In-vivo Human Studies Research Articles

Adrenaline Auto-Injectors for Preventing Fatal Anaphylaxis.

Anaphylaxis affects up to 5% of people during their lifetime. Although anaphylaxis usually resolves without long-term physical consequences, it can result in anxiety and quality of life impairment. Rarely and unpredictably, community anaphylaxis can cause rapid physiological decompensation and death. Adrenaline (epinephrine) is the cornerstone of anaphylaxis treatment, and provision of adrenaline autoinjectors (AAI) has become a standard of care for people at risk of anaphylaxis in the community. In this article, we explore the effectiveness of AAIs for preventing fatal outcomes in anaphylaxis, using information drawn from animal and human invivo studies and epidemiology. We find that data support the effectiveness of intravenous adrenaline infusions for reversing physiological features of anaphylaxis, typically at doses from 0.05 to 0.5 μg/kg/min for 1-2 h, or ~ 10 μg/kg total dose. Intramuscular injection of doses approximating 10 μg/kg in humans can result in similar peak plasma adrenaline levels to intravenous infusions, at 100-500 pg/mL. However, these levels are typically short-lived following intramuscular adrenaline, and pharmacokinetic and pharmacodynamic outcomes can be unpredictable. Epidemiological data do not support an association between increasing AAI prescriptions and reduced fatal anaphylaxis, although carriage and activation rates remain low. Taken together, these data suggest that current AAIs have little impact on rates of fatal anaphylaxis, perhaps due to a lack of sustained and sufficient plasma adrenaline concentration. Effects of AAI prescription on quality of life may be variable. There is a need to consider alternatives, which can safely deliver a sustained adrenaline infusion via an appropriate route.

Detection of microplastics in human tissues and organs: A scoping review.

Research on microplastics has largely focused on the environment and marine organisms until recently. A growing body of evidence has detected microplastics in human organs and tissues, with their exact entry routes being unclear and their potential health effects remain unknown. This scoping review aimed to characterise microplastics in human tissues and organs, examine their entry routes and addressing gaps in research analytical techniques. Eligibility criteria included English language full text articles, in-vivo human studies only, and searching the databases using pre-defined terms. We based our analysis and reporting on the PRISMA guideline and examined the quality of evidence using the risk of bias assessment tool. Of 3616 articles screened, 223 evaluated and 26 were eventually included in this review. Nine were high risk for bias, three were unclear risk and the rest low risk for bias. Microplastics were detected in 8/12 human organ systems including cardiovascular, digestive, endocrine, integumentary, lymphatic, respiratory, reproductive and urinary. Microplastics were also observed in other human biological samples such as breastmilk, meconium, semen, stool, sputum and urine. Microplastics can be characterised based on shape, colours, and polymer type. Potential entry routes into human included atmospheric inhalation and ingestion through food and water. The extraction techniques for analysis of microplastics in human tissues vary significantly, each offering distinct advantages and limitations. Microplastics are commonly detected in human tissues and organs, with distinct characteristics and entry routes, and variable analytical techniques exist.

Measurement of Wall Shear Rate Across the Entire Vascular Wall Using Ultrasound Speckle Decorrelation

ObjectiveThe accurate measurement of the wall shear rate (WSR) plays a crucial role in the early diagnosis of cardiovascular disease progression and acute events such as aneurysms and atherosclerotic plaque ruptures. To address this need, the speckle decorrelation (SDC) technique has been used to measure WSR based on the 2-D out-of-plane blood flow speed. This technique is particularly advantageous because it enables the use of a 1-D array transducer to measure WSR over the entire luminal area. This study aims to develop a region-based singular value decomposition (SVD) filtering technique that selectively suppresses clutter noise in the vascular region to measure WSR using SDC. MethodUltrasound simulations, in-vitro flow experiments, and an in-vivo human study were conducted to evaluate the feasibility of this method's clinical application. ResultsThe results demonstrated that WSR can be effectively measured across entire vascular walls using a conventional 1-D array transducer along with the proposed methodology. ConclusionThis study successfully demonstrates a noninvasive and accurate SDC-based method for measuring vital vascular WSR. This approach holds significant promise for assessing vascular WSR in both healthy individuals and high-risk cardiovascular disease patients.

