An effective antitumor remedy is yet to be developed. All previous approaches for a targeted delivery of anticancer medicine have relied on trial and error. The goal of this study was to use structural insights gained from the study of delivery systems and malignant cells to provide for a systematic approach to the development of next-generation drugs. We used doxorubicin (Dox) liposomal formulations. We assayed for cytotoxicity via the electrical current exclusion method. Dialysis of the samples yielded information about their drug release profiles. Information about the surface of the delivery systems was obtained through synchrotron small-angle X-ray scattering (SAXS) measurements. SAXS measurements revealed that Dox-loading yielded an abraded surface of our Dox liposomal formulation containing soybean oil, which also correlated with an effective reduction of the survival of carcinoma cells. Furthermore, a dialysis assay revealed that a higher burst of Dox was released from soybean oil-containing preparations within the first five hours. We conclude from our results that an abraded surface of Dox-loaded drug delivery system increases their efficacy. The apparent match between surface geometry of drug delivery systems and target cells is suggested as a steppingstone for refined development of drug delivery systems. This is the first study to provide a systematic approach to developing next-generation drug carrier systems using structural insights to guide the development of next-generation drug delivery systems with increased efficacy and reduced side effects.

miR-126 is a key regulator of oncogenic processes. It is functionally linked to cellular proliferation, survival and migration. Vascular endothelial growth factor A (VEGF-A), which is regarded as a tumorgenesis activator, could directly target miR-126 in several tumors. However, the mechanism in esophageal cancer remains unclear.

Long non-coding RNAs (lncRNAs) play critical and complicated roles in the regulation of various biological processes, including chromatin modification, transcription and post-transcriptional processing. Interestingly, some lncRNAs serve as miRNA "sponges" that inhibit interaction with miRNA targets in post-transcriptional regulation. We constructed a putative competing endogenous RNA (ceRNA) network by integrating lncRNA, miRNA and mRNA expression based on high-throughput RNA sequencing and microarray data to enable a comparison of the SHEE and SHEEC cell lines. Using Targetscan and miRanda bioinformatics algorithms and miRTarbase microRNA-target interactions database, we established that 51 miRNAs sharing 13,623 MREs with 2260 genes and 82 lncRNAs were involved in this ceRNA network. Through a biological function analysis, the ceRNA network appeared to be primarily involved in cell proliferation, apoptosis, the cell cycle, invasion and metastasis. Functional pathway analyses demonstrated that the ceRNA network potentially modulated multiple signaling pathways, such as the MAPK, Ras, HIF-1, Rap1, and PI3K/Akt signaling pathways. These results might provide new clues to better understand the regulation of the ceRNA network in cancer.

Synonymous or silent mutations are often overlooked in genetic analyses for disease-causing mutations unless they are directly associated with potential splicing defects. More recent studies, however, indicate that some synonymous single polynucleotide polymorphisms (sSNPs) are associated with changes in protein expression, and in some cases, protein folding and function. The impact of codon usage and mRNA structural changes on protein translation rates and how they can affect protein structure and function is just beginning to be appreciated. Examples are given here that demonstrate how synonymous mutations alter the translational kinetics and protein folding and/or function. The mechanism for how this occurs is based on a model in which codon usage modulates the translational rate by introducing pauses caused by nonoptimal or rare codons or by introducing changes in the mRNA structure, and this in turn influences co-translational folding. Two examples of this include the multidrug resistance protein (p-glycoprotein) and the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR is also used here as a model to illustrate how synonymous mutations can be examined using in silico predictive methods to identify which sSNPs have the potential to change protein structure. The methodology described here can be used to help identify "non-silent" synonymous mutations in other genes.

