Three Small Points: A Cody Complex Problem

Abstract

Three small points which resemble larger Cody Complex projectile points are related to this Complex on the basis of technological and shape attributes. It is concluded that several factors underlie occurrence of tiny Cody points. Resharpening of larger points accounts for one pattern. In addition, diminutive points were produced using two alternative sets of technological procedures. It is suggested that these points were not used in subsistence activities and may reflect ceremonial or symbolic activities practiced by late Paleo-Indian bison hunters.     

Targeting Astrocytomas and Invading Immune Cells with Cannabinoids: A Promising Therapeutic Avenue

The last quarter century has borne witness to great advances in both the detection and treatment of numerous cancers. Even so, malignancies of the central nervous system, especially high-grade astrocytomas, continue to thwart our best efforts toward effective chemotherapeutic strategies. With prognosis remaining bleak, the time for serious consideration of alternative therapies has arrived. Various preparations of the marijuana plant, Cannabis sativa, and related synthetic and endogenous compounds, may constitute just such an alternative. Cannabinoids, although much maligned historically for their psychotropic effects and clear abuse potential, have long been used medicinally and are now staging an impressive comeback, as recent studies have begun to explore their powerful anti-tumoral properties. In this study, we review in vitro and in vivo evidence supporting the use of cannabinoids for treatment of brain tumors. We further propose the continued intense investigation of cannabinoid efficacies as novel anti-cancer agents, especially in models recapitulating such properties within the unique environment of the brain.     

Re-Evaluate the Effect of Hyperbaric Oxygen Therapy in Cancer - A Preclinical Therapeutic Small Animal Model Study

Tumor hypoxia is a known driver of angiogenesis that also facilitates tumor growth. Moreover, poorly oxygenated central tumor area remains relatively radio or chemo resistant. HBO therapy is known to elevate the levels of dissolved oxygen and eliminates tumor hypoxia. It has been one of the modalities in cancer treatment; therefore its optimization is important. In this experimental study, no cancer enhancing effect was seen during the course of HBO therapy; however, post therapy there was an accelerated growth and progression of tumor. HBO treated mice lived shorter and the response to therapy was dose & tumor volume dependent. HBO therapy probably exert its effect on the cancer proliferating cells through multiple pathways such as increased DNA damage, apoptosis & geno-toxicity leading to slow cancer progression while post therapy tumorigenic effect could be due to impaired DNA repair mechanism, mutagenic effect & aneuploidy as well as altered blood supply & nutrients. Tumor growth reached plateau with time and this finding validated theoretical model predicting tumor reaching an asymptotic limit. While, marked asymmetry observed in tumor volume progression or cancer cell proliferation rate in each of the experimental C3H mouse suggested a need for an alternate small animal pre-clinical cancer therapeutic model.     

维生素A对免疫功能的影响

维生素A已经作为一种营养补充剂用在临床治疗和日常膳食中,对机体的免疫系统有重要意义。近年来许多关于维生素A与免疫的关系和机制探讨也随着分子生物学的发展取得了很大进步。该介绍维生素A在体内、体外试验中对细胞免疫、体液免疫的作用,在临床应用中的效用,以及不同剂量作用于免疫系统产生的不同结果等。     

牦牛肠源Lactobacillus acidophilus L3对其肠道分泌型免疫球蛋白A及免疫相关因子的影响

为了研究牦牛肠源Lactobacillus acidophilus L3(嗜酸乳杆菌)对其肠道分泌型免疫球蛋白A(SIg A)及免疫相关因子的影响,将10头健康牦牛(2~2.5岁)随机分为2组,分别为益生菌组和空白对照组,益生菌组在饲料中添加2×109CFU·kg-1L.acidophilus L3,饲喂28 d后取其小肠样品,ELISA检测试验组和对照组十二指肠、空肠、回肠中SIg A、白细胞介素-2(IL-2)、IL-4、IL-6、干扰素γ(IFN-γ)的含量。研究结果表明,L.acidophilus L3可有效增加试验组牦牛肠道SIg A的分泌量(P<0.05),组内比较发现SIg A在回肠含量最高,其次为空肠和十二指肠。IL-2、IL-4、IL-6在试验组小肠中的表达量较对照组显著增加(P<0.05),试验组小肠IFN-γ的表达量较对照组降低(P<0.05)。证实L.acidophilus L3可提高牦牛肠道的黏膜免疫功能。     

Type III CRISPR-Cas Systems: Deciphering the Most Complex Prokaryotic Immune System

Biochemistry (Moscow) - The emergence and persistence of selfish genetic elements is an intrinsic feature of all living systems. Cellular organisms have evolved a plethora of elaborate defense...     

