Cellulose nanofibrils (CNFs) exhibit excellent mechanical properties and are used to reinforce various composites. The effects of incorporating CNFs into commercial mineral trioxide aggregate (MTA) cements (NEX MTA (NEX) and ProRoot^® MTA (PR)) on the underwater setting properties, compressive strength, and flowability were estimated in this study. NEX mixed without CNFs disintegrated after water immersion. NEX mixed with CNF-suspended solutions showed good setting properties under water immersion and a similar compressive strength, which was kept in air (100% relative humidity). PR did not degrade after water immersion, regardless of the presence of CNFs, and no significant difference in the compressive strength caused by CNFs incorporation was detected. The relative flowability of the NEX mixture decreased with increasing CNFs content up to 1.0 w/v%. The application of CNF-incorporated MTA in various dental cases is promising because CNFs prevent the water-immersion-dependent collapse of some MTA cements immediately after mixing.

2024-01-01·Translational Animal Science

Effect of traditional roughage-based or limit-fed, high-energy diets on growth performance and digestion in newly received growing cattle and subsequent implications on feedlot growth performance and carcass characteristics

Article

作者: Montgomery, Sean P ; Titgemeyer, Evan C ; Blasi, Dale A ; Tarpoff, Anthony J ; Scilacci, Morgan A ; Hollenbeck, William R ; O’Quinn, Travis G ; Spore, Tyler J ; Duncan, Zachary M

Abstract:

The objective was to determine the effects of ad libitum-fed roughage-based diets or limit-fed high-energy diets on growth performance, behavior, health, and digestion in newly received growing cattle and subsequent implications on feedlot growth performance and carcass characteristics. In experiment 1, 409 crossbred heifers (initial body weight [BW] = 279 ± 24 kg) in 32 pens were used in a randomized block design. Heifers were fed one of two dietary treatments: a total mixed ration with 0.99 Mcal net energy for gain (NEg)/kg dry matter (DM) fed ad libitum (0.99AL) or 1.32 Mcal NEg/kg DM limit-fed at 85% of intake of heifers fed 0.99AL (1.32LF85%). Both diets contained 40% DM as a branded wet corn gluten feed. In experiment 2, 370 crossbred heifers (initial BW = 225 ± 20 kg) were used in a randomized block design and were fed a diet formulated to contain 0.99 Mcal of NEg/kg DM for ad libitum intake or a diet formulated to contain 1.32 Mcal of NEg/kg DM and fed at 2.2% of BW daily (DM basis; 1.32LF2.2). For experiments 1 and 2, treatment integrity was maintained through the finishing phase where cattle were fed a common diet. Cattle were sorted by BW into heavy and light groups prior to finishing, with light cattle fed longer than heavy cattle to reach similar harvest BW. In experiment 3, eight ruminally cannulated heifers (average BW = 305 ± 23 kg) were used in a 2-period cross-over design and fed treatments from experiment 1 to assess digestibility and ruminal fermentation characteristics. Gain:feed was 47% and 35% greater (P < 0.01) in experiments 1 and 2, respectively, for limit-fed heifers compared with 0.99AL heifers. Rumination time was greater (P < 0.01) for 0.99AL compared with limit-fed treatments in experiments 1 and 2. Activity was greater (P < 0.01) for 1.32LF2.2 than for 0.99AL in experiment 2. In experiment 1, more (P = 0.03) carcasses from light-sort heifers than carcasses from heavy-sort heifers had livers with large, active abscesses. In experiment 2, finishing phase morbidity was greater (P < 0.01) for 1.32LF2.2 than for 0.99AL. Light-sort groups had fewer (P < 0.01) edible livers than heavy-sort groups, suggesting that greater number of days on feed may increase the risk of liver abscess prevalence and condemnation. In experiment 3, apparent total-tract DM and organic matter digestibilities were greater (P < 0.01) for 1.32LF85% than for 0.99AL. Overall, dietary treatments during the growing phase had little carryover effect on feedlot growth performance, carcass characteristics, or liver abscesses prevalence at harvest.

