A novel semi-mechanistic tumor growth fraction model for translation of preclinical efficacy of anti-glypican 3 antibody drug conjugate to human

The growing fraction (GF) of tumor has been reported as one of the predictive markers of the efficacy of chemotherapeutics. Therefore, a semi-mechanistic model has been developed that describes tumor growth on the basis of cell cycle, allowing the incorporation of the GF of a tumor in pharmacokinetic/pharmacodynamic (PK/PD) modeling. Efficacy data of anti-glypican 3 (GPC3) antibody drug conjugate (ADC) in a hepatocellular carcinoma (HCC) patient derived xenograft (PDX) model was used for evaluation of this proposed model. Our model was able to describe the kinetics of growth inhibition of HCC PDX models following treatment with anti-GPC3 ADC remarkably well. The estimated tumurostatic concentrations were used in tandem with human PKs translated from cynomolgus monkey for prediction of the efficacious dose. The projected efficacious human dose of anti-GPC3 ADC was in the range 0.20–0.63 mg/kg for the Q3W dosing regimen, with a median dose of 0.50 mg/kg. This publication is the first step in evaluating the applicability of GF in PK/PD modeling of ADCs. The authors are hopeful that incorporation of GF will result in an improved translation of the preclinical efficacy of ADCs to clinical settings and thereby better prediction of the efficacious human dose.     

Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling

Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells (MSCs) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on MSC senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging MSCs and the downregulation of autophagy can delay MSC senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and MSC senescence and explore the effects and mechanisms of premodulated autophagy on MSC senescence, we induced the up- or down-regulation of autophagy by using rapamycin (Rapa) or 3-methyladenine, respectively, before MSC senescence induced by D-galactose (D-gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated MSC aging induced by D-gal and inhibited ROS generation. p-Jun N-terminal kinases (JNK) and p-38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on MSC senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H₂O₂ on MSC senescence. In summary, the present study indicates that autophagy plays a protective role in MSC senescence induced by D-gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagy-delaying MSC senescence.     

超声引导下经皮微波消融与冷冻消融治疗高风险部位肝癌的对照研究

目的：比较超声引导下经皮微波消融与冷冻消融治疗高风险部位肝癌的临床结局及术后并发症,并分析影响预后和术后复发的因素。 方法：选取2014年4月至2018年3月广州复大肿瘤医院收治的120例高风险部位肝癌患者,其中64例接受微波消融治疗（微波组）,56例接受冷冻消融治疗（冷冻组）。比较两组的治疗结局,主要包括生存、复发及术后并发症。用Cox回归模型分析预后和术后复发的影响因素。 结果：微波消融组1、3、5年总生存率分别为85.8%、63.5%、63.5%,冷冻消融组为92.0%、87.4%、74.9%,两组差异无统计学意义（P=0.141）。微波消融组1、3、5年无复发生存率分别为77.8%、49.0%、49.0%,冷冻消融组分别为81.4%、58.5%、46.8%,两组差异无统计学意义（P=0.469）。微波消融组的3、6、9、12个月的局部进展率分别为3.1%、6.3%、9.4%、15.9%,高于冷冻消融组（分别为0%、0%、3.7%、19.0%）,差异有统计学意义（P=0.003）。微波组的主要和次要并发症发生率（分别为6.3%、82.8%）均高于冷冻组（分别为0%、32.1%）,差异有统计学意义。年龄≥65岁,直径3~5 cm及Child-Pugh分级B级是肝癌术后预后较差的危险因素;直径3~5 cm、多个肿瘤以及多次消融是消融术后复发的危险因素。 结论：冷冻消融治疗高风险部位的肝癌具有与微波消融接近的生存结局,但具有更好的局部肿瘤控制率及更少的并发症,适合在临床中推广应用。     