A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART

Trial Design

Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm³ and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART.

Methods

The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination.

Results

MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8⁺ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses.

Conclusion

MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity.

Trial Registration

ClinicalTrials.gov NCT01571466     

CXCR2 Macromolecular Complex in Pancreatic Cancer: A Potential Therapeutic Target in Tumor Growth

The signaling mediated by the chemokine receptor CXC chemokine receptor 2 (CXCR2) plays an important role in promoting the progression of many cancers, including pancreatic cancer, one of the most lethal human malignancies. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif at its carboxyl termini, which might interact with potential PDZ scaffold/adaptor proteins. We have previously reported that CXCR2 PDZ motif-mediated protein interaction is an important regulator for neutrophil functions. Here, using a series of biochemical assays, we demonstrate that CXCR2 is physically coupled to its downstream effector phospholipase C-β3 (PLC-β3) that is mediated by PDZ scaffold protein Na⁺/H⁺ exchange regulatory factor 1 (NHERF1) into a macromolecular signaling complex both in vitro and in pancreatic cancer cells. We also observe that disrupting the CXCR2 complex, by gene delivery or peptide delivery of exogenous CXCR2 C-tail, significantly inhibits the biologic functions of pancreatic cancer cells (i.e., proliferation and invasion) in a PDZ motif-dependent manner. In addition, using a human pancreatic tumor xenograft model, we show that gene delivery of CXCR2 C-tail sequence (containing the PDZ motif) by adeno-associated virus type 2 viral vector potently suppresses human pancreatic tumor growth in immunodeficient mice. In summary, our results suggest the existence of a physical and functional coupling of CXCR2 and PLC-β3 mediated through NHERF1, forming a macromolecular complex that is critical for efficient and specific CXCR2 signaling in pancreatic cancer progression. Disrupting this CXCR2 complex could represent a novel and effective treatment strategy against pancreatic cancer.     

Simvastatin and Benznidazole-Mediated Prevention of Trypanosoma cruzi-Induced Endothelial Activation: Role of 15-epi-lipoxin A4 in the Action of Simvastatin

Trypanosoma cruzi is the causal agent of Chagas Disease that is endemic in Latin American, afflicting more than ten million people approximately. This disease has two phases, acute and chronic. The acute phase is often asymptomatic, but with time it progresses to the chronic phase, affecting the heart and gastrointestinal tract and can be lethal. Chronic Chagas cardiomyopathy involves an inflammatory vasculopathy. Endothelial activation during Chagas disease entails the expression of cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) through a mechanism involving NF-κB activation. Currently, specific trypanocidal therapy remains on benznidazole, although new triazole derivatives are promising. A novel strategy is proposed that aims at some pathophysiological processes to facilitate current antiparasitic therapy, decreasing treatment length or doses and slowing disease progress. Simvastatin has anti-inflammatory actions, including improvement of endothelial function, by inducing a novel pro-resolving lipid, the 5-lypoxygenase derivative 15-epi-lipoxin A4 (15-epi-LXA4), which belongs to aspirin-triggered lipoxins. Herein, we propose modifying endothelial activation with simvastatin or benznidazole and evaluate the pathways involved, including induction of 15-epi-LXA4. The effect of 5 μM simvastatin or 20 μM benznidazole upon endothelial activation was assessed in EA.hy926 or HUVEC cells, by E-selectin, ICAM-1 and VCAM-1 expression. 15-epi-LXA4 production and the relationship of both drugs with the NFκB pathway, as measured by IKK-IKB phosphorylation and nuclear migration of p65 protein was also assayed. Both drugs were administered to cell cultures 16 hours before the infection with T. cruzi parasites. Indeed, 5 μM simvastatin as well as 20 μM benznidazole prevented the increase in E-selectin, ICAM-1 and VCAM-1 expression in T. cruzi-infected endothelial cells by decreasing the NF-κB pathway. In conclusion, Simvastatin and benznidazole prevent endothelial activation induced by T. cruzi infection, and the effect of simvastatin is mediated by the inhibition of the NFκB pathway by inducing 15-epi-LXA4 production.     