2023-03-01·New microbes and new infections

Monkeypox breakthrough infections and side-effects: Clarion call for nex-gen novel vaccine

Article

作者: Sah, Ranjit ; Mishra, Snehasish ; Mohanty, Aroop ; Padhi, Bijaya Kumar ; Mohapatra, Ranjan K ; Rabaan, Ali A

Monkeypox (mpox) virus belongs to the same family as variola virus causing smallpox. Usually spreading through skin-to-skin contact with the mpox-infected and causing rashes, this viral disease remained neglected before the recent (2022) outbreak. Although severity of the illness is high in the immunocompromised, the pregnant and the children, most of the infected recover in few weeks.However, the current mpox outbreak seems mysterious. The US has approved two vaccinia-derived mpox vaccines as preventives.The CDC recommends ACAM2000 only as an alternative to JYNNEOS for infants (of 1 yr age) and older that are at high mpox infection risk. The common side-effects of both the vaccines are injection-site reactions, headache, muscle pain, fever, chills, fatigue, nausea and altered appetite.A total of 276 participants received single dose ofthe vaccine 11 days after mpox exposure. Mpox infection developed in 12 recipients, of which 10 recipients manifested itin 5 days, 1 in 22 days, and 1 in 25 days after vaccination.However, no severe adverse events or safety concerns were noticed. The recipients that did not develop mpox infection received the second dose after 29-day median. The two participants that manifested breakthrough infections by the 22nd and 25th day had a pet (cat and dog) at home, both the pets although were asymptomatic.However, important limitations of the study were, it was carried out at a single center, them pox exposure was not assessed, and the study did not consider a control group or measures of vaccine-elicited immunity.No verifiable data on the efficacy of JYNNEOS or ACAM2000 against mpox is available yet. To determineits efficacy in the ongoing outbreak better, an open call for international studies on mpox vaccine is urgently contemplated.Considering mutations, the vaccine side effects and break-through infections, developing a mutant-proof, nex-gen vaccine for mpox virus that may be more effective and safe is recommended.

