腹腔镜微创手术与传统开腹手术对结直肠癌患者免疫和生理功能影响的临床观察

目的 探讨对于临床确诊为结直肠癌患者采用腹腔镜手术较传统开放手术的免疫和生理反应方面的影响.方法 选取2013年6月至2014年6月经临床确诊为结直肠癌并于我院消化外科采用腹腔镜手术治疗的50例患者为观察组,同期采用传统开腹手术进行治疗的50例患者为对照组,比较分析两组患者的免疫和生理反应的变化.结果 与对照组比较,术后7天CD4/CD3、术后3天IgM在观察组中升高、术后3天IL-6和CPR在观察组中降低,差异具有统计学意义(P＜0.01);与对照组比较,术后7天TNF-α在观察组中降低,差异具有统计学意义(P＜0.05).在生理功能的比较中,观察组患者在胃动素和胃泌素的分泌方面优于对照组,差异具有统计学意义(P＜0.05).结论 因腹腔镜手术对患者的免疫和生理功能的损伤小,更有利于健康的恢复,值得在临床上推广使用.     

DAB2IP基因沉默引起膀胱癌细胞辐射耐受与化疗抵抗

目的 观察DAB2IP基因对膀胱癌细胞放化疗敏感性的影响.方法 RNA干扰建立DAB2IP表达抑制的膀胱癌细胞,克隆形成实验比较不同DAB2IP表达的细胞对射线放射敏感性的差异,噻唑蓝方法检测不同DAB2IP表达的细胞对常用化疗药物敏感性的变化.结果 DAB2IP基因沉默造成细胞对射线与化疗药物均出现耐受.结论 DAB2IP可能用作预测膀胱癌患者放射或化学治疗预后的分子标志物.     

Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5

In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed “Mendelian vascular diseases,” which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.     

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.Neuronal migration and maturation is a key step in brain development. Defects in this process have been implicated in many disorders, including autism (1) and schizophrenia (2). Thoroughly understanding how neural progenitor cell (NPC) migration is affected in neurodevelopmental disorders requires a means of dissecting the process using cells with genetic alterations matching those in patients. Existing in vitro assays of migration generally involve measurement of cell movement across a scratch or gap or through a membrane toward a chemoattractant in 2D culture systems. Although widely used, such assays may not accurately reveal in vivo differences, as neuronal migration is tightly regulated by physical and chemical cues in the extracellular matrix (ECM) that NPCs encounter as they migrate.In vitro 3D culture systems offer a solution to these limitations (3–7). Compared with 2D culture, a 3D arrangement allows neuronal cells to interact with many more cells (4); this similarity to the in vivo setting has been shown to lengthen viability, enhance survival, and allow formation of longer neurites and more dense networks in primary neurons in uniform matrices or aggregate culture (8, 9). Indeed, 3D culture systems have been used to study nerve regeneration, neuronal and glial development (10–12), and amyloid-β and tau pathology (13). Thus, measuring neuronal migration through a soft 3D matrix would continue this trend toward using 3D systems to study neuronal development and pathology.We sought to develop a 3D assay to examine potential migration and neuronal maturation defects in Rett syndrome (RTT), a genetic neurodevelopmental disorder that affects 1 in 10,000 children in the United States and is caused by mutations in the X-linked methyl-CpG-binding protein-2 (MECP2) gene (14). Studies using induced pluripotent stem cells (iPSCs) from RTT patients in traditional 2D adherent culture have revealed reduced neurite outgrowth and synapse number, as well as altered calcium transients and spontaneous postsynaptic currents (1). However, 2D migration assays seemed unlikely to reveal inherent defects in this developmental process, which could be affected because MeCP2 regulates multiple developmental related genes (15). Migration of RTT iPSC-derived NPCs has not previously been studied.Using a previously unidentified 3D tissue culture system that allows creation of layered architectures, we studied differences in migration of MeCP2-mutant iPSC-derived versus control iPSC-derived NPCs. This approach revealed a defect in migration of MeCP2-mutant iPSC-derived NPCs induced by either astrocytes or neurons. Further, this 3D system accelerated maturation of neurons from human iPSC-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. With mature neurons derived from RTT patients and controls, we further confirmed defective neurite outgrowth and synaptogenesis in MeCP2-mutant neurons. Thus, this 3D system enables study of morphological features accessible in 2D system as well as previously unexamined phenotypes.     

