University, Hefei(China)， School of Animal Science and Technology; Yang Yanou, Anhui Agricultural University, Hefei(China)， School of Animal Science and Technology; Zeng Shuqi, Yangtze University, Jingzhou(China), School of Animal Science
Anhui nong ye da xue xue bao,
20/Apr., Letnik:
36, Številka:
2
Journal Article
在（25±1）℃水温和自然光照下，以4种模式投喂鲜活水蚯蚓，饲养平均初始体重为358．57mg的黄颡鱼（Pelteobagrus fulvidraco ...Richardson）劝鱼48d，第1种模式为对照组，每天投喂，第2、3、4种为试验组，分别是探喂3d后饥饿1d、投喂6d后饥饿2d、投喂12d后饥饿4d，4种模式分别以S0、S1／3、S2/5和S4／12表示。结果显示，3个试验组均表现出补偿生长，其中S1/3组为完全补偿生长，S2/6和S4/12组为超补偿生长，补偿生长由摄食率和饵料转化效率共同提高导致；3个试验组的成活率显著高于对照组，肥满度和内脏指数与对照组无显著差异；试验结束时，3个试验组的鱼体脂肪、蛋白质和能量含量与对照组无显著差异，但S2/6和S4/12组的鱼体干物质含量显著下降。著者文摘
In order to investigate the compensatory growth in yellow catfish （Pelteobagrus fulvidraco Richardson） （initial average weight 358.57 rag） at different feeding regimes,a 48 d growth trial was carried out in a system consisting of 12 tanks （volume：70 cm x55 cm x 37 cm,20 cm water depth） at temperature（25 ± 1 ）℃ and natural photoperiod, and live tubificid worms （Limnodrilus hoffmeisteri） were fed in four feeding regimes. The fish were deprived of food for one day at the beginning of the experiment, then 100 fish were randomly selected, batch- weighed and allocated into each tank respectively. Each feeding regime contained three tanks selected randomly. In the
In this research, optical absorption regulation of Ag nanodisc arrays in a monolayer MoS
2
hybrid system is investigated using the FDTD technique. Ag nanodisc arrays are designed on monolayer MoS
2
...on SiO
2
/Si and Au/SiO
2
substrates. For Ag/1L MoS
2
/SiO
2
/Si, two absorption peaks near 620 nm and 670 nm are showed, with different intensification amplitudes of absorption peaks and slight shifts in peak position changing diameters or spacing of Ag nanodiscs. When the diameter is 220 nm, the strongest absorption peak is displayed at 745 nm. When the spacing
s
is 300 nm, the absorption peak at 759 nm has the highest intensity. When the thickness of the SiO
2
film increases from 90 to 280 nm and 300 nm, the intensity of the absorption peak near 620 nm increases by 1.7 times, and the peak blueshifts to 585 nm. In the band from 550 to 700 nm, the presence of the Ag nanodisc array significantly enhances the absorption of the film system, when the thickness of the SiO
2
film is 300 nm, and the enhancement amplitude of the absorption peak near 620 nm reaches three times. For Ag/1L MoS
2
/Au/SiO
2
, when the diameter or spacing of the Ag nanodisc increases from 100 to 220 nm every 30 nm, the peak positions of 620 nm and 670 nm are changed. When the diameter of the Ag nanodisc is 100 nm and 220 nm, the normalized absorption rates at 686 nm and 707 nm are 0.95 and 0.96, respectively. When the spacing
s
is 200 nm and 400 nm, the normalized absorption rates at 562 nm and 686 nm are 0.94 and 0.96, respectively. By comparing the optical absorption with and without the Ag nanodisc array, the absorption of the monolayer MoS
2
hybrid system is greatly enhanced. When the surrounding medium is changed from air to water, the absorption peaks of 641 nm and 686 nm become 587 nm and 775 nm, the distance between peak positions is enlarged, and the intensity is obviously weakened, which is due to the weakening of the surface plasmon effect of the Ag nanodisc array.
Carbon materials have become a research hotspot in many fields because of their unique properties. In this paper, carbon nanowires (CNWs) were constructed with the finite-difference time-domain ...(FDTD) technique, and the effects of different structural parameters on the optical absorption properties of CNWS arrays at 350–810 nm were investigated. The results show that different lengths, diameters and spacings of the nanowires lead to different absorption properties of the arrays. In addition to a sharp decrease in the absorption at high incidence or viewing angles, the arrays have strong absorption properties at other angles. However, the array absorption at high incidence or viewing angles can be enhanced to some extent by varying the lengths of the nanowires. The wavelength and polarization direction of the excitation light have little effect on the absorption properties of the arrays. It is very important to determine the corresponding structural parameters of CNWs with the strongest absorption for the fabrication of nanowire arrays and their applications in stealth technologies, nanolight-emitting devices, photoelectric sensors and photovoltaic cells.
Nanocarbon materials are emerging as alternative activators of peroxymonosulfate (PMS) for organics decomposition. However, the relatively low activity and complex syntheses hindered their practical ...application and innovation with respect to rational design of carbocatalysts is highly desired. Herein, an in situ replication and transformation strategy was employed to facilely convert porous Fe3O4 microspheres into novel Fe/N codoped large-pore mesoporous carbon spheres (M‑Fe/NC) as Fenton-like catalysts for PMS activation. Benefiting from the abundance of active sites induced by dual heteroatom doping, the enhanced active site exposure due to the unique mesoporous structure, and the high stability of carbon component, the derived M‑Fe/NC was superior to the pristine Fe3O4 for PMS activation to degrade various organics and was efficient over a wide pH range (2–9). Compared with the proposed mechanisms of previous reports, both radical (surface-bound SO4− and OH) and nonradical (1O2 and direct oxidation) pathways are involved in the M‑Fe/NC/PMS system. Furthermore, experimental observations in combination with DFT calculations reveal that graphitic N and FeN4 sites serve as dual reaction centers in the catalysis. This research opened an avenue for development of novel multi-doped carbocatalysts used to activate PMS for sustainable remediation.
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•Fe3O4 was in situ converted into Fe- and N-codoped large-pore mesoporous carbon (M‑Fe/NC).•M‑Fe/NC showed abundant active sites and rapid mass transfer.•Enhanced activation of PMS to degrade various organics by M‑Fe/NC was observed.•Comparative experimental and DFT study of the synergistic effect was performed.
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