Assessment of the advantages and limitations of an innovative silk fibroin scaffold for the reconstruction of the anterior cruciate ligament with preclinical in vitro and in vivo evaluations

Article

作者: Ghezzi, Chiara E ; Giavaresi, Gianluca ; Fini, Milena ; Ghezzi, Chiara E. ; Sartori, Maria ; Freddi, Giuliano ; Del Piccolo, Nicolandrea ; Dallari, Dante ; Erani, Paolo ; Martini, Lucia ; Brogini, Silvia ; Farè, Silvia ; Baleani, Massimiliano ; Alessandrino, Antonio ; Tanzi, Maria Cristina ; Parrilli, Annapaola ; Boschi, Alessandra

The gold standard treatment in anterior cruciate ligament (ACL) reconstruction involves autologous tissue transplantation, but this can have complications. Artificial grafts are an alternative, but the best option is debated. This study aimed to assess the biocompatibility and integration of a silk fibroin textile prosthesis (SF-TP) with peri-implant bone tissue and the native ACL. Twenty-six sheep underwent ACL reconstruction with SF-TP or autologous femoral fascia lata (FFL). Sheep were divided into two groups (3 and 6 months) and retrieved joints processed for histological, morphometrical and mechanical analysis. In vitro, SF-TP showed no cytotoxicity and good cell interaction up to 14 days. Histology revealed fibro-vascular tissue around SF-TP, with a progressive attempt of ligamentous-like tissue formation at 6 months. However, SF-TP group had higher joint damage scores. Micro-CT showed tunnel enlargement in SF-TP group, while FFL group had a decrease. SF-TP reconstructions had lower stiffness and strength (44 % and 64 % decrease) than those of autologous FFL reconstruction and often failed by pull-out from the bone tunnel due to tunnel enlargement. These results indicate poor osteointegration and graft motion with SF-TP, leading to joint damage/bone resorption and reduced mechanical competence. These results do not support the use of SF-TP for ACL reconstruction.

2024-05-01·Journal of Electrocardiology

The effect of anabolic androgenic steroids on heart rate recovery index and electrocardiographic parameters in male bodybuilders

Article

作者: Baytugan, Nart Zafer ; Kandemir, Hasan Çağlayan

BACKGROUNDThe control of the cardiovascular system depends on the autonomic nerve system. Chronic anabolic andorogenic steroids (AAS) use causes sympathovagal imbalance and increases sympathetic nerve activity.OBJECTIVEThe reduction in heart rate from the peak exercise rate following the end of the exercise stress test is known as the heart rate recovery index (HRRI). Several methods have been utilized to assess myocardial repolarization, such as QT interval (QT), corrected QT interval (QTc), and T-wave peak-to-end interval (Tp-e interval). Based on a growing number of data a higher Tp-e/QT ratio is linked to malignant ventricular arrhythmias, and an increased Tp-e interval may correlate with the transmural dispersion of repolarization. Our hypothesis is that the use of chronic AAS was decrease HRRI during maximal exercise and increased risk of cardiac arrhythmias and sudden cardiac death.METHODSThis study included 44 male bodybuilders, with an average age of 29.7 ± 8.14 years, divided into AAS abuse [AAS users (n = 21) and AAS nonuser (n = 23)].RESULTSThe first (p = 0.001) and second minute (p = 0.001) HRRI of the subjects with AAS users were significantly lower than those of the control group. Additionally, HRRI after the third (p = 0.004) and fifth minutes (p = 0.007) of the recovery period were significantly lower in AAS group compared with the control group. Who used AAS had significantly higher QT, QTc, Tp-e, Tp-e/QT, and Tp-e/QTc values than non-users (all p = 0.001).CONCLUSIONSChronic AAS use has been shown to cause sympathetic dominance, which may be a pro arrhythmic state.

2024-05-01·AIDS Research and Human Retroviruses

Intracellular Islatravir-Triphosphate in Dried Blood Spots and Peripheral Blood Mononuclear Cells from Pig-Tailed Macaques

Article

作者: Rohan, Lisa ; Abdelmawla, Farah ; Bushman, Lane ; Choi, Ye Ji ; Nerguizian, David ; Brooks, Kristina ; Patton, Dorothy ; Patel, Sravan Kumar ; Mainella, Vincent ; Anderson, Peter ; Morrow, Mary ; Cosgrove Sweeney, Yvonne

The purpose of this study was to evaluate the relationship between intracellular islatravir-triphosphate (ISL-TP) in paired peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS). Three pig-tailed macaques (PMs) were dosed with a single intravaginal extended-release ISL-etonogestrel film for a period of 31 days. After extraction and quantification, repeated measures correlation (r_rm) was assessed between log-transformed DBS and PBMC ISL-TP concentrations. Twenty-six paired PBMC/DBS samples were included. Peak ISL-TP concentrations in DBS ranged from 262 to 913 fmol/punches, PBMC C_max ranged from 427 to 857 fmol/10⁶ cells. Repeated measures correlation yielded an r_rm value of 0.96 (95% confidence interval 0.92-0.98; p < .0001). Importantly, ISL-TP was quantifiable in DBS and its pharmacokinetics were similar to PBMC in PMs. Human studies should evaluate DBS applications in clinical pharmacokinetic studies to help define ISL's place in the antiretroviral drug armamentarium.