Applicability of Gene Expression in Saliva as an Alternative to Blood for Biodosimetry and Prediction of Radiation-induced Health Effects.

As the great majority of gene expression (GE) biodosimetry studies have been performed using blood as the preferred source of tissue, searching for simple and less-invasive sampling methods is important when considering biodosimetry approaches. Knowing that whole saliva contains an ultrafiltrate of blood and white blood cells, it is expected that the findings in blood can also be found in saliva. This human invivo study aims to examine radiation-induced GE changes in saliva for biodosimetry purposes and to predict radiation-induced disease, which is yet poorly characterized. Furthermore, we examined whether transcriptional biomarkers in blood can also be found equivalently in saliva. Saliva and blood samples were collected in parallel from radiotherapy (RT) treated patients who suffered from head and neck cancer (n = 8) undergoing fractioned partial-body irradiations (1.8 Gy/fraction and 50-70 Gy total dose). Samples were taken 12-24 h before first irradiation and ideally 24 and 48 h, as well as 5 weeks after radiotherapy onset. Due to the low quality and quantity of isolated RNA samples from one patient, they had to be excluded from further analysis, leaving a total of 24 saliva and 24 blood samples from 7 patients eligible for analysis. Using qRT-PCR, 18S rRNA and 16S rRNA (the ratio being a surrogate for the relative human RNA/bacterial burden), four housekeeping genes and nine mRNAs previously identified as radiation responsive in blood-based studies were detected. Significant GE associations with absorbed dose were found for five genes and after the 2nd radiotherapy fraction, shown by, e.g., the increase of CDKN1A (2.0 fold, P = 0.017) and FDXR (1.9 fold increased, P = 0.002). After the 25th radiotherapy fraction, however, all four genes (FDXR, DDB2, POU2AF1, WNT3) predicting ARS (acute radiation syndrome) severity, as well as further genes (including CCNG1 [median-fold change (FC) = 0.3, P = 0.013], and GADD45A (median-FC = 0.3, P = 0.031)) appeared significantly downregulated (FC = 0.3, P = 0.01-0.03). A significant association of CCNG1, POU2AF1, HPRT1, and WNT3 (P = 0.006-0.04) with acute or late radiotoxicity could be shown before the onset of these clinical outcomes. In an established set of four genes predicting acute health effects in blood, the response in saliva samples was similar to the expected up- (FDXR, DDB2) or downregulation (POU2AF1, WNT3) in blood for up to 71% of the measurements. Comparing GE responses (PHPT1, CCNG1, CDKN1A, GADD45A, SESN1) in saliva and blood samples, there was a significant linear association between saliva and blood response of CDKN1A (R2 = 0.60, P = 0.0004). However, the GE pattern of other genes differed between saliva and blood. In summary, the current human invivo study, (I) reveals significant radiation-induced GE associations of five transcriptional biomarkers in salivary samples, (II) suggests genes predicting diverse clinical outcomes such as acute and late radiotoxicity as well as ARS severity, and (III) supports the view that blood-based GE response can be reflected in saliva samples, indicating that saliva is a "mirror of the body" for certain but not all genes and, thus, studies for each gene of interest in blood are required for saliva.

Implications and Mechanisms of Antiviral Effects of Lactic Acid Bacteria: A Systematic Review.

Lactic acid bacteria (LAB) are among the most important strains of probiotics. Some are normal flora of human mucous membranes in the gastrointestinal system, skin, urinary tract, and genitalia. There is evidence suggesting that LAB has an antiviral effect on viral infections. However, these studies are still controversial; a systematic review was conducted to evaluate the antiviral effects of LAB on viral infections. The systematic search was conducted until the end of December 17, 2022, using international databases such as Scopus, Web of Science, and Medline (via PubMed). The keywords of our search were lactic acid bacteria, Lactobacillales, Lactobacillus (as well as its species), probiotics, antiviral, inhibitory effect, and virus. Of 15.408 potentially relevant articles obtained, 45 eligible in-vivo human studies were selected for inclusion in the study from databases, registers, and citation searching. We conducted a systematic review of the antiviral effects of the LAB based on the included articles. The most commonly investigated lactobacillus specie were Lactobacillus rhamnosus GG and Lactobacillus casei. Our study indicates that 40 of the selected 45 of the included articles support the positive effect of LAB on viral infections, although some studies showed no significant positive effect of LABs on some viral infections.

