A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

2型糖尿病患者不同脂质参数与糖尿病肾病的关系

目的:探讨2型糖尿病(T2DM)患者不同脂质参数与糖尿病肾病(DKD)发生的相关性。方法:检测226例T2DM患者血清TC、TG、LDL-C、HDL-C水平及相关生化指标,计算血浆致动脉硬化指数(AIP)以及脂质三角相关指标(TC/HDL-C、TG/HDL-C、LDL-C/HDL-C)。根据DKD临床诊断标准和Mogensen分期标准分为:Ⅰ~Ⅱ期组136例,Ⅲ期组55例,Ⅳ~Ⅴ期组35例。应用多因素logistic回归分析不同脂质参数与DKD发生的关系。结果:与Ⅰ~Ⅱ期组相比,随着DKD分期加重,TC、TG、LDL-C、LDL-C/HDL-C、AIP水平明显增高(P<0.01)。LDL-C/HDL-C和AIP与24 h尿蛋白水平呈正相关(r=0.724;r=0.769,均P<0.05)。LDL-C/HDL-C和AIP是T2DM合并DKD患者的独立预测因子(P=0.002;P=0.004)。结论:LDL-C/HDL-C和AIP对T2DM合并DKD病情进展有较高的预测价值,可为临床诊治提供参考。     

Dynamic Indicators That Impact the Outcomes of Thoracic Endovascular Aortic Repair in Complicated Type B Aortic Dissection

PurposeTo investigate dynamic variables obtained from retrospective computed tomography angiography for ability to predict thoracic endovascular aortic repair (TEVAR) outcomes in patients with complicated type B aortic dissection (cTBAD).Materials and MethodsSeventy-nine patients with cTBAD who received TEVAR from March 2009 to June 2018 were retrospectively enrolled. Relative true lumen area (r-TLA) was computed at the level of tracheal bifurcation every 5% of all R-R intervals. Parameters that reflect the state of intimal motion were evaluated, including difference between maximum and minimum r-TLA (D-TLA) and true lumen collapse. The endpoints comprised early (≤ 30 days) and late (> 30 days) outcomes after intervention.ResultsOverall early mortality rate was 13.9% (11/79), and early adverse events rate was 24.1% (19/79). Patients who received TEVAR within 2 days of symptom onset demonstrated the worst outcomes. A longer time of r-TLA < 25% in 1 cardiac cycle (P = .049) and larger D-TLA (P < .001) were correlated to an increased early death. In addition, D-TLA was an independent predictor of early mortality. Area under the curve of D-TLA was 0.849 (95% confidence interval 0.730–0.967) for predicting early mortality and 0.742 (95% CI 0.611–0.873) for predicting early adverse events. Survival and event-free survival rates during follow-up were decreased in the D-TLA > 21.5% group compared with the D-TLA ≤ 21.5% group (all P < .001).ConclusionsLarger D-TLA is correlated with worse postoperative outcomes and might be a crucial parameter for future risk stratification in patients with cTBAD.     

Optimization of immunohistochemical detection of collagen type II in osteochondral sections by comparing decalcification and antigen retrieval agent combinations

Bone containing tissues such as osteochondral joint are resistant to routine tissue processing, therefore require decalcification. This technique causes removal of mineral salts, but in the process may macerate the organic tissue, hence the need for tissue fixation. Such severe processing demands careful antigen retrieval to necessitate optimal staining. The aim of our study was to compare five different antigen retrieval protocols (heat retrieval and protein digestion) following decalcification of rabbit knee joints using two different techniques (20% formic acid and 10% ethylenediamine-tetra acetic acid: EDTA). Osteochondral sections were compared based on time required for decalcification, ease of sectioning, morphological integrity using HE staining and antigen preservation (Collagen type II) using immunohistochemistry. The two decalcification solutions did not impair the tissue morphology and ease of sectioning. Joints processed with formic acid decalcified four times faster than EDTA. Among the five antigen retrieval approaches, maximal collagen II uptake with minimal nonspecific staining was found with protein digestion (pronase and hyaluronidase) in both formic acid and EDTA sections. For osteo-chondral sections, we recommend using 10% EDTA for decalcification and pronase plus hyaluronidase for antigen retrieval if maintaining tissue morphology is crucial, whereas if time is of the essence, 20% FA with pronase plus hyaluronidase is the faster option while still preserving structural integrity. Clin. Anat. 33:343–349, 2020. © 2019 Wiley Periodicals, Inc.     

