Stroke severity and outcomes for octogenarians receiving statins

Pre-exposure to 3-hydroxy-3-methylgutaryl-coenzyne A reductase inhibitors (statins) appears to improve outcomes in patients with acute ischemic stroke (AIS). Whether this extends to patients over 80 is not known. Patients ≥80 years of age with AIS were retrospectively reviewed from the stroke registry of a tertiary stroke center. Pre-admission statin use, demographics, vascular risk factors, and comorbid conditions were assessed. Primary outcomes were admission National Institutes of Health Stroke Scale (NIHSS) scores and in-hospital mortality/discharge to hospice, and secondary outcomes included subsequent intracerebral hemorrhage (ICH) and modified Barthel index (mBI) at 3 months. Multivariable logistic regression was used to evaluate the association between pre-admission statin use and outcomes among elderly patients. Among 804 patients ≥80, those taking statins prior to AIS admission were overall younger, were more likely to have hypertension, coronary artery disease, diabetes, hyperlipidemia, and were more likely to be on an antiplatelet, but less likely to receive treatment with IV tissue plasminogen activator (tPA). Patients on statin had lower stroke severity (NIHSS > 16: 21.9% vs. 27.6%) and in-hospital mortality/discharge to hospice (22.8% vs. 27.6%), but neither was significant. There was no difference in ICH (1.2% vs. 1.9%), and patients on statins had a non-significant trend toward less disability on mBI (27.5% vs. 35.7%). Pre-admission statin use did not show a statistical difference in either outcome, but it did show a trend toward lower stroke severity and improved short-term outcomes. In addition, our study suggests that statins may be safe in elderly stroke patients and may not increase the risk of ICH.     

Caspase-9和Survivin在肝癌组织中的表达及意义

目的探讨Caspase-9和Survivin在肝细胞癌(HCC)患者肝癌组织中的表达及其临床意义。方法应用免疫组织化学SP法检测92例肝癌患者肝癌组织及其对应癌旁正常肝组织中Caspase-9和Survivin的表达,并分析其表达与HCC临床恶性生物学行为的相关性。组间比较采用卡方检验,相关性分析采用Spearman等级相关法。结果 Caspase-9在肝癌组织中的表达明显低于癌旁组织,而Survivin在肝癌组织中的表达明显高于癌旁组织,差异均具有统计学意义(χ2=6.48、7.05,P0.05)。在TNM分期Ⅲ~Ⅳ期、门静脉癌栓、淋巴结转移的肝癌组织中Survivin的阳性表达率明显增高(χ2=5.07、6.18、8.29,P0.05),而在其他分组中比较差异无统计学意义;在病理分级Ⅲ~Ⅳ级的肝癌组织中Caspase-9的阳性表达率明显降低(χ2=7.63,P0.05),而在其他分组中比较差异无统计学意义。结论 Caspase-9低表达和Survivin异常高表达均参与肝癌的发生过程,Caspase-9低表达可能与肝癌细胞恶性分化密切相关,而Survivin高表达与肝癌的浸润或远处转移等恶性发展密切相关。     

Computational study on natural compounds inhibitor of c-Myc

To screen and identify ideal leading compounds from a drug library (ZINC15 database) with potential inhibition effect against c-Myc to contribute to medication design and development.A series of computer-aided virtual screening techniques were performed to identify potential inhibitors of c-Myc. LibDock from the software Discovery Studio was used to do a structure-based screening after ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was utilized to show the binding affinity and potential mechanism between ligands and c-Myc. Stability of the ligand-receptor complex was analyzed by molecular dynamic simulation at the end of the research.Compounds with more interactive energy which are confirmed to be the potential inhibitors for c-Myc were identified from the ZINC15 databases. Additionally, those compounds are also anticipated with fewer ames mutagenicity, rodent carcinogenicity, nondevelopmental toxic potential, and tolerant with cytochrome p450 2D6(CYP2D6). Dynamic simulation analysis also revealed that the very compounds had more favorable potential energy compared with 10058-F4(ZINC12406714). Furthermore, we prove that those compounds are stable and can exist in natural conditions.This study demonstrates that the compounds are potential therapeutic inhibitors for c-Myc. These compounds are safe and stable for drug candidates and may play a critical role in c-Myc inhibitor development.     