Effects of long-pulsed 1064-nm Nd:YAG laser on telangiectasias and reticular veins: a human in-vivo histological study.

Telangiectasias and reticular veins are associated with aesthetic disorders. Sclerotherapy is the gold standard treatment, but long-pulsed 1064-nm Nd:YAG laser (LP1064 laser) is also used. No data on the human histological effects of these lasers are reported. The objective was to test different LP1064 laser parameters and their histological effects on the dermis, collagen, telangiectasias, and reticular veins. This was a single-center, prospective, single-arm, case-control, human study. During surgery (dermolipectomy), the abdominal section of 10 female patients was irradiated with 6 different transdermal LP1064 laser parameters after anesthesia. Ten pieces with areas of varying irradiation were evaluated according to the characteristics of the vessels identified by area. In each piece, two irradiation areas were performed per group, totaling 12 irradiation areas per piece, with 120 regions later analyzed at the end of the ten samples. After removing the surgical product, histological sections were extracted, and the dermis, telangiectasias, and reticular veins were analyzed. Histological analysis showed that exposition to six different parameters from LP1064 laser led to significant dermal layer separation and collagen alterations. The effects were inconsistent on the loss of endothelial cells, intravascular thrombus formation, and fusion of vascular walls for both telangiectasias and reticular veins. In reticular veins, effects on intravascular thrombus formation and vascular wall fusion were not observed. The LP1064 laser in monotherapy with fixed settings did not lead to a consistent vascular lesion to promote immediate occlusion in telangiectasias and reticular veins. This strategy may not work as monotherapy for small vein treatment, but the possible late response to the LP1064 laser cannot be ruled out and require further investigation.

Anorexia Nervosa in vivo cytokine production: a systematic review

IntroductionThe underlying psychobiology that contributes to Anorexia Nervosa (AN) onset and disease progression remains unclear. New research is emerging suggesting a possible link between inflammation and a variety of mental illnesses. Alterations of cytokines may play a role in the pathogenesis of AN. Some studies have found differences in the cytokine profile of those with AN compared to healthy controls, but results are heterogeneous. The aim of this work was to systematically review existing studies investigating in-vivo cytokine production in those with AN before and after weight restoration compared to controls. MethodsA comprehensive literature search of four electronic databases (PubMed, PsychInfo, EMBASE and CINAH) was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to identify human in-vivo studies investigating the relationship between AN and cytokine production. Data extracted from included studies related to population characteristics (e.g. age, gender, mean mBMI/%IBW), cytokine measurement and relevant findings. Confounding factors (e.g. smoking status, co-morbid mental illness, menstruation status) were also collected. Results36 studies were eligible for this systematic review of which the majority were conducted in Europe (77.8%) and involved female subjects (97.2%). Those with AN ranged in age from 13 to 47 years and had an illness duration of 3 months to 24 years. 15 candidate cytokines and 3 receptors were identified (TNF-alpha, IL-6, IL-1B, CRP, IL-2, IL-7, IL-10, IFN-γ, TNF-R2, IL-1 α, IL-15, TNF-R1, IL-17, IL-18, TGF-B1, IL-12, IL-6R and TGF-B2) exploring in-vivo levels in patients with AN and comparing to controls. TNF-alpha and IL-6 were the most extensively studied with IL-6 being significantly elevated in 4 out of 8 (50%) of longitudinal studies when comparing AN patients at baseline compared to post weight restoration. Following weight restoration, there was no difference in IL-6 levels when comparing to HC in 7 of 8 (87.5%) longitudinal studies examined. ConclusionsThe most promising cytokine potentially involved in the pathogenesis of AN appears to be IL-6, and possibly TNF-alpha pathways. The heterogeneity of clinical and methodology factors impedes the generalizability of results. Future studies may wish to address these methodological shortcomings as alterations in cytokine levels in AN could act as therapeutic targets assisting with weight restoration and psychopathology and may offer diagnostic potential.