Hospital ethics committees (HECs) help clinicians deal with the ethical challenges which have been raised during clinical practice. A comprehensive literature review was conducted to provide a historical background of the development of HECs internationally and describe their functions and practical challenges of their day to day work. This is the first part of a comprehensive literature review conducted between February 2014 and August 2016 by searching through scientific databases. The keyword ethics committee, combined with hospital, clinic, and institution, was used without a time limitation. All original and discussion articles, as well as other scientific documents were included. Of all the articles and theses found using these keywords, only 56 were consistent with the objectives of the study. Based on the review goals, the findings were divided into three main categories; the inception of HECs in the world, the function of HECs, and the challenges of HECs. According to the results, the Americas Region and European Region countries have been the most prominent considering the establishment of HECs. However, the majority of the Eastern Mediterranean Region and South-East Asia Region countries are only beginning to establish these committees in their hospitals. The results highlight the status and functions of HECs in different countries and may be used as a guide by health policymakers and managers who are at the inception of establishing these committees in their hospitals.

Background: Psychological problems such as depression constitute a dilemma that patients with the implantable cardioverter-defibrillator (ICD) usually encounter and may impact their quality of life. The purpose of this study was to evaluate the prevalence of depression among adults with the ICD and the relationship between depression and associated factors. Methods: Totally, 115 individuals with the ICD participated in this cross-sectional study in Tehran, Iran, and depression and other related risk factors were evaluated in them. Two questionnaires, one for demographic characteristics and the Beck Depression Inventory, were applied for data acquisition. The data were analyzed, and the factors associated with depression in the patients with the ICD were assessed. Results: The mean age of the study population was 59.85 ± 11.46 years. Males comprised 88 (76.5%) and females 27 (23.5%) of the patients. The multivariate analysis on the 115 patients revealed that frequency of ICD shocks (OR = 1.08, 95%CI: 1.02 - 1.10), male sex (OR = 2.28, 95%CI: 1.027 - 5.07), more hospital admissions (OR = 1.19, 95%CI: 1.11 - 1.25), smoking cessation (OR = 9.8, 95%CI: 4.48 - 20.07), presence of ICD shocks (OR = 4.5, 95%CI: 2.45 - 7.38), dyslipidemia (OR = 2.8, 95%CI: 1.22 - 4.95), and family history of depression (OR = 6.4, 95%CI: 3.0 - 13.46) were significantly and independently associated with the Beck score classifications. Conclusion: These findings suggest that a poor psychosocial outcome in patients with the ICD may occur as a result of a variety of associated factors, most of which are predictable and preventable.

Drought (Water deficit, WD) poses a serious threat to extensively economic losses of trees throughout the world. Chinese dwarf cherry (Cerasus humilis) is a good perennial plant for studying the physiological and sophisticated molecular network under WD. The aim of this study is to identify the effect of WD on C. humilis through physiological and global proteomics analysis and improve understanding of the WD resistance of plants.

Most functional magnetic resonance imaging (fMRI) experiments record the brain's responses to samples of stimulus materials (e.g., faces or words). Yet the statistical modeling approaches used in fMRI research universally fail to model stimulus variability in a manner that affords population generalization, meaning that researchers' conclusions technically apply only to the precise stimuli used in each study, and cannot be generalized to new stimuli. A direct consequence of this stimulus-as-fixed-effect fallacy is that the majority of published fMRI studies have likely overstated the strength of the statistical evidence they report. Here we develop a Bayesian mixed model (the random stimulus model; RSM) that addresses this problem, and apply it to a range of fMRI datasets. Results demonstrate considerable inflation (50-200% in most of the studied datasets) of test statistics obtained from standard "summary statistics"-based approaches relative to the corresponding RSM models. We demonstrate how RSMs can be used to improve parameter estimates, properly control false positive rates, and test novel research hypotheses about stimulus-level variability in human brain responses.