Health-related quality of life of outpatients with systolic and isolated diastolic dysfunction

Background The impact of isolated diastolic dysfunction (IDD) and systolic dysfunction (SD) on health-related quality of life (HRQOL) is unknown. Methods and Results To evaluate HRQOL in patients with IDD and SD under treatment, information on outpatients aged 60-84 years was extracted from the records of 4,500 consecutive individuals who underwent echocardiographic examination at Sado General Hospital. The medical records of these patients were reviewed and a questionnaire, including the Medical Outcome Study Short Form 36, was mailed to 71 IDD and 99 SD patients; answers were obtained from 66 and 91 patients, respectively. The HRQOL of patients with cardiac dysfunction was impaired even when echocardiographic parameters improved with treatment. Patients with IDD showed an impairment of HRQOL similar to those with SD. Compared with males, female patients had a larger and more significant reduction in the physical and mental components of the HRQOL score. These scores correlated positively with exercise capacity in patients with IDD or SD. Conclusions Impaired HRQOL, in both its mental and physical components, is a serious problem for IDD and SD patients under treatment. Because exercise intolerance may underlie the reduced HRQOL, improving exercise capacity could be an important target for managing outpatients with heart failure. (Circ J 2008; 72: 1436 - 1442).     

Dynamic stabilization of actin filaments

We report here that actin filaments in vitro exist in two populations with significantly different shrinkage rates. Newly polymerized filaments shrink rapidly, primarily from barbed ends, at 1.8/s, but as they age they switch to a stable state that shrinks slowly, primarily from pointed ends, at approximately 0.1/s. This dynamic filament stabilization runs opposite to the classical prediction that actin filaments become more unstable with age as they hydrolyze their bound ATP and release phosphate. Upon cofilin treatment, aged filaments revert to a dynamic state that shows accelerated shrinkage from both ends at a combined rate of 5.9/s. In light of recent electron microscopy studies [Orlova A, et al. (2004) Actin-destabilizing factors disrupt filaments by means of a time reversal of polymerization. Proc Natl Acad Sci USA 101:17664-17668], we propose that dynamic stabilization arises from rearrangement of the filament structure from a relatively disordered state immediately after polymerization to the canonical Holmes helix, a change that is reversed by cofilin binding. Our results suggest that plasticity in the internal structure of the actin filament may play a fundamental role in regulating actin dynamics and may help cells build actin assemblies with vastly different turnover rates.     

Is circumferential pulmonary vein isolation preferable to stepwise segmental pulmonary vein isolation for patients with paroxysmal atrial fibrillation?

BACKGROUND: Stepwise segmental pulmonary vein isolation (SPVI) and circumferential pulmonary vein isolation (CPVI) have been developed to treat patients with atrial fibrillation (AF), but the preferable approach for paroxysmal AF (PAF) has not been established. METHODS AND RESULTS: One hundred and ten patients with symptomatic PAF were randomized into a stepwise SPVI group (n=55) or CPVI group (n=55). Systemic SPVI combined with left atrial linear ablation tailored by inducibility of AF was performed in the stepwise SPVI group. Circumferential linear ablation around the left and right-sided pulmonary veins (PVs) guided by 3-dimensional electroanatomic mapping was performed in the CPVI group. The endpoints of ablation are non-induciblity of AF in the stepwise SPVI group and continuity of circular lesions combined with PV isolation in the CPVI group. After the initial procedures, atrial tachyarrhythmis (ATa) recurred within the first 3 months in 23 of the 55 patients (41.8%) who underwent stepwise SPVI and in 20 of the 55 patients (36.4%) who had CPVI (p=0.69). Repeat procedures were performed in 7 patients from the stepwise SPVI group and 5 from the CPVI group (p=0.76). During the 3-9 months after the last procedure, 46 patients (83.6%) from the CPVI group and 43 (78.2%) from the stepwise SPVI group did not have symptomatic ATa while not taking anti-arrhythmic drugs (p=0.63). Severe subcutaneous hematoma or PV stenosis occurred in 3 patients. CONCLUSIONS: The efficacy of stepwise SPVI is comparable to that of CPVI for patients with PAF.     

Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.     

Studies of Free Radical Polymerization Initiated by Visible Light Photoredox Catalysis

A visible‐light‐induced free radical polymerization has been developed. Distinct from living radical polymerizations, this polymerization process is not controlled in the chain growth step but the initiation step, by in situ generation of a constantly low concentration of initiator radicals. “On”–“off” experiments demonstrate the ease of controllability of the process, which indicate that it may be an improved method for radical polymerization, since it can be initiated immediately by powering on a light, without any process of preheating the reaction mixture, and can also be sharply stopped by turning off the light, without any cooling process. By adjusting the photo irradiation strength, reaction temperature, and the amount of the initiator system, the molar mass as well as conversion rate can be accurately tuned, which is not easy to realize in other free radical polymerization systems. Notably, a molar mass as high as 5.64 × 10⁵ g mol^?1 (? = 1.71) is achieved with this new methodology.