Encapsulation of alpha arbutin, a depigmenting agent, in nanosized ethosomes: Invitro and invivo human studies

Alpha arbutin is a skin-whitening agent in cosmetics. Structurally, it is 4-hydroxyphenyl-α-glucopyranoside. Ethosomes encourage the formation of lamellar-shaped vesicles with improved solubility and entrapment of whitening agents. The objective of this study was to fabricate an optimized nanostructured ethosomal gel loaded with alpha arbutin for the treatment of skin pigmentation.Different ethosomal suspensions of alpha arbutin were prepared by the cold method. Invitro evaluation included zeta potential, droplet size analysis, polydispersity index, entrapment efficiency (EE), scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Stability studies of the optimized ethosomal and control gels were performed for three months under different temperature conditions. The optimized ethosomal gel loaded with alpha arbutin was further analyzed on human volunteers for skin benefits by measuring melanin level, moisture content and elasticity.It was concluded that the optimized formulation had a size, zeta potential, polydispersity index and entrapment efficiency of 196.87 nm, −45.140 mV, 0.217 and 93.458343%, respectively. Scanning electron microscopy (SEM) depicted spherical ethosomal vesicles. Stability data was obtained in terms of pH and conductivity. Rheological analysis revealed non-Newtonian flow. The cumulative drug permeated for ethosomal gel was 78.4%. Moreover, encapsulation of alpha arbutin causes significant improvement in skin melanin, moisture content and elasticity.The overall findings suggested that the arbutin-loaded ethosomal formulation was stable and could be a better approach than conventional formulation for cosmeceutical purposes such as for depigmentation and moisturizing effects.

Comparison between different approaches to evaluate fibrous cap thickness in sequential optical coherence tomography studies.

In this in-vivo human study we tested the reproducibility for optical coherence tomography (OCT) assessment of lumen area (LA) and plaque components measurements, such as lipid arc extension and fibrous cap thickness (FCt). We tested the variability of LA, lipid arc and FCt assessments in two repeated OCT pullbacks from the same diseased coronary segment matched using fiduciary anatomical landmarks. In particular, for the reliability of minimal FCt measurement we compared four different approaches based on continuous (longitudinal) or segmental (spot) individuation of smaller thickness: 1) comparison of single minimal FCt individuated alongside all plaque extension in the two pullbacks (Longitudinal (L)-spot minimal FCt value); 2) comparison of the mean FCt values of the plaque in the two pullbacks (L-plot mean FCt value); 3) comparison between the single minimal FCt value obtained in the first pullback and the single FCt obtained in the matched CS of second pullback (L-spot CS matched FCt value); 4) comparison of measurements obtained by visual selection of CS with minimal FCt s in the two pullbacks (single-spot minimal FCt value). From the paired analyses of 20 non culprit lesions (accounting for a total of 387 matched CS), we found a suboptimal in-segment correlation for LA (Intra-Class Coefficient [ICC] 0.731), but a good in-segment correlation for lipid arc (ICC 0.963). Regarding FCt measurement, a high reproducibility was obtained applying continuous assessment; in particular, the best correlation was observed with L-spot minimal FCt value and the L-plot mean FCt (ICC 0.893 and 0.952, respectively) with small inter-pullback differences (confidence intervals less than 0.04 mm). In this methodological study we observed a good reproducibility for quantitative plaque measurements with OCT confirming its reliability for serial assessment. In particular, longitudinal measurement in multiple adjacent frames seems to be the more accurate and reproducible approach for sequential FCt assessment.

