Human-Organoid Models: Accomplishments to Salvage Test-Animals

Late stage attritions in drug discovery are costly and consuming. Improbable response of test molecules acquired in non-human systems is attributed to be the major cause of clinical failures. While conventional in vitro methods of drug discovery do not truly represent the human system, the animal models used for in vivo validation are also genetically and phenotypically distant from humans. 

However, recent developments in organoid culture are motivating and elevate hopes for replacing test animals with artificial human tissue models. Possibility of creating functional tissue ex vivo has a potential to revolutionize the way human therapeutics is perceived. Not only will it bridge the gap between drug development and its clinical efficacy but also help strategizing regenerative medicine. Successful human-tissue surrogates would liberate test animals or at least minimize their use for research purposes. Potential drug candidates tested on human-tissue equivalents are expected to generate clinically much more relevant data. Here we deliberate upon the options and possibilities of accomplishing human organoid models for in vitro testing and their significance in therapeutics.

Bio-Analytical Method Development and Validation for Estimation of Lume fantrine in Human Plasma by Using Lc-Ms/Ms

Lumefantrine and Glimepiride (IS) were extracted from human plasma by Precipitation followed by Solid phase extraction using Orochem (30 mg/1 CC) solid phase extraction cartridge. The chromatographic separation was performed on Hypurity C18 (50 cm×4.6 mm), 5 μ column. The mobile phase consisted of Acetonitrile: 2 mM Ammonium Acetate (pH: 3.5) (90:10, % v/v) was delivered at rate of 0.600 mL/min with Splitter. Detection and quantitation were performed by a triple quadrupole equipped with electro spray ionization and multiple reaction monitoring inpositive ionization mode (API 3000). The most intense [M-H]- transition for Lume fantrine at m/z 528.0→510.0 and for IS at m/z 491.2→352.0 were used for quantification. 

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Cardiopulmonary Resuscitation as a Graduation Requirement for Biomedical Engineering Students

At the end of a mountain road in Austria during the summer of 2003, I waited for a boat with my family on a dock at a large lake. Suddenly I saw a man fall to the side walk. His skin had turned that ashen blue color, and it was clear to me that he was in cardiac arrest. There was a crowd of more than 75 persons just standing and looking at him. 

I knew what to do when there was no detectable pulse or breathing. Cardio-Pulmonary Resuscitation (CPR) chest compressions were started immediately. His skin color returned to nearly normal. After a few minutes, a single bystander came up and said they knew how to do breaths. At that time, recommendations were for intermittent breathing as well as chest compressions. The stricken person made it alive to the EMS vehicle that took nearly 30 minutes to arrive. While I do not know the eventual outcome, I do know he was successfully resuscitated using an Automated External Defibrillator (AED). Furthermore with the quick application of CPR, he likely had a full recovery. Unfortunately, from the crowd response at that time, there were not enough people trained to act in this emergency situation where seconds really count.

Horizontal Saccadic Eye Movements to Visual and Auditory-Visual Double-Step Stimuli: Saccade Characteristics and Neural Input Estimations

Goal-oriented human saccades were recorded under double-step paradigm. The stimuli consisted of either visual or auditory-visual bi-sensory targets. Eye movement data were analyzed based on a 3rd-order linear horizontal saccadic eye movement model,where the inputs to the muscle were agonist and antagonist active-state tensions that were described by pulse-slide-step wave forms with a post inhibitory rebound burst (PIRB) based on a time optimal controller. Parameter estimations were calculated using the system identification technique for saccade parameters and neural inputs. Saccade amplitude transition function (ATF) and response latency indicated the saccade programming mechanism. The responses were affected by when the second peripheral target was presented. 

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Role of In-silico methods in the identification of Novel Drugs

Drug designing and the molecular dynamic studies are lengthy, intensified and inter-disciplinary activity. Approaches like computational chemistry and molecular modeling are widely applied in the development of in-silico drug design because it is cost effective.  Currently, a vast number of software is used in drug design. Using in-silico drug designing techniques it is possible to produce active lead molecule right from the preclinical discovery stage to late stage clinical development. The lead molecules will be helpful in the selection of potent leads to cure particular diseases. In-silico methods thus are important in target identification and prediction of novel drugs.

