Tissue Affinity Research Articles

Salivary Amylase-Responsive Buccal Tablets Wipe Out Chemotherapy-Rooted Refractory Oral Mucositis.

Oral mucositis (OM) is the most common and refractory complication of cancer chemotherapy and radiotherapy, severely affecting patients' life quality, lowering treatment tolerance, and discouraging patient compliance. Current OM delivery systems mostly affect the comfort of patient use and lead to poor compliance and unsatisfactory effects. Herein, salivary amylases (SAs)-responsive buccal tablets consisting of porous manganese-substituted Prussian blue (PMPB) nanocubes (NCs), anti-inflammatory apremilast (Apr) and starch controller have been engineered. PMPB NCs with large surface area can serve as carriers to load Apr, and their multienzyme-mimicking activity enables them to scavenge reactive oxygen species (ROS), which thus synergize with Apr to mitigate inflammation. More significantly, the starch controller can respond to abundant SAs in the oral cavity and realize the cascade, continuous, and complete drug release after enzymatic decomposition, which not only aids with high tissue affinity to prolong the resistance time but also improves the comfort of use. The preclinical study reveals that contributed by the above actions, such buccal tablets mitigate inflammation, promote endothelium proliferation and migration, and accelerate wound healing for repressing chemotherapy-originated intractable OM with positive oral microenvironment and shorter recovery time, thus holding high potentials in clinical translation.

Brain metastases and lung cancer: molecular biology, natural history, prediction of response and efficacy of immunotherapy.

Brain metastases stemming from lung cancer represent a common and challenging complication that significantly impacts patients' overall health. The migration of these cancerous cells from lung lesions to the central nervous system is facilitated by diverse molecular changes and a specific environment that supports their affinity for neural tissues. The advent of immunotherapy and its varied combinations in non-small cell lung cancer has notably improved patient survival rates, even in cases involving brain metastases. These therapies exhibit enhanced penetration into the central nervous system compared to traditional chemotherapy. This review outlines the molecular mechanisms underlying the development of brain metastases in lung cancer and explores the efficacy of novel immunotherapy approaches and their combinations.

Natural Underwater Bioadhesive Offering Cohesion Modulation via Hydrogen Bond Disruptor: A Highly Injectable and in Vivo Stable Remedy for Gastric Ulcer Resolution.

Injectable bioadhesives are attractive for managing gastric ulcers through minimally invasive procedures. However, the formidable challenge is to develop bioadhesives that exhibit high injectability, rapidly adhere to lesion tissues with fast gelation, provide reliable protection in the harsh gastric environment, and simultaneously ensure stringent standards of biocompatibility. Here, a natural bioadhesive with tunable cohesion is developed based on the facile and controllable gelation between silk fibroin and tannic acid. By incorporating a hydrogen bond disruptor (urea or guanidine hydrochloride), the inherent network within the bioadhesive is disturbed, inducing a transition to a fluidic state for smooth injection (injection force <5N). Upon injection, the fluidic bioadhesive thoroughly wets tissues, while the rapid diffusion of the disruptor triggers instantaneous in situ gelation. This orchestrated process fosters the formed bioadhesive with durable wet tissue affinity and mechanical properties that harmonize with gastric tissues, thereby bestowing long-lasting protection for ulcer healing, as evidenced through in vitro and in vivo verification. Moreover, it can be conveniently stored (≥3m) postdehydration. This work presents a promising strategy for designing highly injectable bioadhesives utilizing natural feedstocks, avoiding any safety risks associated with synthetic materials or nonphysiological gelation conditions, and offering the potential for minimally invasive application.

Injectable phase-separated tetra-armed poly(ethylene glycol) hydrogel scaffold allows sustained release of growth factors to enhance the repair of critical bone defects

With the rising prevalence of bone-related injuries, it is crucial to improve treatments for fractures and defects. Tissue engineering offers a promising solution in the form of injectable hydrogel scaffolds that can sustain the release of growth factors like bone morphogenetic protein-2 (BMP-2) for bone repair. Recently, we discovered that tetra-PEG hydrogels (Tetra gels) undergo gel-gel phase separation (GGPS) at low polymer content, resulting in hydrophobicity and tissue affinity. In this work, we examined the potential of a newer class of gel, the oligo-tetra-PEG gel (Oligo gel), as a growth factor-releasing scaffold. We investigated the extent of GGPS occurring in the two gels and assessed their ability to sustain BMP-2 release and osteogenic potential in a mouse calvarial defect model. The Oligo gel underwent a greater degree of GGPS than the Tetra gel, exhibiting higher turbidity, hydrophobicity, and pore formation. The Oligo gel demonstrated sustained protein or growth factor release over a 21-day period from protein release kinetics and osteogenic cell differentiation studies. Finally, BMP-2-loaded Oligo gels achieved complete regeneration of critical-sized calvarial defects within 28 days, significantly outperforming Tetra gels. The easy formulation, injectability, and capacity for sustained release makes the Oligo gel a promising candidate therapeutic biomaterial.