Boosting NAD blunts T H17 inflammation via arginine biosynthesis and redox regulatory control in healthy control and psoriasis human subjects

Abstract Although NAD +levels modulate metabolism, how this regulates immunometabolism/inflammation remains unclear. Employing Nicotinamide Riboside (NR) to boost NAD, we explored T H17-linked inflammatory in Psoriasis. Primary Psoriasis CD4 +T cells exposed to NR reduced IL-17 secretion and RNA-seq/pathway analysis implicated NR in modulating sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. In parallel, NR reduced CD4 +T cell reactive oxygen species (ROS) levels and activated the NRF2 transcription factor. Depletion of NRF2 or SQSTM1 diminished NR effects on ROS and T H17 activation. Metabolomic analysis implicated NR in arginine biosynthesis and L-arginine replicated NR CD4 +T cell effects. Genetic disruption of the argininosuccinate lyase synthesis enzyme ameliorated NR antiinflammatory effects, supporting that NR, via arginine biosynthesis orchestrates NRF2 activation, CD4 +T cell antioxidant defenses and blunted T H17 responsiveness. A pilot in-vivo human study similarly showed that NR increased arginine, antioxidant enzyme gene expression and blunted T H17 regulation, implicating NAD metabolism in CD4 +T cell-linked inflammation. NHLBI Division of Intramural Research (MNS – ZIA-HL005102), NIH Bench to Bedside award (MNS and RT, HL-129510-04S1) and the NIH Office of Dietary Supplementation (JT) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAP UK).

Design and Evaluation of Gastroretentive Multiple Units of Dipyridamole: in-vitro and in-vivo human studies

Objective: The pH dependent solubility of Dipyridamole was made to select as a model drug for the formulation of gastroretentive drug delivery system. Dipyridamole is highly soluble in acidic pH and as the pH increases the solubility of the drug decreases. The study was planned to formulate, characterize with in-vitro and in-vivo evaluation in human volunteers.
 Method: In this study floating mini matrix tablets of Dipyridamole was formulated using HPMC grade polymers by wet granulation method and prepared multiple units equivalent to one dose were filled in one 000 size empty gelatin capsule. The prepared multiple units were subjected to physical evaluation, in-vitro drug release, and stability studies as per ICH guidelines. The in-vivo radiographic studies were conducted for determining the residence time of dosage form in human subjects.
 Results: All the prepared batches showed good physical properties and in-vitro buoyancy. The optimized FD7 formulation remained buoyant for more than 12 h with drug release of more than 90% in 12 h. The drug release kinetics for optimized formulation FD7 followed a first order kinetics with non fickian mechanism. Formulation FD7 was selected as the best formulation based on the in-vitro characteristics and subjected for stability and in-vivo radiographic studies. These studies revealed that the multiple units were stable during the stability period and remained in the stomach for upto 6 h in human subjects.
 Conclusion: Based on in-vitro characteristics and in-vivo radiographic studies, formulation FD7 was concluded as the best formulation among others. Due to increase in gastric retention time, by choosing floating mini matrix tablets we can improve patient compliance and ensure better disease management.
 Keywords: Dipyridamole, Mini matrix tablets, In-vitro buoyancy, Stability studies Radiographic Studies

Early transcriptional responses of bronchial epithelial cells to whole cigarette smoke mirror those of in-vivo exposed human bronchial mucosa

BackgroundDespite the well-known detrimental effects of cigarette smoke (CS), little is known about the complex gene expression dynamics in the early stages after exposure. This study aims to investigate early transcriptomic responses following CS exposure of airway epithelial cells in culture and compare these to those found in human CS exposure studies.MethodsPrimary bronchial epithelial cells (PBEC) were differentiated at the air–liquid interface (ALI) and exposed to whole CS. Bulk RNA-sequencing was performed at 1 h, 4 h, and 24 h hereafter, followed by differential gene expression analysis. Results were additionally compared to data retrieved from human CS studies.ResultsALI-PBEC gene expression in response to CS was most significantly changed at 4 h after exposure. Early transcriptomic changes (1 h, 4 h post CS exposure) were related to oxidative stress, xenobiotic metabolism, higher expression of immediate early genes and pro-inflammatory pathways (i.e., Nrf2, AP-1, AhR). At 24 h, ferroptosis-associated genes were significantly increased, whereas PRKN, involved in removing dysfunctional mitochondria, was downregulated. Importantly, the transcriptome dynamics of the current study mirrored in-vivo human studies of acute CS exposure, chronic smokers, and inversely mirrored smoking cessation.ConclusionThese findings show that early after CS exposure xenobiotic metabolism and pro-inflammatory pathways were activated, followed by activation of the ferroptosis-related cell death pathway. Moreover, significant overlap between these transcriptomic responses in the in-vitro model and human in-vivo studies was found, with an early response of ciliated cells. These results provide validation for the use of ALI-PBEC cultures to study the human lung epithelial response to inhaled toxicants.

Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders

Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

ASSESSMENT OF CAROTID INTRAPLAQUE HEMORRAGE BY PHOTOACUSTICS IMAGING (PAI) IN PATIENTS UNDERGOING TROMBOENDOARTERIECTOMY: FIRST IN-VIVO HUMAN VALIDATION STUDY

Objective: The aim of the study is the validation of a portable multimodal photoacoustic imaging (PAI) system, for the identification of intraplaque haemorrhage and compare with MRI and histology (gold standard). Design and method: 25 patients with carotid stenosis>70% and clinical indication to tromboendoarterectomy were recruited. Angio-MRI for intraplaque hemorrhage assessment (Cube sequence) was performed. PAI clips (5 seconds, Frame rate 1000/sec) were acquired. Each clip was scored for the presence of PAI signal by means of an integrated scoring system (semiquantitative, from 0 to 12). Semiquantitative grading scales were used to assess plaque histological features of hemorrage and vulnerability. Results: 18 patients had no missing MRI, PAI and histology data and were included in this analysis. Mean age was 73 ± 8 years, 60% men, 80% Caucasians, 92% hypertensives, 60% with a previous stroke. Only 3 plaques out of 21 showed no signs of intraplaque hemorrhage, 4 showed small hemorrage, while 14 (67%) showed large hemorrhages. PAI score (best cut-off >4) correctly classified 14 out of 18 patients (Sensitivity 73.3%, specificity 100%, AUC 0.867). MRI performance was substantially similar (Sensitivity 60%, specificity 100%, AUC 0.800, 12 patients correctly classified), with a non-significant difference in AUC compared to PAI (p = 0.420). Conclusions: In this first in-vivo human study, PAI is able to identify histological intraplaque hemorrhage with an excellent specificity and acceptable sensitivity, equivalent to MRI. The very high specificity, with a low number of false positives, make PAI a good candidate for evaluation of plaques prior to surgery to i.e. reinforce the decision to perform surgery.

Is HPV the Novel Target in Male Idiopathic Infertility? A Systematic Review of the Literature.

Infertility is an important health problem that affects up to 16% of couples worldwide. Male infertility is responsible for about 50% of the cases, and the various causes of male infertility may be classified in pre-testicular (for example hypothalamic diseases), testicular, and post-testicular (for example obstructive pathologies of seminal ducts) causes. Sexually transmitted infections (STI) are increasingly widely accepted by researchers and clinicians as etiological factors of male infertility. In particular, several recent reports have documented the presence of HPV in seminal fluid and observed that sperm infection can also be present in sexually active asymptomatic male and infertile patients. In this review, we aimed to perform a systematic review of the whole body of literature exploring the impact of HPV infection in natural and assisted fertility outcomes, from both an experimental and a clinical point of view. Starting from in-vitro studies in animals up to in-vivo studies in humans, we aimed to study and evaluate the weight of this infection as a possible cause of idiopathic infertility in males with any known cause of conception failure.