项与 OT-15 相关的新闻（医药）

2022-06-20

·医药魔方Info

第5项！一线食管鳞癌！信达生物「信迪利单抗」新适应症获批

6月20日，药监局官网显示，信达生物PD-1抑制剂信迪利单抗注射液（商品名：达伯舒）新适应症上市申请获批，联合化疗（顺铂+紫杉醇/顺铂+5-氟尿嘧啶）一线治疗食管鳞癌。信迪利单抗是信达生物和礼来共同合作研发的具有国际品质的创新PD-1抑制剂药物。它是一种人类免疫球蛋白G4（IgG4）单克隆抗体，能特异性结合T细胞表面的PD-1分子，从而阻断导致肿瘤免疫耐受的 PD-1/程序性死亡受体配体1（PD-L1）通路，重新激活淋巴细胞的抗肿瘤活性，从而达到治疗肿瘤的目的。目前，信迪利单抗已在中国获批5项适应症。此前获批的4项适应症均被纳入医保目录。此次新适应症申请是基于一项随机、双盲、国际多中心III期临床研究（ORIENT-15）——信迪利单抗联合化疗对比安慰剂联合化疗一线治疗晚期或转移性食管鳞癌。基于独立数据监察委员会（IDMC）进行的期中分析，不论PD-L1表达情况，信迪利单抗联合化疗对比安慰剂联合化疗显著延长了患者的总生存期（OS），达到预设的优效性标准，安全性特征与既往报道的信迪利单抗相关临床研究结果一致，无新的安全性信号。ORIENT-15研究是一项由北京大学肿瘤医院沈琳教授牵头，在全球79家临床研究中心开展，旨在比较信迪利单抗联合化疗（顺铂+紫杉醇/5-氟尿嘧啶，TP/CF）与安慰剂联合化疗（TP/CF）一线治疗不可切除的局部晚期、复发或转移性食管鳞癌（ESCC）患者的疗效和安全性。截至期中分析，本研究共入组659例受试者，按1:1随机分配进入试验组或对照组，分层因素包括PD-L1表达水平、ECOG评分、是否肝转移和化疗方案的选择等，主要研究终点为PD-L1阳性（CPS≥10）人群和全人群的总生存期（OS）。ORIENT-15研究达到了双重主要研究终点——全人群和PD-L1 CPS≥10人群OS均显著获益。在全人群中，信迪利单抗联合治疗组对比化疗组显著延长了中位OS（16.7月vs. 12.5月，HR=0.63），死亡风险降低了37%；在PD-L1 CPS≥10的患者中，信迪利单抗联合治疗组对比化疗组同样显著延长了中位OS（17.2月 vs. 13.6月，HR=0.64），死亡风险降低了36%。在全人群和PD-1 CPS≥10的患者中，OS曲线均早期分离，并在长期随访中保持稳定，显示信迪利单抗联合化疗能带来长期OS获益。亚组分析显示，使用信迪利单抗联合化疗可以显著延长患者生存，且不受PD-L1表达水平影响。此外，该研究涵盖两种食管鳞癌常用化疗方案，证明信迪利单抗联合不同化疗方案的普遍适用性。其次，信迪利单抗联合化疗也可显著延长全人群和CPS≥10人群的无进展生存期（PFS）获益，降低患者的疾病进展风险。在全人群中，信迪利单抗组客观缓解率（ORR）更高（66.1% vs. 45.5%），对比化疗组提高了20.6%；信迪利单抗组中位缓解持续时间（DoR）长达9.7个月，与化疗组相比延长了2.8个月。信迪利单抗组的整体安全性可控，两组3级以上治疗相关不良事件（TRAEs）发生率相当（60% vs. 55%）。健康相关生活质量分析显示，信迪利单抗组生活质量恶化风险降低。食管癌是来源于食管黏膜上皮的恶性肿瘤，是全球最常见恶性肿瘤之一。根据 GLOBOCAN 2020 数据，全世界食管癌新发病例约60万，位居所有恶性肿瘤中第7位，死亡病例约54万，位居所有恶性肿瘤中第6位。全世界食管癌超过50%的新发病例和死亡病例出现在中国，中国食管癌新发病例约32万，发病率位居所有恶性肿瘤中第5位，死亡病例约30万，死亡率位居所有恶性肿瘤中第4位，5年总生存率仅有30%左右。食管癌的主要病理类型有鳞癌和腺癌，在中国，90%以上的食管癌患者为鳞癌。对于晚期或转移性食管鳞癌患者，目前已有PD-1单抗类产品获批用于食管鳞癌的治疗。资源专区大礼包：来了！2022跨年医药数据资源大礼包来了更多资源请点击：ByDrug医药资源云—医药魔方推荐阅读：新鲜出炉！2022年全球TOP50制药企业榜单公布！中国药企刷新最好成绩2021年市场表现最好的20款新药2022 AACR总结：最值得关注的小分子药物研发方向TOP10