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer

Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf^V600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.Mutations in the v-raf murine sarcoma viral oncogene homolog B (BRAF) kinase occur in ∼60% of papillary thyroid carcinomas (PTCs) (www.cbioportal.org/public-portal/data_sets.jsp). PTC generally exhibits an excellent prognosis with conventional therapy, including surgery and selective use of radioiodine (1). PTC may progress to clinically aggressive forms of thyroid cancer, including poorly differentiated thyroid carcinoma (PDTC), which exhibits more rapid growth and poorer clinical outcome. Less commonly, PTC progresses to undifferentiated (anaplastic) thyroid carcinoma (ATC) that is associated with a grim prognosis with a median survival of 5 mo and a 1-y survival of only 20% (2).Focused sequencing of clinically aggressive subsets of thyroid cancers including PDTC and ATC suggests acquired cooperating mutations drive thyroid cancer progression (3, 4). Mutations in tumor protein p53 (TP53) occur with increasing frequency in more aggressive forms of thyroid cancer, culminating in ATC, which harbors the highest frequency of TP53 mutations (5–7). ATC may progress from well-differentiated thyroid carcinomas and is also believed to arise spontaneously, possibly from clinically undetectable microscopic well-differentiated thyroid tumors. In the former scenario, ATCs frequently harbor mutations in BRAF, and these mutations are concordant between the anaplastic and papillary components. This implicates BRAF mutation as an initiating somatic genetic event and supports the hypothesis that loss of p53 function is important for progression to ATC (3, 8).Mouse models of thyroid cancer have supported the model of acquired mutations driving tumor progression. Although each study has technical limitations, including embryonic oncogene expression and/or elevated circulating thyroid-stimulating hormone (TSH) levels, this work generally supports the notion that BRAF^T1799A is sufficient to initiate PTC (9–12). In addition, deletion of p53 enabled tumor progression to high-grade thyroid carcinomas in a transgenic mouse model of translocations targeting the ret proto-oncogene (RET/PTC) driven PTC, and a model of follicular thyroid carcinoma initiated by tissue-specific phosphatase and tensin homolog (Pten) deletion (13, 14). These studies provide functional evidence of an important tumor suppressive role for p53 during thyroid carcinoma progression, although to date this has not been tested in models of BRAF-mutant PTC.Given the high frequency of BRAF and RAS mutations in thyroid carcinomas and the success of targeted therapy trials for advanced thyroid cancers, the potential utility of small-molecule inhibitors of the MAPK pathway has garnered much recent attention (15). These drugs have also been studied in models of BRAF-mutant thyroid carcinoma. Initial observations using a thyroid-specific doxycycline-inducible BRAF^T1799A allele suggested that BRAF or mapk/Erk kinase (MEK) inhibition induced thyroid carcinoma regression and differentiation (9). However, a recent study from the same laboratory showed a mitigated response to BRAF (PLX4032, vemurafenib) inhibition in human papillary and ATC cell lines and in an endogenous Braf^V600E-driven PTC mouse model. In response to PLX4032/vemurafenib, feedback inhibition of the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase was abrogated, leading to reactivation of MAPK signaling (16). In addition, responses in patients treated with the BRAF inhibitor vemurafenib have exhibited modest activity (17).To develop an adult-onset autochthonous model of clinically aggressive thyroid carcinoma, we generate a thyroid-specific CreER transgenic mouse and use conditional Braf^T1799A and Trp53 alleles. We demonstrate that expression of BRAF^V600E is sufficient to initiate tumorigenesis in adult animals, and p53 loss enables progression to bona fide ATC recapitulating the cardinal features of the human disease including intrinsic resistance to BRAF inhibitors.     