Novel Trends in Drug Delivery and Application of Curcumin in Dentistry

The frequent use and misuse of the currently used therapeutic agents have led to the evolution of resistantstrains of common pathogens as well as increased incidence of adverse effects associated with their usage.Hence, the search for phytochemicals isolated from plants is considered as a good alternative source. Theminimum number of plant species worldwide has been phytochemically investigated until date, there isa great potential for discovering novel bioactive compounds and drugs. The design and development ofherbal nanoparticles have become frontier research in the nanoformulation arena. Curcumin, a hydrophobicpolyphenol (diferuloylmethane) is a potent Phyto molecule obtained from turmeric (Curcuma longa, FamilyZingiberaceae) has a wide range of biological activities in chronic diseases and a large number of in-vitroand invivo studies in both humans and animals reported that curcumin has provoked properties like antiinflammatory, antioxidant, antimicrobial, antiseptic, antimutagenic, hepatoprotective and immunostimulant.Due to these properties, it is quite useful in dentistry. It has a role in the treatment of periodontal diseasesand oral cancers. But the clinical application of curcumin was limited due to its poor oral bioavailability,which may result from its poor water solubility, its poor pharmacokinetic profile, rapid metabolism, andrapid elimination which ultimately results in poor bioavailability upon oral administration. Therefore theintroduction of novel drug delivery technologies gained the importance to achieve modified delivery ofherbal drugs by increasing the therapeutic value and provides a solution towards increased bioavailabilityof curcumin. However, there is a scarcity of research and information in this field and much work is neededto further investigate the pharmacokinetics, enhance the delivery at the target tissue, the bioavailability, andthe medicinal value of curcumin. In this review, various nanoparticles, micellar formulations, cyclodextrininclusion compounds, and liposomes have been reported in order to improve the bioavailability, solubility,and efficacy of curcumin.

Subacromial bursal preservation can enhance rotator cuff tendon regeneration: a comparative rat supraspinatus tendon defect model study

The role of subacromial bursa in rotator cuff surgery is unknown. This study aimed to assess the subacromial bursa's role in the healing of supraspinatus tendon injury in a rat model. Twenty-three male Sprague-Dawley rats (9 weeks old; weight, approximately 296 g) were used in this study. Three rats used as biomechanical study controls were killed at 12 weeks of age. A supraspinatus tendon defect was made bilaterally in 20 rats, whereas an additional subacromial bursa sectioning was performed on the left side. Six rats were killed for biomechanical testing and 4 were killed for histologic observation at 3 and 9 weeks, respectively. The regenerated tendon in the bursal preservation group showed significantly superior biomechanical properties in maximum load to failure at 3 and 9 weeks and stiffness at 9 weeks after surgery compared with the bursal removal group. The modified Bonar scale scores showed better regenerated supraspinatus tendons in the bursal preservation group. The present study found that the subacromial bursa plays an important role in rotator cuff regeneration in this rat supraspinatus injury model. Extensive bursectomy of the subacromial bursa may not be recommended in rotator cuff repair surgery, though future invivo human studies are needed to confirm these observations.

First in-human study of in vivo imaging of ex vivo labeled CAR T cells with dual PET-MR.

3557 Background: This is a first in human in-vivo biodistribution of ex-vivo labelled CAR T cells assessed in a cohort of patients. Cells were labelled with novel Cu-64 labelled superparamagnetic iron oxide nanoparticles (SPION) and infused IV into patients with solid tumors & tracked using clinical dual PET-MR. The study validates the clinical translation of CAR T cell in-vivo tracking in real time. Methods: Cu-64 radioisotope was bound to silica coated SPION using electrolysis plating with tin & palladium seeding. Cellular uptake of Cu-64 SPION was facilitated with a transfecting agent. Functional assays including 51Chromium release, cytometric bead array demonstrated that labelling process did not affect cytotoxicity & cytokine secretion (TNFα & IFN-g). T cells were transduced with retroviral vector constructs encoding for second-generation chimeric T-cell receptor specific for carbohydrate Lewis Y antigen. Modified T-cells were expanded ex-vivo & were labelled with Cu-64 (~300 MBq) prior to re-infusion (3 x108 labelled cells). Scanning is performed with Siemens 3T dual PET-MR scanner. Results: In this first in human in-vivo study (HREC/16/PMCC/30) a cohort of patients received ex-vivo labelled CAR T cells to determine how many labelled cells distribute to solid tumor sites within 3-5 days. Our results demonstrate that cells can be efficiently labelled (≤60%) with high cell viability (≥85%) at a sensitivity sufficient to detect labelled cells at tumor site for up to 5 days. An observed trend in SUVmean & SUVmax provided insight into efficacy & individual response to therapy. Early time points showed moderate uptake of labelled cells in lungs posterior basal segments without increased activity over next few days, suggesting a transient process. Mild, diffuse bone marrow & relatively intense uptake of labelled cells in liver & spleen suggests margination of cells to reticulo-endothelial system. Distinct PET signal at some of the tumor sites at 24 h suggests antigen specific localization & time taken to reach these sites. Excretion via hepatobiliary indicated reabsorption from GI tract & re-circulation of labelled cells. Minimal uptake in brain & heart supported safety profile of labeling agent. Conclusions: This is first in human in-vivo study to provide highly valuable visual and dynamic data in real time and provides insight into individual responses to therapy. CAR T cell functionality largely remain unchanged due to labeling process. The findings indicate that labelled cells traffic to tumor sites at later time points & remain persistent for extended period of time.

