Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence-Defined Components.

Human transferrin protein (Tf) modified polyplexes have already displayed encouraging potential for receptor-mediated nucleic acid delivery into tumors. The use of a blood-derived targeting protein and polydisperse macromolecular cationic subunits however presents a practical challenge for pharmaceutical grade production. Here, Tf receptor (TfR) targeted small interfering RNA (siRNA) polyplexes are designed that are completely composed of synthetic, monodisperse, and sequence-defined subunits generated by solid-phase supported synthesis. An optimized cationizable lipo-oligoaminoamide (lipo-OAA) is used for siRNA core polyplex formation, and a retro-enantio peptide (reTfR) attached via a monodisperse polyethylene glycol (PEG) spacer via click chemistry is applied for targeting. Improved gene silencing is demonstrated in TfR-expressing KB and DU145 cells. Analogous plasmid DNA (pDNA) polyplexes are successfully used for receptor-mediated gene delivery in TfR-rich K562 cells and Neuro2a cells. Six lipo-OAAs differing in their lipidic domain and redox-sensitive attachment of lipid residues are tested in order to evaluate the impact of core polyplex stability on receptor-dependent gene transfer.

Optimizing pDNA Lipo-polyplexes: A Balancing Act between Stability and Cargo Release.

When optimizing nanocarriers, structural motifs that are beneficial for the respective type of cargo need to be identified. Here, succinoyl tetraethylene pentamine (Stp)-based lipo-oligoaminoamides (OAAs) were optimized for the delivery of plasmid DNA (pDNA). Structural variations comprised saturated fatty acids with chain lengths between C2 and C18 and terminal cysteines as units promoting nanoparticle stabilization, histidines for endosomal buffering, and disulfide building blocks for redox-sensitive release. Biophysical and tumor cell culture screening established clear-cut relationships between lipo-OAAs and characteristics of the formed pDNA complexes. Based on the optimized alternating Stp-histidine backbones, lipo-OAAs containing fatty acids with chain lengths around C6 to C10 displayed maximum gene transfer with around 500-fold higher gene expression than that of C18 lipo-OAA analogues. Promising lipo-OAAs, however, showed only moderate in vivo efficiency. In vitro testing in 90% full serum, revealing considerable inhibition of lytic and gene-transfer activity, was found as a new screening model predictive for intravenous applications in vivo.

Effect of different restorative crown and customized abutment materials on stress distribution in single implants and peripheral bone: A three-dimensional finite element analysis study.

STATEMENT OF PROBLEM: In recent years, the use of resin-matrix ceramics and polyetheretherketone (PEEK) abutments has been suggested to absorb excessive stresses on dental implants. However, only a few studies have evaluated the effect of these materials on stress distribution in implants and peripheral bone structure. PURPOSE: The purpose of this finite element analysis was to evaluate the biomechanical behaviors of resin-matrix ceramics and PEEK customized abutments in terms of stress distribution in implants and peripheral bone. MATERIAL AND METHODS: Three-dimensional (3D) models of a bone-level implant system and a titanium base abutment were created by using the standard tessellation language (STL) data of original implant components. An anatomic customized abutment and a maxillary right second premolar crown were then modeled over the titanium base abutment. A bone block representing the maxillary right premolar area was created, and the implant was placed in the bone block with 100% osseointegration. Six different models were created according to combinations of restoration materials (translucent zirconia [TZI], lithium disilicate glass ceramic [IPS], polymer-infiltrated hybrid ceramic [VTE]), and customized abutment materials (PEEK and zirconia). In each model, the implants were loaded vertically (200 N) and obliquely (100 N). The stress distribution in the crown, implant, and abutments was evaluated through the von Mises stress analysis, and the stress distribution in the peripheral bone was examined through the maximum and minimum principal stress analyses. RESULTS: The oblique load resulted in high stress values in the implant components, restorative crown, and cortical bone. Low stress values were observed in the VTE crowns. Zirconia customized abutments exhibited higher stress values than PEEK customized abutments. The stress distributions in the implant and peripheral bone were similar in all models. CONCLUSIONS: Changes in restoration and customized abutment material did not affect stress distribution in the implant and peripheral bone.

Treatment of insomnia with hypnotics resulting in improved sexual functioning in post-menopausal women.