项与 Nex-G 相关的新闻（医药）

2022-11-08

·研发客

T细胞治疗深度玩家：CAR-T和TCR-T悉数尽收 | 江湖

☆ 药明巨诺还将探索倍诺达®用于套细胞淋巴瘤等多种血液肿瘤的治疗，以及自身免疫疾病红斑狼疮的临床研究；在已获批的大B细胞淋巴瘤适应症上，一线和二线治疗的临床试验也都在计划或进行中。☆ 与2seventy bio合作开发的MEGA-A4 TCR项目，是利用一种高效的TCR识别HLA呈递的MAGE-A4多肽，同时使用了再生元和2seventy bio合作开发的CTBR12 TGF-beta “FLIP”受体新技术。☆ 药明巨诺在开发下一代技术及产品Nex-G，与倍诺达®同样靶向于CD19。继去年拿下倍诺达®（瑞基奥仑赛注射液）的上市许可之后，药明巨诺管线又新增一员——10月27日，药明巨诺宣布与美国肿瘤免疫细胞治疗公司2seventy bio达成战略合作，并将首先在中国开发用于治疗实体肿瘤的MAGE-A4 TCR项目。就在这个交易宣布的前两周，国家药监局批准了倍诺达®拓展适应症用于经过二线或以上系统性治疗的成人难治性或24个月内复发的滤泡性淋巴瘤（r/r FL）。在细胞治疗领域的融资、并购、合作热潮下，药明巨诺怎样规划包括倍诺达®在内的管线，公司未来发展方向在哪里？研发客带着这些疑问，采访了药明巨诺的首席医学官Mark J. Gilbert博士和临床科学与医学服务副总裁秦耘女士。在采访中，Gilbert博士表示：“药明巨诺将继续致力于开发T细胞治疗新技术用于癌症治疗，持续关注和评估新技术，将我们认为具有前景和价值的技术及产品纳入我们的研发管线中。”由CAR结构组成决定的差异化特性倍诺达®是中国首款自主开发的CAR-T产品，是药明巨诺在巨诺医疗（一家百时美施贵宝的公司）的CAR-T细胞工艺平台的基础上自主开发的靶向CD19的细胞治疗产品。去年9月，该产品首次获批用于复发或难治性大B细胞淋巴瘤（r/r LBCL）的三线治疗。一年后，又获批了第二个适应症——滤泡性淋巴瘤。截止今年10月底，倍诺达®已累计临床应用于近300名患者（包括临床试验和商业化使用）。Gilbert博士表示：“我们认为倍诺达®可能是同类产品中最优（best-in-class）的靶向CD19的自体CAR-T细胞治疗产品。首先，我们在RELIANCE试验，即倍诺达®用于复发/难治性大B细胞淋巴瘤和复发/难治性滤泡性淋巴瘤的关键研究中，观察到非常好的临床结果。而倍诺达®的嵌合抗原受体（CAR）的结构正是这种优秀临床表现的基础。此外，我们还进一步优化了倍诺达®的生产工艺，一方面为每位患者生产高品质的细胞产品，另一方面可随着时间的推移而降低生产成本。”药明巨诺首席医学官 Mark J. Gilbert他还补充说，倍诺达®在两个批准的适应症中，单次输注后都产生了较高的完全缓解率，且相比同类产品，CAR-T 细胞相关毒性，如细胞因子释放综合征和神经毒性并不高。“大B细胞淋巴瘤患者的总缓解率接近77%，治疗两年后的总生存率接近70%；滤泡性淋巴瘤患者的总缓解率为100%。”“我们认为这是倍诺达®中CAR结构的组成所决定的，它影响了与严重毒性相关的快速T细胞增殖能力，以及杀伤表达低水平CD19的肿瘤细胞的能力。倍诺达®的CAR结构的共刺激域、跨膜结构域和铰链区的设计，不仅使其可以限制毒性，同时还能杀死在细胞膜表面表达少量CD19 的肿瘤细胞。”“正是这些重要特性使得我们的首款商业化CD19 CAR-T细胞治疗产品与众不同。”Gilbert博士说。药明巨诺首席执行官李怡平11月11日将在研发客临床年会上主持主题讨论，敬请留意！继续拓展更多适应症当问及为何会选择滤泡性淋巴瘤作为倍诺达®的第二个适应症时，秦耘介绍说，虽然在非霍奇金淋巴瘤里，滤泡性淋巴瘤是一种惰性淋巴瘤，但是有相当部分的患者在经过化疗治疗后会进入到一个反复复发的难治阶段。患者长期处于对复发的恐惧中，频繁就诊。而这类患者在接受倍诺达®一次治疗后，除了获得极高的缓解率外，很多患者同时可以维持很多年的无病状态，极大改善了他们的生存质量。药明巨诺正是看到了这一临床价值而选择开发这个适应症。药明巨诺研发管线来源|药明巨诺网站，数据截止至2022年8月除了已获批的适应症外，药明巨诺还积极开展多个临床试验，探索倍诺达®用于多种血液肿瘤的治疗。秦耘告诉研发客，目前，套细胞淋巴瘤的注册研究正在积极推进患者招募，是进展较前的适应症之一；此外，也在积极开展儿童适应症的研究，包括儿童和年轻成人的急性淋巴细胞白血病。