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Sequence Features and Subset Selection Technique for the Prediction of Protein Trafficking Phenomenon in Eukaryotic Non Membrane Proteins

Protein trafficking or protein sorting is the mechanism by which a cell transports proteins to the appropriate position in the cell or outside of it. This targeting is based on the information contained in the protein. Many methods predict the sub cellular location of proteins in eukaryotes from the sequence information. However, most of these methods use a flat structure to perform prediction. In this work, we introduce ensemble methods to predict locations in the eukaryotic protein-sorting non membrane pathway hierarchically.

We used features that were extracted exclusively from full length protein sequences with feature subset selection for classification. Sequence driven features, sequence mapped features and sequence auto correlation features were tested with ensemble learners and classifier performances were compared with and without feature subset selection technique. This study shows the new features extracted from full length eukaryotic protein sequences are effective at capturing biological features among compartments in eukaryotic non membrane pathways at two levels. Feature subset selection techniques helped to reduce the time taken for building the classification model.

An Ultrasound Based Eye Tracking System

A novel, non-contact ultrasound device is detailed for recording and analyzing 3D fast eye movements (saccades) and smooth pursuit eye movements. Saccades are studied to gain a better understanding of the human oculomotor plant and neuromuscular systems. Abnormal saccades can be indicators of both neurological disorders and mild traumatic brain injury (MTBI). Limitations in existing saccade measurement devices prevent them from being used to measure saccades immediately after a possible MTBI event or easily outside of the clinical environment. 

The device proposed is portable allowing saccade measurements in the field to immediately assess neurological dysfunction associated with MTBI. Ease of use and portability allow collection of data at times and places not possible with devices currently available. This increased database of saccades will expand our knowledge of the relationship between saccades and the neurological functioning of the brain. The focus of this paper is the development of a finite element model to establish a starting point for such a design.

Cytotoxic Effects of Aflatoxin B1 Standard in Relation to Aflatoxin Extracts from South African Compound Feeds on Human Lymphocytes

Cytotoxicity testing of aflatoxin (AF) on the viability of cells grown in cultures can be widely used to predict the potential toxic effects of AF in animals. To this end, an in vitro experimental study was conducted to ascertain the toxic effects of AF extracts obtained from compound feeds in South Africa on human lymphocytes in comparison to that of an AFB1 standard. The approach adopted was on the basis of viable cells reducing methyl tetrazolium bromide (MTT) from blue to a purple formazan dye, which was then spectrophotometrically quantified to provide the rate of cytotoxicity. 

Data obtained indicated no cytotoxic response in control cells, as the viability of cells without treatment with AF standard or methanolic extracts of AF extracts [negative control] using methanol as the reconstituting solvent, was 99.9% after 24 hrs. of incubation. However, cell viability significantly (p<0.001) decreased upon exposure to AF extracts especially for poultry feed. This was influenced by both the dose and duration of exposure, which was much more pronounced when the cells were exposed to AFB1 standard than for all the AF extracts tested. This implies that these feeds on exposure to AF can greatly influence animal health with respect to both the contamination dose and exposure time.

Bioengineered Cranial Bones with Multiple Intelligent Functions for the Effective Treatment of Currently Intractable Brain Disorders: Prospects and Challenges

Many neurological and psychiatric disorders with predominantly cerebral cortical pathology, including most severe strokes, traumatic brain injuries, malignant brain tumors, intractable focal epilepsies and dementias such as Alzheimer’s disease are currently difficult, if not impossible, to treat. This causes suffering in almost 100 million people worldwide. 

We propose that bioengineered cranial bones with multiple intelligent functions, including site specific Tran’s meningeal drug delivery and neurotoxin drainage with EEG feedback, can provide effective treatment of these brain disorders by drug combinations that act on both synapses and genes with concomitant selective drainage of harmful extracellular molecules. After examining and summarizing the rationale and feasibility of this proposal, we suggest novel methods for extending the functions of the involved components including synergies with existing devices and we highlight relevant pre clinical results, discussing medical prospects of this novel neuro therapeutic approach. Finally, we discuss key engineering, scientific, clinical and ethical challenges to introducing bio engineered cranial bones with multiple intelligent functions to the clinic within a decade. 