BACKGROUND: This study sought to determine whether trazodone used in hypnotic doses, compared to the hypnotic agent zopiclone, had any specific positive effect on sexual function in non-depressive post-menopausal women with insomnia. SUBJECTS AND METHODS: Fifty (50) subjects participated in the study. Insomnia and sexual performance were evaluated before and after 4 weeks of hypnotic treatment. RESULTS: At week four, both treatments improved sleep quality to a similar degree. Sexual function also improved significantly with both treatments, with no significant difference between the groups. CONCLUSIONS: In post-menopausal women, sexual problems and sleep problems may be related and solving sleep problems may help sexual functioning, independently of depression.

Advanced NH3 Detection by 1D Nanostructured La:ZnO Sensors with Novel Intrinsic p-n Shifting and Ultrahigh Baseline Stability.

Due to its stability, transportability, and ability to be produced using renewable energy sources, NH3 has become an attractive option for hydrogen production and storage. Detecting NH3 is then essential, being a toxic and flammable gas that can pose dangers if not properly monitored. ZnO chemiresistive sensors have shown great potential in real NH3 monitoring applications; yet, research and development in this area are ongoing due to reported limitations, like baseline instabilities and sensitivity to environmental factors, including temperature, humidity, and interferent gases. Herein, we suggest an approach to obtain sensors with competitive performance based on ZnO semiconducting metal oxides. For this purpose, one-dimensional nanostructured pure and La-doped ZnO films were synthesized hydrothermally. Incorporating large rare earth ions, like La, into the bulk lattice of ZnO is challenging and can lead to surface defects that are influential in gas-sensing reactions. The sensors experienced a temperature-induced p-n shifting at about 100 °C, verified by the Hall effect and AC impedance measurements. The doped sensor showed exceptional stepwise baseline stability and outstanding performance at a relatively low operating temperature (150 °C) with a sensing response of 91 at best (@ 50 ppm NH3) and recorded a tolerance to water vapor up to 70% RH. Alongside p-n shifting, the enhanced performance was discussed in correlation with La doping-triggered changes in the nanostructural and surfacial properties of the films. We validated the proposed technique by producing similar sensors and performing multiple replicates to ensure consistency and reproducibility. We also introduced the fill factor concept into the gas sensor field as a new trustworthy parameter that could improve sensor performance assessment and help rate sensors based on deviation from ideality.

Prognostic value of diffuse cancer inflammation index (ALI), serum neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) in advanced-stage lung cancer.

INTRODUCTION: Lung cancer is the most common type of cancer that causes death worldwide. Systemic inflammation has been shown to play a role in cancer etiopathogenesis and can be activated from oncogenic changes in cancer cells. In our study, the prognostic effects of inflammatory parameters calculated from serum were investigated in lung cancer. METHOD: One hundred fifteen patients with locally advanced and advanced lung cancer who were diagnosed in our chest diseases clinic between 2013 and 2015 were retrospectively analyzed. The relationship between advanced lung cancer inflammation index (ALI index), serum neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) levels at the time of diagnosis were calculated, and their relationship with overall survival (OS), disease-free survival, and the treatment response and their effect on predicting prognosis were investigated. FINDINGS: When the ALI value was examined in the group with non-small cell lung, the OS was found to be 9.018 months in the group over 18 years of age and it was 3.78 months in the group below. Low ALI index was significantly associated with short survival ( P <.05). When the NLR values were examined in the entire patient group, OS more than 5 was 5.95 months and less than 9.63 months. A high NLR value was significantly associated with short survival ( P <.05). No significant relationships were detected between PLR and OS. When the determined cut-off values were used, no significant correlation was found between NLR, ALI, and PLR levels and progression-free survival ( P >.05). CONCLUSION: In our study, it was concluded that elevated NLR levels and low ALI values at the time of diagnosis of advanced-stage lung cancer were associated with poor survival, and those values may be useful in predicting survival and prognosis when the cut-off values were used. These parameters can be useful in routine use because they can be easily calculated without additional costs.

Peptide nucleic acid-zirconium coordination nanoparticles.