 In a cohort of patients hospitalized with acute heart failure (AHF) the prevalence of anemia and the existence of a correlation between anemia and the severity of the clinical picture were assessed. Methods: 50 consecutive patients (34 men, 16 women, mean age 67.5 years) hospitalized with AHF were enrolled.  Statistical analysis was performed for studying correlations between anemia and the presence/levels of diverse parameters (clinical, laboratory, echocardiographic, treatment related)  reflecting the severity and prognosis of AHF (α=0.05). Results: 21 patients (14 men, 7 women, mean age 69.6 years), representing 42%, had anemia  at admission. Comparing patients with and without anemia there were no significant differences regarding age,  gender,  presence of atrial fibrillation (p=0.75), diabetes (p=1), ischemic heart disease (p=0.9), left ventricular ejection fraction (EF) (p=1), hypotension (p=0.34) and tachycardia>100 b/min at admission (p=0.75), level of eGFR (p=0.72), and need of high dose (>80 mg/day)  loop diuretic (p=0.23). However, EF showed a significant positive correlation with eGFR only in AHF patients with anemia (r=0,65, p=0.001). In a multiple regression model, EF had a significant effect on the eGFR quartiles (p=0,004). Conclusions: Anemia is a frequent finding in patients hospitalized with AHF. The presence of anemia was not correlated with other factors related to AHF severity and prognosis. However, a low EF associated with low eGFR was characteristic for patients with anemia, suggesting that the decrease of renal perfusion by low cardiac output further aggravates anemia on the background of chronic kidney disease.

X-linked agammaglobulinemia (XLA) is an extremely rare inherited primary immunodeficiency characterized by recurrent bacterial infections, decrease in number of mature B cells and low serum immunoglobulins. XLA is caused by mutations in the gene encoding Bruton's tyrosine kinase. We report a case of a young Indian boy suspected to have XLA. Immunophenotyping was performed for the affected child using CD20, CD19 and CD3 antibodies. Whole exome sequencing was performed using trio-based approach. The variants were further analyzed using capillary sequencing in the trio as well as maternal grandmother. Initial immunophenotyping in the affected child showed decreased count of CD19+ B cells. To strengthen the clinical findings and confirm the diagnosis of XLA, we performed whole exome sequencing. Our analysis identified a novel frameshift insertion (c.1325dupT) in the BTK gene, which was further validated by Sanger sequencing. Our approach shows the potential in using whole exome sequencing to pinpoint the molecular lesion, enabling timely diagnosis and genetic counseling, and potentially offering prenatal genetic testing for the family.

Background: Osteoporosis is a condition in which the bones become brittle, increasing the risk of fractures. Complementary medicines have traditionally used animal bones for managing bone disorders, such as osteoporosis. This study aimed to discover new natural products for these types of conditions by determining mineral and protein content of bone extracts derived from the Australian wallaby. Methods: Inductively coupled plasma-mass spectrometry and Fourier transform infrared spectroscopic analysis were used for mineral tests, proteome analysis was using LC/MS/MS and the effects of wallaby bone extracts (WBE)s on calcium deposition and alkaline phosphatase activity were evaluated in osteogenic cells derived from adipose tissue-derived stem cells (ADSCs). Results: Concentrations of calcium and phosphorus were 26.21% and 14.72% in WBE respectively. Additionally, minerals found were wide in variety and high in concentration, while heavy metal concentrations of aluminium, iron, zinc and other elements were at safe levels for human consumption. Proteome analysis showed that extracts contained high amounts of bone remodelling proteins, such as osteomodulin, osteopontin and osteoglycin. Furthermore, in vitro evaluation of WBEs showed increased deposition of calcium in osteoblasts with enhanced alkaline phosphatase activity in differentiated adipose-derived stem cells. Conclusion: Our results demonstrate that wallaby bone extracts possess proteins and minerals beneficial for bone metabolism. WBEs may therefore be used for developing natural products for conditions such as osteoporosis and further investigation to understand biomolecular mechanism by which WBEs prevent osteoporosis is warranted.

Background: Medicinal plants are widely used to treat infectious diseases, metabolic disorders and cancer. Argemone mexicana L. (A. mexicana), commonly found on desolate land of Marathwada (Maharashtra, India) has been used to treat oral cavity infections. Methods: In this study, cold aqueous and methanolic extracts were prepared from A. mexicana stem and leaves. These extracts were tested for their antifungal and anticancer activities. The antifungal activity was tested using the agar well diffusion method, while the anticancer activity against immortalized cell lines was assessed by trypan blue assay. Results: It was observed that both cold aqueous and methanolic extracts of A. mexicana stem and leaves inhibited the growth of Mucor indicus, Aspergillus flavus, Aspergillus niger and Penicillum notatum. Antifungal activity of the extract was comparable to that of Amphoterecin-B. A. mexicana extracts had a cytotoxic effect on A549, SiHa and KB immortalized cell lines that were similar to that of berberine. Conclusion: The A. mexicana leaf and stems exhibit strong antifungal and anticancer potential.