聚焦超声消融治疗子宫小肌瘤的疗效评价

摘要 目的：探讨聚焦超声消融治疗无症状子宫小肌瘤的临床价值。方法：采用对照回顾性研究,将2011年03月至2018年03月在遂宁市中心医院妇科收治入院行聚焦超声消融治疗的无症状的子宫小肌瘤患者设置为治疗组,将同期未经任何治疗的门诊随访的无症状子宫小肌瘤患者设置为对照组,比较两组在6个月、12个月、18个月、24个月后子宫肌瘤的体积变化、是否出现临床症状及妊娠情况。结果：治疗组在聚焦超声消融治疗后6个月、12个月、18个月、24个月,随着时间的推移,子宫小肌瘤的体积较治疗前逐渐缩小,均未出现临床症状;对照组子宫小肌瘤的体积逐渐增大,并出现临床症状;治疗组和对照组24个月内的妊娠率分别为17.48%和8.42%,比较两组差异有统计学意义(P＜0.05)。聚焦超声消融治疗后无严重并发症发生。结论：对于孕龄期有生育要求的黏膜下或肌壁间的无症状子宫小肌瘤患者,可行聚焦超声消融手术缩小病灶,维持子宫腔的正常形态,避免或延迟临床症状的出现,提高妊娠率。     

Exploring the Effect of Hesperetin–HSPC Complex—A Novel Drug Delivery System on the In Vitro Release, Therapeutic Efficacy and Pharmacokinetics

Hesperetin is known to exhibit a variety of pharmacological activities in mammalian cell systems. Although it shows appreciable bioavailability when administered orally, its faster elimination from body creates the need of frequent administration to maintain effective plasma concentration. To overcome this limitation, a phospholipid complex of hesperetin was prepared and evaluated for antioxidant activity and pharmacokinetic profile. The hesperetin content of the complex was determined by a spectrophotometer and the surface characteristics of the complex were studied by means of microscope. The antioxidant activity was evaluated in carbon-tetrachloride-intoxicated rats at a dose level of 100 mg/kg body weight, p.o. The complex was studied for in vitro drug release characteristics and effect of complexation on serum concentration of hesperetin in rats was also studied along with main pharmacokinetic parameters. The results showed that the complex has a sustained release property and enhanced antioxidant activity (P < 0.05 and <0.01) as compared to free hesperetin at the same dose level. Pharmacokinetic study depicted that the complex has higher relative bioavailability and acted for a longer period of time. The study therefore suggests that phospholipid complex of hesperetin produced better antioxidant activity than free drug at the same dose level and the effect persisted for a longer period of time, which may be helpful in solving the problems of faster elimination of the molecule.     

醒脑静注射液对老年肺炎支原体肺炎患者血清TNF-alpha、CRP水平及免疫 功能的影响

目的：探讨醒脑静注射液对老年肺炎支原体肺炎患者血清肿瘤坏死因子-alpha(TNF-alpha)、C- 反应蛋白(CRP)水平及免疫功能影 响。方法：收集我院收治的老年肺炎支原体肺炎患者80例,随机分为实验组和对照组。对照组予阿奇霉素治疗,实验组在对照组 基础上加用醒脑静注射液。分别于治疗前、治疗后测定和比较两组血清TNF-alpha、CRP、CD3+、CD4+、CD8+水平,并对比较两组患者 咳嗽、头痛、发热等症状及X 线检查肺部阴影消失时间。结果：①治疗后,两组患者血清TNF-alpha、CRP水平均下降,实验组比对照组 下降更明显;CD3+、CD4+均上升,CD8+均下降,实验组较对照组上升及下降均更明显,差异有统计学意义(P＜0.05);②治疗后,实 验组咳嗽、头痛、X 线肺部阴影等各症状及体征消失时间均明显短于对照组,差异有统计学意义(P＜0.05)。结论：醒脑静注射液可 显著降低老年肺炎支原体肺炎患者血清TNF-alpha、CRP水平,调节机体细胞免疫功能,显著改善患者的症状及体征。     

Orally Administered Therapeutic Peptide Delivery: Enhanced Absorption Through the Small Intestine Using Permeation Enhancers