Ideal drug carriers feature a high loading capacity to minimize the exposure of patients with excessive, inactive carrier materials. The highest imaginable loading capacity could be achieved by nanocarriers, which are assembled from the therapeutic cargo molecules themselves. Here, we describe peptide nucleic acid (PNA)-based zirconium (Zr) coordination nanoparticles which exhibit very high PNA loading of [Formula: see text] w/w. This metal-organic hybrid nanomaterial class extends the enormous compound space of coordination polymers towards bioactive oligonucleotide linkers. The architecture of single- or double-stranded PNAs was systematically varied to identify design criteria for the coordination driven self-assembly with Zr(IV) nodes at room temperature. Aromatic carboxylic acid functions, serving as Lewis bases, and a two-step synthesis process with preformation of [Formula: see text] turned out to be decisive for successful nanoparticle assembly. Confocal laser scanning microscopy confirmed that the PNA-Zr nanoparticles are readily internalized by cells. PNA-Zr nanoparticles, coated with a cationic lipopeptide, successfully delivered an antisense PNA sequence for splicing correction of the [Formula: see text]-globin intron mutation IVS2-705 into a functional reporter cell line and mediated splice-switching via interaction with the endogenous mRNA splicing machinery. The presented PNA-Zr nanoparticles represent a bioactive platform with high design flexibility and extraordinary PNA loading capacity, where the nucleic acid constitutes an integral part of the material, instead of being loaded into passive delivery systems.

Effect of Ni and Al doping on structural, optical, and CO2 gas sensing properties of 1D ZnO nanorods produced by hydrothermal method.

In the present study, the one-dimensional ZnO nanorod structures are produced within the different nickel and aluminum molecular weight ratios of 0-7% using the hydrothermal method. It is found that the aluminum (Al) and nickel (Ni) impurities with different ionic radius, chemical valence, and electron configurations of outer shell cause to vary the fundamental characteristic features including the crystallinity quality, crystallite size, surface morphology, nanorod diameter, optical absorbance, energy band gap, resistance, gas response, and gas sensing properties. The structural analyses performed by powder X-ray diffraction (XRD) and scanning electron microscopy (SEM) indicate that the samples are found to crystallize in the hexagonal wurtzite structure. The presence of optimum nickel and aluminum in the crystal system improves considerably the crystallinity quality and surface morphology. Additionally, the combination of electron dispersive X-ray (EDX) and XRD results declare that the Ni and Al impurities incorporate successfully into the ZnO crystal structure. Moreover, the diameters of nanorod structures in 1D orientation are determined to be 80 nm or below. The hexagonal wurtzite-type ZnO nanorod structure prepared by 5% Ni has more space between the nanorods and thus presents higher response to the CO2 detection. Further, the optical absorbance spectra display that the band gap value is observed to decrease regularly with the increment in the doping level as a result of band shrinkage effect depending on the enhancement of mobile hole carrier concentrations in the crystal structure. In other words, the doping mechanism leads to vary the homogeneities in the interfacial charges, nanorod diameters, ZnO oxide layer composition and thickness. The last test conducted in this study is responsible for the determination of CO2 gas sensing levels. The obtained gas sensing results are further compared with each other and literature findings. It is observed that 5% Ni-doped sample provides more successful results than other samples in the sensing CO2 gas at the different concentrations. All in all, the paper establishing a strong methodology between doping mechanism and change in the fundamental characteristic features of hexagonal wurtzite-type ZnO with the aid of advanced microscopy techniques will become pioneering research to answer key questions in materials sciences and electronic research.

Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma.

Sodium iodide symporter (NIS) gene transfer for active accumulation of iodide in tumor cells is a powerful theranostic strategy facilitating both diagnostic and therapeutic application of radioiodide. In glioblastoma (GBM), the blood-brain barrier (BBB) presents an additional delivery barrier for nucleic acid nanoparticles. In the present study, we designed dual-targeted NIS plasmid DNA complexes containing targeting ligands for the transferrin receptor (TfR) and the epidermal growth factor receptor (EGFR), thus providing the potential for active transport across the BBB followed by targeting of tumor cells. In vitro 125I transfection studies confirmed TfR- and EGFR-dependent transfection efficiency and NIS-specific iodide uptake of dual-targeted polyplexes. In vivo gene transfer in mice bearing orthotopic U87 GBM xenografts was assessed at 48 h after intravenous polyplex injection by positron emission tomography (PET) imaging using 18F-labeled tetrafluoroborate (TFB) as tracer. The tumoral 18F-TFB uptake of mice treated with dual-targeted polyplexes (0.56% ± 0.08% ID/mL) was significantly higher compared with mice treated with EGFR-mono-targeted (0.33% ± 0.03% ID/mL) or TfR-mono-targeted (0.27% ± 0.04% ID/mL) polyplexes. In therapy studies, application of 131I induced a superior therapeutic effect of the dual-targeted therapy, demonstrated by a significant delay in tumor growth and prolonged survival.