Background: Alzheimer's disease is one of the most prevalent dementias in the elderly population with increasing numbers of patients. One pivotal hallmark of this disorder is the deposition of protein aggregates stemming from neurotoxic amyloid-beta peptides. Synthesis of those peptides has been efficiently prevented in AD model mice by activation of an enzyme called alpha-secretase. Therefore, drugs with the capability to increase the expression of this enzyme, named ADAM10, have been suggested as a valuable therapeutic medication. Methods: We investigated 69 substances from a drug library derived from traditional Chinese medicine by luciferase reporter assay in human neuronal cells for their potential to selectively induce alpha-secretase expression. Western blot analysis was used to confirm results on the protein level. Results: Ten of the 69 investigated compounds led to induction of ADAM10 transcriptional activity while BACE-1 (beta-site APP cleaving enzyme 1) and APP (amyloid precursor protein) expression were not induced. Two of them-Norkurarinol and Phlogacantholide C-showed substantial elevation of ADAM10 protein levels and Phlogacantholide C also increased secretion of the ADAM10-derived cleavage product APPs-alpha. Conclusion: Phlogacantholide C represents a novel ADAM10 gene expression enhancer from traditional Chinese medicinal herbs that may lay the groundwork for evolving potential novel therapeutics in Alzheimer's disease.

Recent advances in human immunology have led to the identification of novel immune cell subsets and the biological function of many of these subsets has now been identified. The recent US Food and Drug Administration approval of several immunotherapeutics for the treatment of a variety of cancer types and the results of ongoing immunotherapy clinical studies requires a more thorough interrogation of the immune system. We report here the use of flow cytometry-based analyses to identify 123 immune cell subsets of peripheral blood mononuclear cells. The use of these panels defines multiple differences in younger (< 40 years) vs. older (≥ 40 years) individuals and between aged-matched apparently healthy individuals and metastatic cancer patients, aspects not seen in the analysis of the following standard immune cell types: CD8, CD4, natural killer, natural killer-T, regulatory T, myeloid derived suppressor cells, conventional dendritic cells (DCs), plasmacytoid DCs and B cells. The use of these panels identifying 123 immune cell subsets may aid in the identification of patients who may benefit from immunotherapy, either prior to therapy or early in the immunotherapeutic regimen, for the treatment of cancer or other chronic or infectious diseases.

This study shows that fibroblasts migrating into a collagen matrix release numerous microvesicles into the surrounding medium. By spreading in regions of the matrix far distant from cells of origin, microvesicles carry metalloproteinase 9 (MMP-9) to act upon the collagen fibrils. As a result, the collagen matrix is gradually transformed from a laminar to a fibrillar type of architecture. As shown by western blots and gelatin zymography, MMP-9 is secreted as a 92 kDa precursor and activated upon release of 82 kDa product into the culture medium. Activation is more efficient under three-dimensional than in two-dimensional culturing conditions. While MMP-9 labeling is associated with intraluminal vesicles clustered inside the microvesicles, the microvesicle's integrin β1 marker is bound to the outer membrane. The intraluminal vesicles are recruited from the cortical cytoplasm and eventually released following uploading inside the microvesicle. Here, we propose that fusion of the intraluminal vesicles with the outer microvesicle's membrane could work as a mechanism controlling the extent to which MMP-9 is first activated and then released extracellularly.

Activation of cell death in mammals can be assessed by an increase of an amount of cell-free DNA (cf-DNA) in urine or plasma. We investigated the excretion of cf nuclear DNA (nDNA) and cf mitochondrial DNA (mtDNA) in the urine of rats 3 and 24 months in age after X-irradiation and metformin administration. Analyses showed that prior to treatment, the amount of cf-nDNA was 40% higher and cf-mtDNA was 50% higher in the urine of aged rats compared to that of young animals. At 12 h after irradiation, the content of cf-nDNA and cf-mtDNA in the urine of young rats was increased by 200% and 460%, respectively, relative to the control, whereas in the urine of aged rats, it was 250% and 720% higher. After 6 h following metformin administration, the amount of cf-nDNA and cf-mtDNA in the urine of young rats was elevated by 25% and 55% and by 50% and 160% in the urine of aged rats. Thus, these preliminary data suggest that X-rays and metformin cause a significant increase of cf-DNA in the urine of older rats caused by the active cell death in tissues. These results also suggest that metformin possibly initiates the death of the cells containing structural and functional abnormalities.

