Statistical finite element method for real-time tissue mechanics analysis

The finite element (FE) method can accurately calculate tissue deformation. However, its low speed renders it ineffective for many biomedical applications involving real-time data processing. To accelerate FE analysis, we introduce a novel tissue mechanics simulation technique. This technique is suitable for real-time estimation of tissue deformation of specific organs, which is required in computer-aided diagnostic or therapeutic procedures. In this method, principal component analysis is used to describe each organ shape and its corresponding FE field for a pool of patients by a small number of weight factors. A mapping function is developed to relate the parameters of organ shape to their FE field counterpart. We show that irrespective of the complexity of the tissue's constitutive law or its loading conditions, the proposed technique is highly accurate and fast in estimating the FE field. Average deformation errors of less than 2% demonstrate the accuracy of the proposed technique.     

Reduced exercise tolerance and pulmonary capillary recruitment with remote secondhand smoke exposure

Rationale

Flight attendants who worked on commercial aircraft before the smoking ban in flights (pre-ban FAs) were exposed to high levels of secondhand smoke (SHS). We previously showed never-smoking pre-ban FAs to have reduced diffusing capacity (Dco) at rest.

Methods

To determine whether pre-ban FAs increase their Dco and pulmonary blood flow () during exercise, we administered a symptom-limited supine-posture progressively increasing cycle exercise test to determine the maximum work (watts) and oxygen uptake () achieved by FAs. After 30 min rest, we then measured Dco and at 20, 40, 60, and 80 percent of maximum observed work.

Results

The FAs with abnormal resting Dco achieved a lower level of maximum predicted work and compared to those with normal resting Dco (mean±SEM; 88.7±2.9 vs. 102.5±3.1%predicted ; p = 0.001). Exercise limitation was associated with the FAs'' FEV₁ (r = 0.33; p = 0.003). The Dco increased less with exercise in those with abnormal resting Dco (mean±SEM: 1.36±0.16 vs. 1.90±0.16 ml/min/mmHg per 20% increase in predicted watts; p = 0.020), and amongst all FAs, the increase with exercise seemed to be incrementally lower in those with lower resting Dco. Exercise-induced increase in was not different in the two groups. However, the FAs with abnormal resting Dco had less augmentation of their Dco with increase in during exercise (mean±SEM: 0.93±0.06 vs. 1.47±0.09 ml/min/mmHg per L/min; p<0.0001). The Dco during exercise was inversely associated with years of exposure to SHS in those FAs with ≥10 years of pre-ban experience (r = −0.32; p = 0.032).

Conclusions

This cohort of never-smoking FAs with SHS exposure showed exercise limitation based on their resting Dco. Those with lower resting Dco had reduced pulmonary capillary recruitment. Exposure to SHS in the aircraft cabin seemed to be a predictor for lower Dco during exercise.     

Distance-dependent atomic knowledge-based force in protein fold recognition

We have recently introduced a novel model for discriminating the correctly folded proteins from well-designed decoy structures using mechanical interatomic forces. In the model, we considered a protein as a collection of springs and the force imposed to each atom was calculated by using the relation between the potential energy and the force. A mean force potential function is obtained from statistical contact preferences within the known protein structures. In this article, the interatomic forces are calculated by numerical derivation of the potential function. For assessing the knowledge-based force function we consider an optimal structure and define a score function on the 3D structure of a protein. We compare the force imposed to each atom of a protein with the corresponding atom in the optimum structure. Afterwards we assign larger scores to those atoms with the lower forces. The total score is the sum of partial scores of atoms. The optimal structure is assumed to be the one with the highest score in the dataset. Finally, several decoy sets are applied in order to evaluate the performance of our model.     

Plant growth promoting activity of an auxin and siderophore producing isolate of <Emphasis Type="Italic">Streptomyces</Emphasis> under saline soil conditions

A biocontrol Streptomyces isolate (C) was tested for its plant growth promoting qualities under saline conditions. Exposure to elevated osmotic strengths up to 300 mM NaCl increased dry weight and cfu/ml significantly. The isolate C produced indolyl-3-acetic acid (IAA) into the medium in the amount of 2.4 μg/ml. The amount of auxin increased after adding salt and reached to 4.7 μg/ml in 300 mM NaCl. Biosynthesis of siderophore was detectable and increased in presence of NaCl. Streptomyces isolate C showed good solubilization of tricalcium phosphate in culture medium with 92 mg/l. Solubilization decreased in presence of NaCl. Soil treatment with isolate C increased the growth and development of wheat plant in normal and saline conditions. In this treatment there were significant increases in germination rate, percentage and uniformity, shoot length and dry weight compared to the control. Applying the bacterial inocula increased the concentration of N, P, Fe and Mn in wheat shoots grown in normal and saline soil, but had non-significant effect on other micro and macronutrients concentrations. Results of this study show that Streptomyces isolate C has potential to be utilized as biofertilizer in saline soils.     

Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate objective responses in up to 50% of malignant melanoma patients with a good performance status refractory to standard treatments. Current protocols for generation of TILs rely on open surgery for access to tumor tissue. We obtained tumor material by ultrasound-guided core needle biopsy or surgery from melanoma patients with progressive disease and were able to isolate >5 × 10⁶ TILs from 23 of 24 patients who were subsequently treated with these cells. One-third of the individual TIL-positive cultures displayed interferon gamma activity after stimulation with relevant melanoma cell lines. When expanded TILs were used for treatment in combination with daily low dose s.c. IL-2 after prior lymphodepleting chemotherapy, we observed objective clinical responses in one patient treated with TILs obtained from surgery and 4 patients treated with TILs from core biopsies. The results of this study demonstrate for the first time the potential of core biopsies for generation of relevant numbers of TILs that can mediate objective responses in patients with metastatic malignant melanoma. Ultrasound-guided core needle biopsy is a robust, safe and inexpensive approach to obtain tumor tissue for TIL generation, and is especially valuable in instances where surgery is contraindicated.     

Determination of Selenium in Serum Samples of Preterm Newborn Infants with Bronchopulmonary Dysplasia Using a Validated Hydride Generation System

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is one of the most challenging complications in premature newborn infants. Selenium plays a role in antioxidant system by protecting cell membranes and neutralizing the deleterious effects of free radicals. The aim of this study was to determine the relationship between selenium concentration and incidence of bronchopulmonary dysplasia using a validated analytical method. Umbilical cord blood and blood samples 30 days after the birth were collected from 38 preterm newborn infants with gestation age of 32 weeks or less, and the separated serums were kept at -70°C until analysis time. Selenium concentration of serum was determined using an atomic absorption spectrophotometer. The method was validated on the basis of standard validation techniques. The analytical method was linear in the range of 1 to 500 μg/L with the limit of detection of 0.4 μg/L. Samples were collected from 38 infants whose gestation age was 32 weeks or less. The blood samples were collected from the umbilical cord blood at birth in 19 cases. In 25 cases, blood samples were collected 1 month after birth. Of the 15 patients diagnosed with BPD, 10 were boys (p = 0.02). The mean serum selenium concentration was not different at birth between patients with and without BPD, but it was significantly lower at 30 days after birth in patients with BPD (38.5 ± 14.1vs. 45.4 ± 18.7 μg/L, p = 0.02). Preterm newborn infants with BPD had lower serum selenium concentrations 1 month after birth.     

CREB-binding protein (CREBBP) and preeclampsia: a new promising target gene

Molecular Biology Reports - Preeclampsia (PE) is a major complication of pregnancy and remains a leading cause of neonatal and maternal mortality worldwide. Several studies have revealed that the...     

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data

Background aimMesenchymal stromal cells (MSCs) hold promise for the treatment of tissue damage and injury. However, MSCs comprise multiple subpopulations with diverse properties, which could explain inconsistent therapeutic outcomes seen among therapeutic attempts. Recently, the adenosine triphosphate-binding cassette transporter ABCB5 has been shown to identify a novel dermal immunomodulatory MSC subpopulation.MethodsThe authors have established a validated Good Manufacturing Practice (GMP)-compliant expansion and manufacturing process by which ABCB5⁺ MSCs can be isolated from skin tissue and processed to generate a highly functional homogeneous cell population manufactured as an advanced therapy medicinal product (ATMP). This product has been approved by the German competent regulatory authority to be tested in a clinical trial to treat therapy-resistant chronic venous ulcers.ResultsAs of now, 12 wounds in nine patients have been treated with 5 × 10⁵ autologous ABCB5⁺ MSCs per cm² wound area, eliciting a median wound size reduction of 63% (range, 32–100%) at 12 weeks and early relief of pain.ConclusionsThe authors describe here their GMP- and European Pharmacopoeia-compliant production and quality control process, report on a pre-clinical dose selection study and present the first in-human results. Together, these data substantiate the idea that ABCB5⁺ MSCs manufactured as ATMPs could deliver a clinically relevant wound closure strategy for patients with chronic therapy-resistant wounds.     

Network analysis and the impact of Aflibercept on specific mediators of angiogenesis in HUVEC cells

Angiogenesis, inflammation and endothelial cells’ migration and proliferation exert fundamental roles in different diseases. However, more studies are needed to identify key proteins and pathways involved in these processes. Aflibercept has received the approval of the US Food and Drug Administration (FDA) for the treatment of wet AMD and colorectal cancer. Moreover, the effect of Aflibercept on VEGFR2 downstream signalling pathways has not been investigated yet. Here, we integrated text mining data, protein-protein interaction networks and multi-experiment microarray data to specify candidate genes that are involved in VEGFA/VEGFR2 signalling pathways. Network analysis of candidate genes determined the importance of the nominated genes via different centrality parameters. Thereupon, several genes—with the highest centrality indexes—were recruited to investigate the impact of Aflibercept on their expression pattern in HUVEC cells. Real-time PCR was performed, and relative expression of the specific genes revealed that Aflibercept modulated angiogenic process by VEGF/PI3KA/AKT/mTOR axis, invasion by MMP14/MMP9 axis and inflammation-related angiogenesis by IL-6-STAT3 axis. Data showed Aflibercept simultaneously affected these processes and determined the nominated axes that had been affected by the drug. Furthermore, integrating the results of Aflibercept on expression of candidate genes with the current network analysis suggested that resistance against the Aflibercept effect is a plausible process in HUVEC cells.