An association of the MCP-1 and CCR2 gene polymorphisms with oral lichen planus.

OBJECTIVE: The purpose of this study was to investigate the frequency of monocyte chemoattractant protein (MCP)-1 CCR2 gene polymorphisms in Turkish patients with oral lichen planus (OLP). STUDY DESIGN: A cohort of 50 patients with OLP and 142 control participants without OLP were recruited to investigate the frequency of MCP-1 and CCR2 gene polymorphisms. Chi-square and Fisher's exact tests were used. Student t test and analysis of variance were used to compare demographic data between groups. RESULTS: The MCP AA genotype was less common in the patient group (52%) than in the control group (66.2%; odds ratio [OR] = 0.553; 95% confidence interval [CI], 0.287-1.065; P = .075). The MCP G allele was higher in the patient group (48%) than in the control group (33.8%; OR = 1.808; 95% CI, 0.939-3.479; P = .075). The frequency of the MCP GG genotype was observed to be higher in the patient group (4%) than in the controls (0.7%; OR: 5.875, 95% CI:0.521-66,24; p = 0.106). The CCR2 64I64I genotype was more common in the patient group (6%) than in the control group (2.8%). All results were not statistically significant. CONCLUSION: We suggest that the G allele of MCP-1 and 64I64I genotype of CCR2 polymorphisms do not pose an increased risk for Turkish patients with OLP to develop oral squamous cell carcinoma.

Eating disorder symptoms improved by antireflux surgery: a case report with a six-year follow up.

BACKGROUND: Anorexia nervosa (AN) is a chronic disorder that can overlap with lower esophageal sphincter failure and delayed gastric emptying. Patients with anorexia nervosa or other eating disorders may have a high incidence of gastrointestinal complaints, which can also be observed in gastroesophageal reflux disease (GERD). The overlap in the symptoms of these disorders may cause problems in differential diagnosis and treatment decisions. CASE DESCRIPTION: We report on a case of a patient with anorexia nervosa who did not benefit from conventional treatment strategies such as psychotropic drugs and psychotherapy, but remitted after antireflux surgery. CONCLUSION: When dealing with patients with symptoms of anorexia nervosa, physicians should keep in mind that these patients may have serious esophagogastric complications that can affect their response to psychiatric treatment. Alternatively, some patients with primary esophageal disorders may present with symptoms of eating disorders.

LFM-Pro: a tool for detecting significant local structural sites in proteins.

MOTIVATION: The rapidly growing protein structure repositories have opened up new opportunities for discovery and analysis of functional and evolutionary relationships among proteins. Detecting conserved structural sites that are unique to a protein family is of great value in identification of functionally important atoms and residues. Currently available methods are computationally expensive and fail to detect biologically significant local features. RESULTS: We propose Local Feature Mining in Proteins (LFM-Pro) as a framework for automatically discovering family-specific local sites and the features associated with these sites. Our method uses the distance field to backbone atoms to detect geometrically significant structural centers of the protein. A feature vector is generated from the geometrical and biochemical environment around these centers. These features are then scored using a statistical measure, for their ability to distinguish a family of proteins from a background set of unrelated proteins, and successful features are combined into a representative set for the protein family. The utility and success of LFM-Pro are demonstrated on trypsin-like serine proteases family of proteins and on a challenging classification dataset via comparison with DALI. The results verify that our method is successful both in identifying the distinctive sites of a given family of proteins, and in classifying proteins using the extracted features. AVAILABILITY: The software and the datasets are freely available for academic research use at http://bioinfo.ceng.metu.edu.tr/Pub/LFMPro.