Maternal smoking during pregnancy (MSDP) has detrimental effects on fetal development and on the health of the offspring into adulthood. Energy homeostasis through ATP production via the mitochondria (mt) plays a key role during pregnancy. This study aimed to determine if MSDP resulted in differences in DNA methylation to the placental mitochondrial chromosome at the transcription and replication control region, the D-Loop, and if these differences were also present in an alternate neonatal tissue (foreskin) in an independent birth cohort. We investigated mtDNA methylation by bisulfite-pyrosequencing in two sections of the D-Loop control region and in long interspersed nuclear element-1 (LINE-1) genomic sequences in placenta from 96 mother-newborn pairs that were enrolled in a Rhode Island birth cohort along with foreskin samples from 62 infants from a Kentucky birth cohort. In both placenta and foreskin, mtDNA methylation in the light chain D-Loop region 1 was positively associated with MSDP in placenta (difference+2.73%) (P=0.001) and foreskin (difference+1.22%) (P=0.08). Additionally, in foreskin, a second segment of the D-Loop-heavy chain region 1 showed a small but significant change in methylation with MSDP (+0.4%, P=0.04). No methylation changes were noted in either tissue at the LINE-1 repetitive element. We identified a similar pattern of epigenetic effect to mitochondria arising in cells from different primordial lineages and in different populations, associated with MSDP. These robust and consistent results build evidence that MSDP may impact mt D-Loop methylation, as one mechanism through which this exposure affects newborn health.

Orbital fractures are a common facial fracture managed by multiple surgical specialties. Methods: A retrospective review of the electronic medical records of patients (age, 18-85 years) presenting to Northwestern Memorial Hospital and Northwestern Medical Faculty Foundation in Chicago, IL, USA with International Classification of Diseases, Ninth Revision codes for facial fractures or CPT (Current Procedural Terminology) codes for orbital fracture repair.

We present the clinical course, management, and final outcome of spontaneous suprachoroidal hemorrhage (SSCH) in an age-related macular degeneration (AMD) patient-a 64-year-old male receiving antiplatelet therapy who developed SSCH during the Valsalva maneuver. In addition to our case study, we discuss the results of a systemic review of the literature and reference lists of retrieved studies published from January 2001 to December 2013. Among a total of 31 patients (32 eyes), acute secondary glaucoma was a complication in 87.5% of the cases, and over half of the cases (20 eyes, 62.5%) received surgery. Twenty cases (64.5%) were characterized by systemic hypertension (HTN), followed by cardiovascular or cerebral vascular disease in 17 cases (54.8%). The Valsalva maneuver was performed in five cases (16.1%) prior to the episode. Twenty-three cases (74.2%) had abnormal hemostasis, including use of anticoagulants or thrombolytic agents (18 cases), chronic renal failure (CRF, 5 cases), and blood dyscrasia (3 cases). AMD was the most common (17 eyes of 16 patients, 53.1%) ocular disease. Visual acuity was classified as hand motion (HM) or worse in 20 eyes (of 28 eyes, 71.4%) at initial presentation and in 24 eyes (of 30 eyes, 80%) upon final examination. Anticoagulated patients with AMD should be informed of the risk of intraocular hemorrhage. Medical therapy usually fails in the treatment of glaucoma. Surgical intervention provides an option for the purpose of pain relief. Even so, the final visual prognosis is usually poor.

To explore: (1) whether during exercise metabolic equivalents (METs) appropriately indicate the intensity and/or metabolic cost for post-myocardial infarction (MI) males and (2) whether post-exercise VO2 parameters provide insight into the intensity and/or metabolic cost of the prior exercise.