抗体免疫疗法小分子药物合作AACR会议

2022-03-04

·PATSNAP

Cancer Cell发表！君实生物抗PD-1单抗一线治疗食管癌3期研究结果公布

近日，由中山大学肿瘤防治中心徐瑞华教授牵头开展的JUPITER-06研究结果发表在国际权威学术期刊Cancer Cell上。该研究结果显示，PD-1抑制剂特瑞普利单抗一线治疗晚期或转移性食管鳞状细胞癌（ESCC）患者，可显著改善患者无进展生存期（PFS）和总生存期（OS），且无论PD-L1表达如何，该联合方案均有疗效，同时显著提高客观缓解率（ORR）和疾病控制率（DCR），安全性可管理，为晚期食管鳞癌的治疗提供了新的一线治疗方案。特瑞普利单抗是以PD-1为靶点的单抗药物，已在中国获批多个适应症，涵盖黑色素瘤、鼻咽癌、尿路上皮癌等多个瘤种。 JUPITER-06是一项在中国开展的多中心、随机、双盲、安慰剂对照、3期临床研究，旨在评估与安慰剂联合化疗相比，特瑞普利单抗联合紫杉醇/顺铂（TP）化疗用于晚期食管鳞状细胞癌一线治疗的疗效及安全性。主要联合终点为由盲态独立评审委员会（BICR）根据RECIST v1.1进行评估的PFS和OS结果。 JUPITER-06研究共纳入了514例未经治疗的患者，随机分配至特瑞普利单抗联合TP化疗组（n=257）或安慰剂联合TP化疗组（n=257），分别接受特瑞普利单抗或安慰剂联合化疗方案治疗最多6个周期，随后接受特瑞普利单抗或安慰剂维持治疗。结果显示，与安慰剂联合化疗相比，特瑞普利单抗联合化疗：1）可显著延长ESCC患者PFS，可使疾病进展或死亡风险降低42%；2）中位OS显著延长（17.0个月 vs 11.0个月），患者死亡风险降低42%；3）ORR提高17.2%（69.3% vs 52.1%）。安全性方面，相比安慰剂联合化疗组，特瑞普利单抗联合化疗组≥3级治疗期间不良事件（TEAE）发生率为73.2%（vs 70.0%），与研究治疗相关的致死性AE分别为0.4% vs 1.2%，严重不良事件发生率为36.2% vs 28.8%。两组中免疫相关不良事件（irAE）发生率分别为37.0% vs 26.5%，≥3级irAE发生率分别为7.0% vs 1.6%。两组中最常见的irAE包括皮疹、甲状腺功能减退和瘙痒。 JUPITER-06研究证实，与单纯化疗相比，特瑞普利单抗联合TP化疗一线治疗ESCC患者可以获得显著更优的PFS和OS，研究达到双终点阳性结果，且安全性可管理。研究还将继续随访OS数据，研究者认为，JUPITER-06研究有望为晚期或转移性ESCC患者提供新的一线标准治疗方案。据君实生物新闻稿介绍，食管癌是全球十分常见的恶性肿瘤，发病率和死亡率均位居前列，新诊断的患者病理类型以食管鳞癌为主。食管癌患者早期症状较轻，常常确诊时即为晚期。对于晚期或转移性食管鳞癌患者，当前一线治疗多采用含铂双药化疗方案，但由于不同方案疗效相似，且生存获益有限，因此临床迫切需要新的药物和治疗方案。君实生物高级副总裁姚盛博士表示：“特瑞普利单抗通过独特的结合表位与T细胞表面 PD-1 FG环相互作用，并在结合后诱导强劲的受体内吞作用，从而使T细胞表面的PD-1持续减少。我们认为这种独特的作用可以使T细胞针对肿瘤抗原产生更积极的应答，因此在我们的临床试验中，包括JUPITER-06研究，都在密切监测PD-L1的表达以及PD-L1高表达和低表达患者对抗PD-1抗体治疗的临床疗效。” 本次发表时，Cancer Cell同时刊登了来自日本国立癌症研究中心中央医院Ken Kato博士作为通讯作者的随刊社评，文章中提到，“JUPITER-6研究显示，与单纯化疗相比，特瑞普利单抗联合化疗为既往未接受过治疗的晚期ESCC患者带来了优越的无进展生存期和总生存期，为免疫检查点抑制剂是晚期ESCC一线治疗的关键药物提供了确凿证据。” 参考资料： [1] 重磅！JUPITER-06研究结果获国际权威学术期刊Cancer Cell发表. Retrieved Mar 4，2022, from https://mp.weixin.qq.com/s/g-15QMZTS2xq6N62qy4yhQ [2] Wang et al., Toripalimab plus chemotherapy in treatment-naive, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial, Cancer Cell. 2022. https://doi.org/10.1016/j.ccell.2022.02.007 [3] Yamamoto and Kato, JUPITER-06 establishes immune checkpoint inhibitors as essential first-line drugs for the treatment of advanced esophageal squamous cell carcinoma, Cancer Cell. 2022. https://doi.org/10.1016/j.ccell.2022.02.009 内容来源于网络，如有侵权，请联系删除，谢谢。

抗体免疫疗法AACR会议

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