CD40靶向小干扰RNA抑制大鼠异体肢体移植急性排斥反应后细胞凋亡及P53、P21表达

目的探讨CD40靶向小干扰RNA（即短发夹RNA，shRNA）对大鼠异体肢体移植急性排斥反应及细胞凋亡的影响。方法以纯系SD大鼠为供体，纯系Wistar大鼠为受体，行同种异体右后肢移植。27只大鼠肢体移植后随机分为3组：实验组．注射梭华一Sofast（15μl）-siCD40—2，pSilencer（100μg）载体复合物600μl；空载体对照组，在肢体移植后，即注射Sofast（15μl）-pSilencer4．1-CMVneo（100μg）空载体复合物600μl；生理盐水对照组，在肢体移植注射生理盐水600μl。观察移植物排斥反应征象及存活情况，并于第7天对产生免疫耐受大鼠进行混合淋巴细胞反应（MLR），同时进行组织学检查。结果与其他组相比．实验组移植物发生排斥反应的时间及存活时间均显著延长（P〈0．01）（〉13d），未见排斥反应征象，其他组均于术后近期发生排斥反应；实验组大鼠对供体的淋巴细胞呈现低反应性，移植的供体同系大鼠的肢体得以存活。实验组移植物细胞凋亡率低于其他组。结论在术后不应用免疫抑制剂的情况下，CD40靶向的shRNA干扰可以抗大鼠异体肢体移植急性排斥反应。     

TAC-101, a benzoic acid derivative, inhibits liver metastasis of human gastrointestinal cancer and prolongs the life-span

We examined the anti-tumor effect of a novel benzoic acid derivative, TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) on models with liver metastasis. Oral administration of TAC-101 significantly inhibited spontaneous liver metastasis of AZ-521 (human gastric cancer ) by orthotopic implan-tation to athymic nude mice. It also inhibited both the liver metastasis of AZ-521 induced by intrasplenic injection and the secondary lung metastasis from the liver. In addition, TAC-101 inhibited the proliferation of Co-3 (human colon adenocarcinoma) that formed a single nodule in the liver of athymic nude mice by intrahepatic implantation. The growth inhibitory effect of TAC-101 on AZ-521 experimental liver metastasis was observed when treatment was started on day 7, 14, or 21 which may correspond to the progressive stage of liver metastasis in clinical settings. Multiple administration of TAC-101 (8 mg/kg/day) significantly prolonged survival time of the animals with liver met astasis by intrasplenic injection of AZ-521 (T/C = 230%) and A549 (human lung adenocarcinoma; T/C = 186%). These effects of TAC-101 were stronger than those of 5-FU, CDDP or ATRA. Furthermore, TAC-101 inhibited the binding of AP-1 to DNA on electrophoretic mobility shift assay using nuclear extract of AZ-521 cells, although ATRA did not inhibit. These findings suggested that TAC-101 may be a candidate for a new class of anti-cancer agents for liver metastasis. © Rapid Science Ltd.     

Laser-assisted zona pellucida thinning prior to routine ICSI

BACKGROUND: In MII oocytes showing difficult oolemma breakage, ICSI can cause an increase in the degeneration rate. This may be overcome by laser-assisted ICSI using a 5-10 micro m opening in the zona pellucida for injection. However, such a small opening might impair the hatching process, especially if assisted hatching is applied in addition. In order to prevent this, the present study used routine injection through an area of zona pellucida in which laser zona thinning had been applied, providing for both a reduced mechanical stress to the oocyte and assisted hatching. METHODS: This prospective study involved 100 cycles with 1016 MII oocytes. Conventional ICSI (control group) was compared with a modified laser-assisted ICSI (study group) in sibling oocytes. In the latter group oocytes were injected through an extended area of zona thinning. RESULTS: Degeneration rate was significantly lower in the study group (P < 0.004). There were no differences in fertilization, or formation and quality of blastocysts. In the study group embryo quality on day 2 was significantly better (P = 0.004) and herniation of day 5 blastocysts was increased (P = 0.005). Rates of implantation and pregnancy were not affected. However, on day 3 laser-assisted ICSI proved beneficial (P = 0.038) in terms of clinical pregnancy rate. CONCLUSIONS: The new method combines a less invasive ICSI technique with assisted hatching. Our preliminary data indicate that in addition to an improved oocyte survival, this new approach increases the hatching rate in vitro, which may explain the increase in pregnancy rate, at least in day 3 transfers.     