Intraductal Carcinoma of the Prostate Diagnosed by Multi-Parametric Prostate Magnetic Resonance Imaging (MRI) and MRI/Ultrasound Fusion-Guided Biopsy

Although, the term “intraductal carcinoma of the prostate” (IDC-P) was first used by Rhamy, McNeak and Yemoto, were the first to delineate IDC-P as a distinct biological entity with definable histological and clinical features. IDC-P is defined as aproliferation of malignant prostate adeno carcinoma cells distending or completely spanning the lumen of pre-existing prostatic ducts and acini, with at least focal preservation of basal cells. Watts et al. estimated the incidence of IDC-P to 2.8% in prostate biopsies.

Histological criteria for the diagnosis of IDC-P include solid; dense cribriform (>50% cellularity of the lumen); trabecular/micropapillary; and loose cribriform intraductal proliferation of malignant cells. The latter two growth patterns share much similarity with HGPIN. In these instances, additional diagnostic criteria, such as marked nuclear pleomorphism (nuclear enlargement > 6x normal nuclei), and nonfocal comedonecrosis (> 1 duct showing comedonecrosis) are criteria needed to differentiate it from HGPIN.

Preliminary Evaluation of the Effects of Cold Atmospheric Plasma Application Rate on the Proliferation Behavior of Keratinocytes in Vitro Measured Using CK-5, CK-10, CK-14, Ki-67 and p53 Expression

Tissue tolerable plasma has been used in preclinical and more recently in clinical settings for the debridement of dead tissue and the removal of bacterial biofilms. Cold plasma therapy is an emerging field in medical sciences; it is mainly due to the beneficial effects that low temperature plasma has demonstrated: anti-inflammatory, ant tumorigenic and anti-microbial effects. 

The advantage of cold plasma therapy over conventional thermal plasma treatments, arc coagulators and desiccators, is that it allows for more precise application and therefore more controllable effects on the tissue. Additionally, cold plasma treatment showed stimulatory effects on wound healing and tissue regeneration. Experiments show that cold atmospheric plasma treatment allows for efficient, non-contact, painless, and antiseptic effects without damaging healthy tissue. As a result of the better understanding of complex plasma phenomena and the development of new plasma sources in the past few years, plasma medicine has developed into an innovative and promising field of research.

Editorial for International Journal of biomedical Data Mining

This issue of the International Journal of Biomedical Data Mining presents two contributed articles. The first article, entitled Data Inventory for Cancer Patients Receiving Radiotherapy for Outcome Analysis and Modeling, authored by Jason Vickress, Rob Barnett and Slav Yartsev, describes a database created for storing and analyzing patient specific data related to pre-treatment condition, treatment planning, and treatment outcomes, for patients receiving radiotherapy based cancer treatment. 

The proposed database can perform automated analysis regarding quality assurance, dose accumulation for multiple treatments on different machines and can assist physicians in choosing the optimal radiation therapy for new patients. The second article, entitled Likelihood Ratio Test of Hardy-Weinberg Equilibrium Using Uncertain Genotypes for Sibship Data, authored by Qiong Li, Helene Massam and Xin Gao, is concerned with the problem of testing for Hardy-Weinberg equilibrium of genotype frequencies in the area of population genetics.

Are Kinematic and Kinetic Analyses Useful to Evaluate Patellofemoral Disorders in the Clinical Practice?

Current methods for the assessment of the outcome after anterior knee pain or lateral patellar instability treatment have several limitations, for example their subjectivity. Therefore, new technologies are needed to objectively evaluate the outcomes of treatments for patellofemoral disorders. 