First in Human Study of In-vivo Imaging of Ex-Vivo Labelled CAR T Cells with Dual PET-MR

Background & Aim This is a first in human in-vivo biodistribution of ex-vivo labelled CAR T cells assessed in a cohort of patients. Cells were labelled with novel Cu-64 labelled superparamagnetic iron oxide nanoparticles (SPION) and infused IV into patients with solid tumors & tracked using clinical dual PET-MR. The study validates the clinical translation of CAR T cell in-vivo tracking in real time. Methods, Results & Conclusion Methods Cu-64 radioisotope was bound to silica coated SPION using electrolysis plating with tin & palladium seeding. Cellular uptake of Cu-64 SPION was facilitated with a transfecting agent. Functional assays including 51Chromium release, cytometric bead array demonstrated that labelling process did not affect cytotoxicity & cytokine secretion (TNFα & IFN-g). T cells were transduced with retroviral vector constructs encoding for second-generation chimeric T-cell receptor specific for carbohydrate Lewis Y antigen. Modified T-cells were expanded ex-vivo & were labelled with Cu-64 (∼300 MBq) prior to re-infusion (3 × 108 labelled cells). Scanning is performed with Siemens 3T dual PET-MR scanner. Results In this first in human in-vivo study (HREC/16/PMCC/30) a cohort of patients received ex-vivo labelled CAR T cells to determine how many labelled cells distribute to various body organs and lesions within first 3-5 days. Our results demonstrate that both fresh (N =3) and thawed cells (N =3) can be efficiently labelled in the range of 40% - 80% with high cell viability (≥90%). An observed trend in SUVmean provided insight into efficacy & individual response to therapy. Early time points showed moderate uptake of labelled cells in lungs posterior basal segments without increased activity over next few days, suggesting a transient process. Mild, diffuse bone marrow & relatively intense uptake of labelled cells in liver & spleen suggests margination of cells to reticulo-endothelial system. Excretion via hepatobiliary indicated reabsorption from GI tract & re-circulation of labelled cells. The initial data shows that labelled cell may remain with in the system for upto 10-15 days. Minimal uptake in brain & heart supported safety profile of labeling agent. Conclusions This is first in human in-vivo study to provide highly valuable visual and dynamic data in real time and provides insight into individual responses to therapy. CAR T cell functionality largely remain unchanged due to labeling process. The findings indicate that labelled cells remain persistent for extended period of time.

Towards Clinical Translation of LED-Based Photoacoustic Imaging: A Review.

Photoacoustic imaging, with the capability to provide simultaneous structural, functional, and molecular information, is one of the fastest growing biomedical imaging modalities of recent times. As a hybrid modality, it not only provides greater penetration depth than the purely optical imaging techniques, but also provides optical contrast of molecular components in the living tissue. Conventionally, photoacoustic imaging systems utilize bulky and expensive class IV lasers, which is one of the key factors hindering the clinical translation of this promising modality. Use of LEDs which are portable and affordable offers a unique opportunity to accelerate the clinical translation of photoacoustics. In this paper, we first review the development history of LED as an illumination source in biomedical photoacoustic imaging. Key developments in this area, from point-source measurements to development of high-power LED arrays, are briefly discussed. Finally, we thoroughly review multiple phantom, ex-vivo, animal in-vivo, human in-vivo, and clinical pilot studies and demonstrate the unprecedented preclinical and clinical potential of LED-based photoacoustic imaging.