而在已获批的大B细胞淋巴瘤适应症上，药明巨诺也在积极探索将治疗推进到更前线，目前一线和二线治疗的临床试验也都在计划或进行中。此外，据秦耘介绍，倍诺达®用于自身免疫疾病红斑狼疮的临床研究也已经在准备阶段，预计不久就将实现首例患者入组。她告诉研发客，药明巨诺做了大量的研究，发现从发病机制上来看，B细胞剥夺可以作为治疗红斑狼疮的一个有效手段，因此从今年年初就开始着手制定方案，尝试使用倍诺达®来治疗这一自身免疫疾病。通过合作授权获得新技术平台Gilbert博士和秦耘向研发客解释了药明巨诺这次选择与2seven bio合作的原因。首先，MAGE-A4（黑色素瘤相关抗原A4）在多种实体瘤中大量表达，如食管鳞癌、卵巢癌、肺鳞癌、头颈癌等，这些瘤种均存在巨大的未满足的临床需求。其次，此次与2seventy bio合作开发的MEGA-A4 TCR项目，是利用一种高效的TCR识别HLA呈递的MAGE-A4多肽，同时使用了再生元（Regeneron）和2seventy bio合作开发的CTBR12 TGF-beta“FLIP”受体新技术，克服了TGF-beta在肿瘤中的免疫抑制作用，并将其转化为T细胞的刺激信号。这一技术平台是世界范围内公认的最优平台之一。“基于2seventy bio在细胞治疗方面的平台优势，加上药明巨诺优秀的工艺开发能力、临床开发经验以及对中国市场的了解，我们有信心能够尽快将这些技术转化为临床应用，并带来实体瘤的新突破。”秦耘说。药明巨诺临床科学与医学服务副总裁秦耘关于接下来该项目在中国的开发，Gilbert博士和秦耘表示，药明巨诺会开展一系列的临床研究以获取早期的疗效和安全性数据。在选择适应症时，会结合该靶点的表达，同时充分考量未满足的临床需求，尤其是中国不同的发病谱，可能优先在食管鳞癌、卵巢癌和肺癌等瘤种中进行早期的临床探索。“这些癌症的总体生存期仍然很短，相信在中国有着巨大的临床价值和市场潜力。”积极研发更多自体T细胞产品Gilbert博士表示，药明巨诺聚焦创新，致力于“开发T细胞治疗新技术用于癌症治疗”，其创新“以多种方式反映在近期的临床管线中”。公司首个产品倍诺达®是基于引进的技术平台而自主开发的细胞治疗产品，并且正在积极探索在多种适应症上的应用。他告诉研发客：“我们可能是全球唯一一家探索CD19 CAR-T产品用于自身免疫疾病的生物技术公司”。此外，基于从优瑞科（Eureka）及Lyell引进的技术平台，药明巨诺正在开发针对实体瘤治疗的自体T细胞治疗产品。其中，JWATM204 是基于ARTEMIS技术平台自主开发的一款靶向于GPC3的细胞治疗产品，目前针对肝细胞癌的临床研究正在积极入组中。基于上述平台，药明巨诺还开发出了另一款产品JWATM214，其在靶向GPC3的同时还加入了cJUN蛋白调控，以增强T细胞功能，延缓细胞耗竭。该款产品也已经进入临床阶段，预计有望在明年获得一些可供公布的临床数据。基于该平台开发的还有靶向AFP的两款候选产品，药明巨诺希望未来能尽快将它们推向临床。药明巨诺的创新不仅局限于基于许可技术上的开发。在采访中，Gilbert博士和秦耘都提到了在年内上任的首席科学官Shaun Cordoba 博士。Cordoba 博士曾在伦敦大学学院从事学术工作，并在Autolus Therapeutics担任科学领导职务。他的加入使得药明巨诺的自主研发能力得到进一步增强。据介绍，Cordoba 博士已经在上海建立了一个药物发现研究团队，专注于建立创新模式来提升CAR-T在实体瘤和血液肿瘤中的效果，从而开发出先导候选产品。这些新的细胞治疗产品将不仅为中国市场开发，还将着眼于走出国门，进入全球市场。秦耘提到，药明巨诺也在开发下一代技术及产品。Nex-G是源自药明巨诺自研平台的一款新产品，它与倍诺达®同样靶向于CD19。作为下一代产品，“我们希望改造现有的生产工艺，进一步提升产品的性能”，并根据临床需求开发更多的适应症。“过去的一年是药明巨诺快速增长的时期，除了第一个适应症，倍诺达®已迎来了第二个适应症。我们推进了实体瘤项目，建立了商业化能力，开展了数项新合作，并且建立了我们的自主研发团队。”提及已经取得的成绩，Gilbert博士很兴奋。对于未来的发展方向，他总结道：“包括CAR-T和TCR-T 在内的T细胞治疗，将成为我们未来几年产品组合的重点。”总第1751期访问研发客网站可浏览更多文章www.PharmaDJ.com

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