Kinematic and kinetic analyses during dynamic activities under realistic loading conditions that trigger or aggravate the symptoms can: evaluate the patellofemoral patient in an objective way before surgery; analyse the defense mechanisms the patient develops in order to reduce pain and/or instability; improve our knowledge of the aetiopathogeny and therefore of a suitable treatment for patellofemoral disorders; and objectively evaluate the result of the treatment. However, the kinetic and kinematic analyses are not diagnostic tools.

Likelihood Ratio Test of Hardy-Weinberg Equilibrium Using Uncertain Genotypes for Sibship Data

Testing for Hardy-Weinberg equilibrium of genotype frequencies is a crucial first step in the study of population genetics. In this paper, we develop an Expectation-Maximization algorithm to estimate the genotype frequencies for sibship data with genotype uncertainty. We also develop a likelihood ratio test of Hardy-Weinberg equilibrium for sibships with no parental genotypes available and with possible genotyping errors. Simulations show that our likelihood ratio test maintains valid control of the type I error rate and good statistical power. Finally, the likelihood ratio test is extended across strata when a sample is stratified by multiple ethnic populations with different genotype frequencies.

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Data Inventory for Cancer Patients Receiving Radiotherapy for Outcome Analysis and Modeling

Data collection for cancer patients is recognized as an important task in the USA, where the National Program of Cancer Registries (NPCR) administered by the Centers for Disease Control and Prevention collects data on the occurrence, type, extent, and location of the cancer, and the type of initial treatment. The International Consortium for Health Outcomes Measurements (ICHOM) aims at providing a global resource of in-use outcome measures and risk adjustment factors by medical condition and creating a global standard for measuring results. 

These initiatives will enable public health professionals to understand and address the cancer burden more effectively. We have recently proposed to use the pre-treatment, planning, and treatment outcomes data for cancer patients undergoing radiation therapy to provide guidelines for optimal choice of both radiation modality and planning for new patients. It is important to determine the most influential patient features (or their combinations) that has the strongest correlation with the outcomes. We propose an Overlap Volume Histogram as a valuable representation of size and shape for tumor and organs at risk important for planning.

Identification of Double-Step Saccades from Auditory Double-Step Stimuli is useful to guide the future stimulus designs

Voluntary Saccadic eye movements exhibit visual, auditory, and auditory-visual bisensory origins. The study that tried to examine how changing the type of sensory inputs reveals the type of saccade the oculo motor system release; whether single step or double stepped. 

The double-step auditory stimuli designed for human triggered saccadic eye movements, detecting each saccade and estimated the saccade response characteristics, namely duration and latency. Based on the latency, it is possible to determine the type of saccade generated by the subject through a clustering technique. While keeping their duration unchanged, the number of double-step saccades rises. The hindsight from this finding is useful to guide the future stimulus designs to trigger specific saccade types in humans. It demystifies the nature of dominant saccadic response as we explore the changes of sounds in any controlled environment.

Analytic Formulas for the Clinical Issues of a UV-Light-Activated Corneal Crosslinking Device

Modeling the critical issues of the dynamics of UV-light-initiated crosslinking of corneal collagen including the new safety criteria, crosslinking time and the efficacy. A coupled dynamic equations is numerically solved and analytic formulas are derived for three critical parameters: the safety dose (E*), the cross linking time (T*) and the efficacy defined by the increase of corneal stiffness (S). The critical issues of corneal crosslinking is explored by nine parameters: the three extinction coefficients, concentration and diffusion depth of the riboflavin solution, the UV light dose, irradiation duration, the cytotoxic energy threshold of endothelial cells and the corneal thickness.

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A Similarity Retrieval Tool for Functional Magnetic Resonance Imaging Statistical Maps

A fundamental goal in functional neuroimaging is to identify areas of activation in the brain relative to a given task. Functional magnetic resonance imaging (fMRI) is one technique used to identify such changes because changes in neuronal activity along a given region of the brain can be captured by a corresponding change in voxel value intensity on the acquired fMRI image. Statistical parametric mapping (SPM) [13] is the current popular technique used to analyze fMRI images. An SPM image contains test statistics determined at each pixel by the ratio between the intensity of the signal and its variance across experimental conditions.