中晚期重型乙型肝炎血浆置换与内科治疗生存率的比较

观察血浆置换、内科治疗对中晚期重型乙型病毒性肝炎生存率的影响,探索中晚期重型肝炎的治疗方法。方法观察在内科治疗基础上给予血浆置换患者的肝功能、并发症及疾病的转归,与同期仅予内科综合治疗的患者相比较,对相应的临床资料进行统计学分析,从而了解两种治疗方法的疗效。结果血浆置换组36例,18例好转、18例死亡,内科治疗组32例,13例好转、19例死亡,两组之间患者生存情况无统计学差异;肝功能指标(ALT、AST、SB、ALB、TC、ChE和凝血酶原时间(PT)也无统计学差异。结论与内科治疗相比较,在其基础上给予血浆置换并不能提高中晚期重型病毒性肝炎生存率;中晚期重型肝炎患者的预后决定于其肝功能衰竭的程度。     

Interleukin-15 is not required for the induction or maintenance of orally induced peripheral tolerance

Orally induced tolerance is a physiologically relevant form of peripheral tolerance, which is believed to be important for the prevention of pathological immune responses in the gut. Of several mechanisms proposed to mediate oral tolerance, one that has received much attention recently is the concept of regulatory CD4+ T cells. As recent studies have suggested that interleukin (IL)-15 may be important for the differentiation and maintenance of regulatory CD4+ T cells, we have examined the role of IL-15 in oral tolerance, using a soluble form of the IL-15 receptor (sIL-15R) which blocks the biological effects of IL-15 in vivo. Oral tolerance induced by feeding mice ovalbumin (OVA) in a low-dose regimen believed to induce regulatory T cell activity was not affected by the administration of sIL-15R during either the induction or maintenance phase of tolerance. Thus, oral tolerance does not involve an IL-15-dependent mechanism.     

Prolongation of graft survival in allogeneic islet transplantation by (−) 15-deoxyspergualin in the rat

Summary The effect of 15-Deoxyspergualin, a novel drug which has been described to have anti-tumour activity, on allogeneic graft survival (Dark Agouti Lewis rats) after pancreatic islet transplantation was tested. A marked prolongation of graft survival could be shown using doses of 1.0, 2.5 and 5.0mg Deoxyspergualin/kg on day 0 until day +9 post transplantation. A maximum of 55.6 days (average) survival time was observed using 2.5mg/kg Deoxyspergualin compared to 5.2±0.6 days without immunosuppression. Using the chemiluminescence reaction of recipient monocytes after islet transplantation, a marked suppression of the monocyte system exceeding the treatment period could be observed. Since, in contrast to cyclosporin, B-cell toxicity could not be shown, the new drug seems to be a hopeful step towards successful allogeneic islet transplantation for treatment of diabetes.     

The effect of lucanthone on sublethal radiation damage, in vivo

The capacity of the Chinese hamster jejunal crypt cell to accumulate and repair sublethal radiation damage was determined by analyzing the return of the shoulder of the radiation dose-crypt microcolony survival curve (Dr) after a priming dose of 1250 rad. The control split dose crypt cell survival curve exhibited a D0, Dr and "n" of 179 +/- 3 rad, 261 +/- 3 rad and 4.3 respectively; repair of sublethal radiation damage was completed by two hours post-irradiation. The effect of lucanthone (an antischistosomal DNA intercalating agent) on the crypt cell's capacity to accumulate and repair sublethal radiation damage was determined by injecting the drug (100 mg/kg, i.p.) at intervals before irradiation with a priming dose of 1250 rad, followed two hours later by graded doses. Injection coincident with the priming dose of radiation resulted in a 22 rad reduction of the Dr (compared to control Dr). Injection eight hours before the priming dose almost completely inhibited the accumulation and repair of sublethal radiation damage so that the resultant Dr two hours later was only 29 rad (a 232 rad reduction). At no time was the D0 of the crypt cell survival curve affected by lucanthone. These data confirm previous results from whole crypt analysis and LD50/7 analysis that non-toxic concentrations of lucanthone reversibly inhibit the accumulation and repair of sublethal radiation damage in a time-dependent manner with complete inhibition approximately eight hours post-injection. This drug is useful for the study of sublethal radiation damage in vivo and may be beneficial in radiation therapy of cancer when it is desirable to inhibit the repair of sublethal radiation damage.     