Peptide therapeutics (PTs) is generally regarded as highly effective macromolecule therapeutics at very low concentrations. The main issues surrounding the administration of PTs is guaranteeing that they are bioavailable, reach the desired therapeutic index and distribute throughout the body effectively. The oral administration, a non-invasive route, of PTs is considered a major complication due to inadequate oral absorption through biological membranes such as the small intestine epithelium due to presystemic proteolytic enzymatic activity. PTs bioavailability is further diminished in the systemic circulation due to low stability in the plasma and rapid excretion from the body. Many alternative routes can be considered non-invasive such as transdermal and nasal routes, but this review focuses on the oral route, specifically the small intestine region of the gastrointestinal tract. Although this region has the highest density of proteolytic enzymes, it contains tight junctions which have the lowest trans-epithelial electrical resistance throughout the body; thus paracellular transport of these large PTs can be achieved more readily. The use of a natural polysaccharide polymer, such as trimethyl chitosan (TMC), which enhances the bioavailability of these PTs through the small intestine, will also be discussed in great detail. TMC has been considered because it could potentially solve many of the mechanistic and chemical problems associated with oral therapeutic peptide administration. The safety of orally administered PTs through the small intestinal epithelium employing a polymer such as TMC is also discussed as this is a significant issue for regulatory bodies.     

A Hippo in the ointment: MST signalling beyond the fly

The regulation of cell cycle and apoptosis is fundamental to the control of cell growth and organism homeostasis. Failure to efficiently regulate these processes often results in the increased cell growth observed in tumours. Accumulation of genetic lesions frequently eliminates these regulatory steps so it is imperative that multiple signalling pathways are employed to ensure that efficient control is maintained. Over the last few years a novel signalling pathway entered the limelight that prevents inappropriate activation of the cell cycle and can elicit apoptosis to limit cell numbers. Denoted the MST/hippo pathway, it is involved in regulating cell number in organism development and tumour progression. Here we aim to review the evidence for a conserved pathway from flies to mammals, and of equal importance to initiate the discussion on the additional cellular and signalling processes that have been adopted by this pathway to achieve further regulation and diversified cellular outcomes in mammals.     

个体化护理可干预糖尿病合并高血压患者脂联素、Cys-c水平及治疗依从性和生活质量

本研究回顾性选取2015年12月至2017年2月我院收治的糖尿病合并高血压患者142例,根据护理方法不同分为对照组和观察组。对照组患者采用常规护理,观察组患者采用个体化护理,分析两组患者护理后的效果,以探讨个体化护理对糖尿病合并高血压患者治疗依从性及生活质量的影响。研究结果显示:干预前,两组患者血压、血糖水平比较无统计学差异(p>0.05),干预后,观察组患者收缩压(systolic blood pressure,SBP)、舒张压(diastolic blood pressure, DBP)、空腹血糖(fasting plasma glucose, FPG)、餐后2 h血糖(2 hourspost prandial plasma, P2hPG)水平低于对照组(p<0.05);干预前,两组患者细胞一氧化氮(nitric oxide, NO)、脂联素(adiponectin)、基质金属蛋白酶-9 (matrix metalloproteinase-9, MMP-9)、细胞间黏附分子-1 (intercelluaradhension molecule-1, ICAM-1)、胱抑素C (cystatin C, Cys-c)水平比较无统计学差异(p>0.05),干预后,观察组患者NO、脂联素水平高于对照组,MMP-9、ICAM-1、Cys-c水平低于对照组(p<0.05);干预前,两组患者对饮食、运动、用药、心理方面的依从性评分比较无统计学差异(p>0.05),干预后,观察组患者各方面的依从性评分水平高于对照组(p<0.05);干预前,两组患者生活质量评分比较无统计学差异(p>0.05),干预后,观察组患者社会功能、生理职能、情感职能、躯体状况、心理状况评分水平高于对照组(p<0.05)。我们的研究初步得出结论:个体化护理干预可提高糖尿病合并高血压患者的依从性,控制患者血压、血糖、MMP-9、ICAM-1水平,提高患者生活质量。     

A forest beyond the trees: Tree cutting in rural Ghana

In this paper I examine the complexity of human forces involved in tree cutting in a Ghanaian forest region. I provide evidence to link the indiscriminate tree-cutting activities of some local communities to the gradual loss of communal control over land and the replacement of kin group control with state property regimes. I point to the interrelated factors of the state's promotion of an exportled development strategy, the intensification of agricultural commercialization, and household and group variations in access to land as all having deleterious impacts on local traditions of sustainable forestry.