复方番石榴制剂治疗超重肥胖2型糖尿病的疗效分析

【目的】评价复方番石榴制剂治疗超重肥胖2型糖尿病的临床疗效。【方法】将120例超重肥胖2型糖尿病患者随机分为治疗组和对照组各60例,治疗组给予口服二甲双胍肠溶片及复方番石榴制剂治疗,对照组给予口服二甲双胍肠溶片治疗,疗程均为12周。观察2组治疗前后腰围(WC)、体质量指数(BMI)、空腹血糖(FBG)、餐后2h血糖(P2hBG)、糖化血红蛋白(HbA1c)、胆固醇(TC)、甘油三酯(TG)、游离脂肪酸(FFA)等的变化情况,评估复方番石榴制剂的临床疗效。【结果】(1)中医证候总疗效:治疗后,治疗组的总有效率为95.00%,优于对照组的70.00%,差异有统计学意义(P0.01)。(2)治疗后,治疗组的WC和BMI均较治疗前显著下降(P0.01),而对照组均无明显下降(P0.05),治疗组对WC和BMI的下降作用均优于对照组(P0.05)。(3)治疗后,2组FBG、P2hBG、HbA1c、TC、TG、FFA水平均较治疗前显著改善(P0.05),且治疗组对上述各项指标的改善作用均优于对照组(P0.05)。(4)安全性评价:除治疗组有3例患者出现轻度的胃部不适感,未予特殊处理后自行缓解外,其余患者均未发现不良反应。【结论】复方番石榴制剂联合二甲双胍治疗超重肥胖2型糖尿病,疗效确切,可有效降糖、降脂、减肥及改善中医证候。     

Does Outcome/Survival of Patients With Myelodysplastic Syndromes Should Be Predicted by Reduced Levels of ADAMTS-13? Results From a Pilot Study

IntroductionVon Willebrand factor (vWF) cleaving protease ADAMTS-13 has a key role for maintaining normal size of vWF. A deficiency or dysfunction of vWF cleaving protease is associated with ultra large vWF multimers and thrombotic microangiopathy. Patients with cancers have reduced levels of vWF cleaving protease. In this pilot study, we have evaluated whether or not deficiencies of ADAMTS-13 were present in myelodysplastic syndromes (MDS). Moreover, we assessed if a reduction in basal levels of ADAMTS-13 may play a role in the prognosis of MDS.Patients and MethodsWe measured and compared the levels of vWF cleaving protease ADAMTS-13 in 100 patients with MDS and 35 healthy controls. Patients were divided into 2 groups according to the International Prognostic Scoring System: group I consisting of 44 patients with low-risk MDS and group II of 56 patients with high-risk MDS. Patients with high-risk and low-risk MDS presented significantly lower levels of ADAMTS-13 than controls (P < .001 and P = .0177, respectively). High-risk patients had significantly lower levels of ADAMTS-13 when compared with the low-risk group (P < .001).ResultsWe found that reduced levels of ADAMTS-13 have a relationship with overall survival (P < .001). Statistical analysis showed that ADAMTS-13 correlates with cytogenetics (P < .001) and a tendency of slight correlation with platelet count and basal levels of ADAMTS-13 (R, 0.35; P value, 0.001). Moreover, we found that levels of ADAMTS-13 have correlation with response to treatment (P < .001).ConclusionsADAMTS-13 in MDS might represent a surrogate marker of prognosis, response to therapy, or disease progression. Further studies are needed.     

Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1

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Riesgo de recurrencia tras retirada de la anticoagulación en pacientes con enfermedad tromboembólica venosa no provocada: validación externa del nomograma de Viena y del modelo predictivo DASH

IntroductionScales for predicting venous thromboembolism (VTE) recurrence are useful for deciding the duration of the anticoagulant treatment. Although there are several scales, the most appropriate for our setting has not been identified. For this reason, we aimed to validate the DASH prediction score and the Vienna nomogram at 12 months.MethodsThis was a retrospective study of unselected consecutive VTE patients seen between 2006 and 2014. We compared the ability of the DASH score and the Vienna nomogram to predict recurrences of VTE. The validation was performed by stratifying patients as low-risk or high-risk, according to each scale (discrimination) and comparing the observed recurrence with the expected rate (calibration).ResultsOf 353 patients evaluated, 195 were analyzed, with an average age of 53.5 ± 19 years. There were 21 recurrences in 1 year (10.8%, 95% CI: 6.8%-16%). According to the DASH score, 42% were classified as low risk, and the rate of VTE recurrence in this group was 4.9% (95% CI: 1.3%-12%) vs. the high-risk group that was 15% (95% CI: 9%-23%) (p <.05). According to the Vienna nomogram, 30% were classified as low risk, and the rate of VTE recurrence in the low risk group vs. the high risk group was 4.2% (95% CI:0.5%-14%) vs. 16.2% (95% CI: 9.9%-24.4%) (p <.05).ConclusionsOur study validates the DASH score and the Vienna nomogram in our population. The DASH prediction score may be the most advisable, both because of its simplicity and its ability to identify more low-risk patients than the Vienna nomogram (42% vs. 30%).