负压封闭引流治疗深度烧伤创面及对炎性因子、致痛因子的影响

目的研究负压封闭引流(VSD)治疗深度烧伤创面(DBW)及对血清炎性因子、致痛因子的影响。方法 2015年1月—2017年12月内江市第一人民医院治疗DBW患者106例,其中男性69例,女性37例;年龄25～59岁,平均44. 5岁;受伤至入院时间0. 5～13d,平均5. 65d。致伤原因:火烧伤75例,热液烧伤31例。按照治疗方法分为VSD组(n=53)和对照组(n=53),VSD组行VSD+游离植皮治疗,对照组行常规清创换药+游离植皮治疗。治疗7d后观察两组创面愈合率及视觉模拟疼痛评分(VAS)、创面完全愈合时间、住院时间、住院费用,治疗前及治疗后7d血清超敏C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)、白介素-8(IL-8)、补体C3a等炎性因子及血清5-羟色胺(5-HT)、脑内神经肽(NPY)、前列腺素E2(PGE2)等致痛因子水平。结果治疗后7d VSD组创面愈合率大于对照组[(80. 86±9. 12)%vs.(69. 58±7. 30)%],疼痛评分、创面完全愈合时间、住院时间及住院费用均少于对照组[(2. 78±0. 29)分vs.(5. 79±0. 62)分,(19. 26±2. 04) d vs.(25. 74±2. 65) d,(23. 63±2. 44) d vs.(30. 51±3. 19) d,(3. 29±0. 35)万元vs.(3. 92±0. 41)万元](P <0. 05)]。治疗后7d,VSD组血清CRP、TNF-α、IL-8、补体C3a及5-HT、NPY、PGE2水平均低于对照组[(8. 92±9. 93) mg/L vs.(18. 87±1. 96) mg/L,(35. 74±3. 61)μg/L vs.(67. 94±6. 88)μg/L,(32. 92±4. 37)μg/L vs.(60. 76±6. 19)μg/L,(13. 52±1. 50)μg/L vs.(16. 77±1. 72)μg/L,(109. 92±10. 16) ng/L vs.(143. 97±15. 22) ng/L,(112. 86±11. 41)μg/L vs.(154. 37±16. 03)μg/L,(121. 33±12. 42) pg/m L vs.(186. 93±18. 72) pg/m L,P <0. 05)]。结论 VSD可促进DBW愈合,降低炎性因子及致痛因子水平,患者康复快。     

Synthesis and preliminary evaluation of a 99mTc‐labeled folate‐PAMAM dendrimer for FR imaging

Folate receptor is an ideal target for tumor‐specific diagnostic and therapeutic. The aim of this study was to synthesize ^99mTc‐labeled folate‐polyamidoamine dendrimer modified with 2‐hydrazinonicotinic acid (^99mTc‐HP ₃FA ) for FR imaging. The ^99mTc‐HP ₃FA conjugate was prepared using N‐tris‐(hydroxymethyl)‐methylglycine and trisodium triphenylphosphine‐3,3′,3″‐trisulfonate as coligands. Physicochemical properties, in vitro cell uptake study, and in vivo micro‐single‐photon emission computed tomography/CT imaging were performed. The radiolabeled ^99mTc‐HP ₃FA conjugate was prepared with high radiolabeling yield, good stability, and water solubility (logP  = ?1.70 ± 0.21). In cell uptake study, the radiolabeled conjugate showed high uptakes in the FR ‐abundant KB cells and could be blocked significantly by excess folic acid. The 7721 cells which served as control group substantially had no uptakes. The results of micro‐single‐photon emission computed tomography/CT imaging exhibited that high accumulation of activity was found in FR ‐overexpressed KB tumor, and the tumor‐to‐muscle ratio was approximately 25.78, while, using free FA as inhibitor, the uptakes of ^99mTc‐HP ₃FA in KB tumor and kidney were obviously inhibited. In summary, a new radiocompound was synthesized successfully with specific FR targeting ability. The feasibility of ^99mTc‐HP ₃FA for early diagnosis of FR ‐positive tumors with non‐invasive single‐photon emission computed tomography imaging was demonstrated and the possibility of imaging‐guided drug delivery based on multifunctional polyamidoamine will be studied in the future.