Influence of different implant-abutment connections on stress distribution in single tilted implants and peripheral bone: A three-dimensional finite element analysis.

BACKGROUND: The load transfer between the implant-bone interface depends on various factors, including loading type; material properties of the implant and prosthesis; and implant geometry, length, diameter, and shape. OBJECTIVE: The purpose of this study was to evaluate stress distribution in single tilted bone-level implants with different connections and peripheral bone under vertical and oblique loads using three-dimensional (3D) finite element analysis (FEA).METHOS.3D models of four different implant systems and their abutments were created from the data (computer-aided design) of original implants and abutments scanned with an optical scanner. The implants were placed in the bone block at degrees of 0°, 15°, and 30°. Then, a 3D model of the metal-ceramic crown was created and a 100-N total load was applied vertically and obliquely. RESULTS: Stress analyses showed variable results depending on the connection design and tilting angle; however, the tube in tube (TIT) connection type exhibited lower stress values in most loading and tilting simulations. CONCLUSIONS: Increase in tilting angle showed variable results in each connection design. The TIT connection design was found to be more successful in terms of stress distributions in the implant components and the peripheral bone.

The Efficacy of VATS and Intrapleural Fibrinolytic Therapy in Parapneumonic Empyema Treatment.

BACKGROUND: Development of multiloculation-septation is a challenging entity in empyema patients. In this study, it is aimed to investigate the success rates of videothoracoscopic deloculation (VATS-D) and intrapleural fibrinolytic (IPFib) application after tube thoracostomy. METHODS: The study retrospectively examined the patients diagnosed with empyema with multiloculation and septation between January 2005 and December 2014. Among these patients, the study included those who received VATS-D or IPFib therapy. RESULTS: VATS-D (Group 1) was applied to 54 patients and IPFib (Group 2) was applied to 24 patients. The success of both procedures was evaluated considering the need of decortication in the following periods. In the VATS-D group, 4 (7.4%) patients required decortication via thoracotomy where it was 1 (4.1%) patient (p = 0.577) in the IPFib group. The length of hospital stay was 6.81 ± 2.55 (4-15) days in Group 1 compared to 14.25 ± 6.44 (7-27) days in Group 2 (p <0.001). CONCLUSIONS: It was demonstrated that both of the methods applied in the study have high efficacy and are preferable methods based on the general conditions of patients. Additionally, the shorter length of hospital stays in patients received VATS-D was established as a significant parameter.

Prolonged air leakage in secondary spontaneous pneumothorax: is proportion of emphysema important?

INTRODUCTION: Prolonged air leakage is the most common complication that can cause severe problems in cases of secondary spontaneous pneumothorax (SSP). The purpose of this study was to explore whether Goddard Classification Score (GCS) can be a marker of prolonged air leakage, particularly during the post-operative period, for patients with emphysema. METHODS: Fifty patients, who underwent tube thoracostomy for SSP, were retrospectively evaluated. For the evaluation of emphysematous on the preoperative computed tomography image, visual scoring system described by Goddard was used. The correlations between age, duration of hospitalization, duration of drainage, number of pneumothorax episodes, prolonged air leakage and GCS parameters, were evaluated. RESULTS: When 50 patients were scored, based on GCS, the distribution was as follows: G1: four cases, G2: 16 cases, G3: 17 cases, and G4: 13 cases. The mean number of pneumothorax episodes was 1.3 ± 0.5, the mean duration of drainage was 15.7 ± 11.3 days, and the mean duration of hospitalization was 9.2 ± 5.1 days. Prolonged air leakage was seen in 26 (52.2%) cases. The rate of prolonged air leakage was significantly higher in higher GCS cases (P = 0.035). There was a positive correlation between age and GCS (P = 0.011). The number of pneumothorax episodes rose significantly with increasing GCS (P = 0.011). The duration of hospitalization increased with the growing number of pneumothorax episodes (P = 0.027). CONCLUSION: Prolonged air leakage and the recurrence rate of SSP rise with increasing GCS. Taking this condition into consideration in the treatment algorithm can be helpful for clinicians in patient follow-up.

Psychological outcomes of an outpatient pulmonary rehabilitation program in patients with chronic obstructive pulmonary disease.