贲门腺癌组织中RKIP表达变化及其与血清NF-κBp65蛋白、T淋巴细胞亚群的关系

目的：观察Raf激酶抑制蛋白（ RKIP）在贲门腺癌组织中的表达变化,进一步探讨贲门腺癌的发生、发展机制。方法收集160例贲门腺癌患者（腺癌组）的腺癌组织及其癌旁组织,应用免疫组织化学SP法检测RKIP表达;采用ELISA法和流术细胞术分别检测腺癌组和50例查体健康者（对照组）的血清NF-κB p65蛋白、T淋巴细胞亚群水平。采用Spearman秩和相关分析法分析指标间的关系。结果贲门腺癌及癌旁组织中RKIP表达阳性率分别为38．7％、52．5％（P＜0．05）,在有、无淋巴结转移者中的表达阳性率分别为24．4％、53．1％（P＜0．05,t＝4．34）;腺癌组血清总NF-κB p65蛋白水平高于对照组（P＜0．05）,但RKIP表达阳性与阴性者水平无显著差异（P＞0．05）,有淋巴结转移者高于无淋巴结转移者（P＜0．05）;腺癌组细胞免疫功能低于对照组,尤以RKIP表达阴性者为著（ P＜0．05）。结论 RKIP在贲门腺癌组织中表达降低并与肿瘤发生、发展、浸润转移有关,可能机制为抑制NF-κB活性及细胞免疫功能,使肿瘤细胞逃避机体的免疫监视。     

Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites

BACKGROUND:

There are data suggesting a link between proton pump inhibitor (PPI) use and the development of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites; however, these data are controversial.

OBJECTIVE:

To assess whether the use of PPIs in cirrhotic patients with ascites is associated with an increased risk for SBP.

METHODS:

A retrospective case-control study (June 2004 to June 2010) was conducted at the Centre Hospitalier de l’Université de Montréal in Montreal, Quebec. Fifty-one cirrhotic patients admitted with paracentesis-proven SBP (≥250 neutrophils/mm³), occurring within seven days of hospital admission, met the inclusion criteria. These patients were matched 1:2 (for age, Child-Pugh class and year of admission) with 102 comparable cirrhotic patients with ascites who were admitted for conditions other than SBP.

RESULTS:

Patients with SBP had a significantly higher rate of pre-hospital PPI use (60.8%) compared with cirrhotic patients without SBP (42.2%; P=0.03). On multivariate analysis, PPI use was the only factor independently associated with SBP (OR 2.09 [95% CI 1.04 to 4.23]; P=0.04). Thirty-five (35%) patients in both groups had no documented indication for PPI use in their charts. Forty-five percent of the remaining cirrhotic patients with SBP had an inappropriate indication, as defined in the protocol, for PPI use compared with 25% of controls.

CONCLUSIONS:

Cirrhotic patients with SBP were twice as likely to have taken PPIs than patients without SBP. These findings reinforce the association between PPI use and SBP observed in other studies. A high percentage of cirrhotic patients were taking a PPI without any documented indication.     

Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface

Advances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as “break-through therapies,” providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus? with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented.     

Proposal of a Parameter for OATP1B1 Inhibition Screening at the Early Drug Discovery Stage

It is known that potent inhibition of organic-anion-transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study was to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most compounds classified as “contraindicated” or “should be avoided” when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R = 1 + plasma unbound fraction (fu) × maximum inhibitor concentration at the inlet to the liver/IC₅₀ are used to evaluate the extent of clinical drug interaction. However, clinical doses and C_max cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC₅₀. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC₅₀ of these compounds was >0.1 L/μmol. On the other hand, fu/IC₅₀ of other compounds was ≤0.03 L/μmol. This study indicates that fu/IC₅₀ is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage.     

Effect of Renin–Angiotensin System Inhibition on Cardiovascular Events in Older Hypertensive Patients with Metabolic Syndrome

Objective

Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS.

Materials/Methods

We used the Cardiovascular Health Study, a prospective cohort study of individuals > 65 years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events.

Results

ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR = 0.658, 95 % C.I. [0.436–0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017–0.952] and [0.321–0.875]).

Conclusions

ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.