Validating Restricted Mean Survival Time Estimates From Reconstructed Kaplan-Meier Data Against Original Trial Individual Patient Data From Trials Conducted by the Canadian Cancer Trials Group

ObjectivesThe development of novel cancer therapies, including immuno-oncology agents, has increased interest in reconstructed individual patient data (IPD) based restricted mean survival time (RMST) analyses. Additionally, reconstructed IPD–based RMST is recommended in cost-effectiveness analyses when original trial IPD are not available. Nevertheless, recently concerns regarding potential bias of reconstructed-IPD RMST have been presented, because reconstructed-IPD RMSTs have not been validated and previous validation endpoints may not capture the entire Kaplan-Meier (KM) curve, especially the “tail.” Our study aims to validate the recommended method of IPD reconstruction by comparing reconstructed IPD– and original trial IPD–based RMST.MethodsCanadian Cancer Trials Group trials from 1990 to 2017 were included. Overall survival and progression-free survival IPD were reconstructed based on published KM curves using the Guyot method. Analysts were blinded to original trial IPD. RMST was calculated at 1 year and over the entire KM curve. Reconstructed-IPD and original trial–IPD (gold-standard) RMSTs were compared for accuracy and predictive error via mean deviation, mean absolute error (MAE), mean percentage bias, and Bland-Altman plots and across KM curve quality (vector traced or bitmapped).ResultsWe identified 39 trials. The mean deviation, MAE, and mean percentage bias of RMST between the reconstructed IPD and original trial IPD were small. In particular, the mean deviation was ?0.01 months and ?0.04 months, MAE was 0.19 months and 0.24 months, and mean percentage bias was 0.82% and 0.84% in overall survival KM curves in control and experimental arms, respectively. Accuracy was generally not associated with KM curve quality.ConclusionsRMST derived from reconstructed IPD displayed excellent accuracy and predictive error compared with the gold standard. Reconstructed IPD could be used to calculate RMST in lieu of original trial IPD, to facilitate decision making for clinicians, researchers, and policy makers.     

Mg2+ Transporters in Digestive Cancers

Despite magnesium (Mg²⁺) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg²⁺ homeostasis is regulated by Mg²⁺ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg²⁺ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg²⁺ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg²⁺ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg²⁺ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.     

How Assessment-Schedule Matching Limits Bias When Comparing Progression-Free Survival in Single-Arm Studies: An Application in Second-Line Urothelial Carcinoma Treatments

ObjectivesPopulation-adjusted comparisons of progression-free survival (PFS) from single-arm trials of cancer treatments can be derived using matching-adjusted indirect comparisons (MAICs); however, results are still susceptible to bias, particularly if the trials had different tumor assessment schedules. This study aims to assess the effects of assessment-schedule matching (ASM) on the relative effectiveness on the PFS of avelumab versus approved comparator immunotherapies or chemotherapy after population matching in the second-line (2L) setting for metastatic urothelial carcinoma.MethodsThe MAIC used patient-level data for avelumab from the JAVELIN Solid Tumor trial (NCT01772004). PFS was compared with published curves for other treatments to obtain population-adjusted hazard ratios (HRs). The MAIC was repeated after conducting ASM for differences in tumor assessment scheduled first at 6 weeks for avelumab and durvalumab and at 8 or 9 weeks for other treatments.ResultsMAIC adjustment alone altered the HR estimates up to 23%, whereas MAIC plus ASM resulted in up to 32.7% reductions from naive comparisons. Even in cases in which MAIC had little effect, ASM brought an additional change of 11.1% to 15.4%. Overall, the HR range of avelumab versus other treatments changed from 0.83 to 1.25 for naive comparisons to 0.76 to 0.99 after ASM plus MAIC, numerically favoring avelumab.ConclusionsSmall variations in assessment schedules can introduce bias in unanchored indirect treatment comparisons of interval-censored time-to-event outcomes. In this study, adjusted PFS was comparable across second-line urothelial carcinoma treatment options, numerically favoring avelumab versus immunotherapies and chemotherapy agents. Correcting this bias is especially important when HRs are applied in cost-effectiveness models to transition patients between states.