STUDY/PRINCIPLES: The effects of an outpatient pulmonary rehabilitation program on psychological morbidity (anxiety and depressive symptoms) were examined in patients with chronic obstructive pulmonary disease (COPD). METHODS: The 26 rehabilitation patients with COPD were compared with 19 control patients with COPD similar in age, gender, COPD severity and other variables. Initial assessment included lung function testing, health status, exercise tolerance, dyspnea intensity and psychiatric interviews using Hamilton depression rating scale (HAM-D) and Hamilton anxiety rating scale (HAM-A). A pulmonary rehabilitation program was carried out during the following 2 months; psychiatric interviews and measurements of health status, exercise tolerance and dyspnea intensity were done again on completion of the study at 2 months. RESULTS: There was a decrease in HAM-A scores in the rehabilitation group and the decrease was statistically significant (P=0.010). On the contrary the HAM-A scores did not change in control group. The decrease in HAM-A scores in rehabilitation group was also statistically significant compared with the control group (P=0.042). There was no significant difference in HAM-D scores within the two groups and also there was no significant difference between the two groups in HAM-D scores. The health status, exercise tolerance and dyspnea intensity improved significantly in the rehabilitation group compared to the control group. CONCLUSION: This study shows that our outpatient rehabilitation program leads to a benefit in anxiety and depressive symptoms in COPD patients. The benefit was especially significant in anxiety symptoms. In addition to the improvement in psychological symptoms, the health status, exercise tolerance and dyspnea intensity were also significantly improved in COPD patients who underwent the rehabilitation program. This outpatient-based rehabilitation program was well accepted by the patients. The relatively simple design of the program makes it feasible independently of expensive equipment.

The risk factors and symptomatology of perimenopausal depression.

OBJECTIVES: The aim of this study is to determine if the depression in perimenopausal women is symptomatologically different than depression in premenopausal women, and if these depressive women are under more risk for depression when factors like premenstrual dysphoric syndrome, socio-economical status, vasomotor symptoms and familial inclination to depression are considered. METHODS: Fifty major depressive women with hormonally established perimenopause (follicle stimulating hormone (FSH) levels over 20IU/l and estrogen levels lower than 40IU/l) and who were not taking any psychotropic or hormone replacement therapy, were enrolled in the study. In order to investigate the characteristic clinical features of perimenopausal depression, a drug free control group consisting of 48 pre-perimenopausal women with a diagnosis of major depression was formed. Another control group was formed with 53 non-depressive perimenopausal women in order to investigate the risk factors of perimenopausal depression. RESULTS: The depressive and non-depressive groups did not differ from each other according to level of education, marital and economical status and comorbid physical problems. No major symptomatological difference between perimenopausal depression and pre-perimenopausal depression was found. No correlation was found between the severity of vasomotor symptoms and severity of depression. CONCLUSIONS: Findings of our study suggest that vasomotor symptoms and socio-economical status do not predict the severity and existence of perimenopausal depression. Episodes of major depression are not necessarily the normal result of such vasomotor symptoms. Therefore, the evaluation and management of perimenopausal depression should be carried out as carefully as is done in episodes of depression seen in the rest of women's life span.

The effect of amine-free initiator system and the polymerization type on color stability of resin cements.

We investigated the short-term (4 weeks) color stability of light-cure and dual-cure resin cements. Sixty disk-shaped test specimens of adhesive resin cement (10 × 1 mm) were prepared. One feldspathic porcelain test specimen (12 × 14 × 0.8 mm) was prepared from a prefabricated ceramic block. The feldspathic sample was placed on the resin cement disk and all the measurements were performed without cementation. Specific color coordinate differences (ΔL, Δa, and Δb), and the total color differences (ΔE) were calculated after immersion in distilled water for different periods. Data were compared using one-way analysis of variance (ANOVA) (α = 0.05). The test results revealed that different chemical structures and curing modes affected the ΔE values (P < 0.05). The highest ΔE values were obtained for RelyX Unicem dual-cure cement (2.14 ± 0.40), and the lowest for NX3 light-cure cement (0.78 ± 0.34). Third generation adhesive resin cement free of tertiary amines and benzoyl peroxide showed relatively slight color change in both test groups (light-cure and dual-cure resin cement). (J Oral Sci 58, 157-161, 2016).