New synthetic monophenolic antioxidant TS-13 penetrates the blood-brain barrier

TS-13 (sodium 3-(3’-tert-butyl-4’-hydroxyphenyl)propylthiosulfonate) is a synthetic antioxidant that has demonstrated biological effectiveness in numerous studies in modeling pathological conditions in vivo, in particular, in the model of Parkinson’s disease. In order to establish whether these effects are mediated or associated, among other things, with the direct effect of TS-13 on the organs and tissues of animals, in this work, the concentration of TS-13 in rat blood plasma and brain after intragastric administration was determined. Material and methods. After a single intragastric administration of a solution of TS-13 at a dose of 100 mg/kg, biomaterial (blood, brain) was taken for 24 h in male Sprague Dawley stock rats (n = 57). To measure the concentration of a substance in samples, a bioanalytical method was developed and validated using high-performance liquid chromatography with UV detection. Results and discussion. The method of quantitative determination was developed by us for the first time and validated before the study. It has been established that the calculated values of the calibration samples meet the acceptance criteria (have the required accuracy and precision) in the concentration range from 0.05 to 6 µg/ml, R=0.9998. The results of determining TS-13 concentration in rat blood plasma and brain showed that after a single administration per os, the compound enters the blood, where it is detected for 15 h (mean retention time 7.94 h, half-life 7.59 h, elimination constant 0.13 h-1, total clearance 40.1 l/(kg × h)), and also penetrates the blood-brain barrier, quickly entering the brain (maximum concentration is reached after 1 h). The compound has a low affinity for brain tissue (tissue availability 0.32), and therefore its concentration does not reach high values, however, a slow excretion of the substance is observed - the average retention time is 6.56 h, the half-life is 6.43 h, the elimination constant 0.11 h-1. Conclusions. After a single intragastric administration to rats, TS-13 enters the blood, where at least part of it is detected unchanged after 30 minutes, reaching maximum values after 1 hour. Similar kinetics of the substance is characteristic of the brain, where it is found in smaller amounts. Thus, as a result of the study, it was shown that TS-13 penetrates the blood-brain barrier and is able to directly affect brain structures, which, however, does not negate the possibility of an indirect effect mediated by the ability to change the activity of intra- and intercellular signaling systems.

COVID-19-induced gastrointestinal autonomic dysfunction: A systematic review.

It is common for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to occur in the gastrointestinal tract, which can present itself as an initial symptom. The severity of coronavirus disease 2019 (COVID-19) is often reflected in the prevalence of gastrointestinal symptoms. COVID-19 can damage the nerve supply to the digestive system, leading to gastrointestinal autonomic dysfunction. There is still much to learn about how COVID-19 affects the autonomic nervous system and the gastrointestinal tract. To thoroughly explore the epidemiology and clinical aspects of COVID-19-induced gastrointestinal autonomic dysfunction, including its manifestations, potential mechanisms, diagnosis, differential diagnosis, impact on quality of life, prognosis, and management and prevention strategies. We conducted a thorough systematic search across various databases and performed an extensive literature review. Our review encompassed 113 studies published in English from January 2000 to April 18, 2023. According to most of the literature, gastrointestinal autonomic dysfunction can seriously affect a patient's quality of life and ultimate prognosis. Numerous factors can influence gastrointestinal autonomic nervous functions. Studies have shown that SARS-CoV-2 has a well-documented affinity for both neural and gastrointestinal tissues, and the virus can produce various gastrointestinal symptoms by reaching neural tissues through different pathways. These symptoms include anorexia, dysgeusia, heartburn, belching, chest pain, regurgitation, vomiting, epigastric burn, diarrhea, abdominal pain, bloating, irregular bowel movements, and constipation. Diarrhea is the most prevalent symptom, followed by anorexia, nausea, vomiting, and abdominal pain. Although COVID-19 vaccination may rarely induce autonomic dysfunction and gastrointestinal symptoms, COVID-19-induced autonomic effects significantly impact the patient's condition, general health, prognosis, and quality of life. Early diagnosis and proper recognition are crucial for improving outcomes. It is important to consider the differential diagnosis, as these symptoms may be induced by diseases other than COVID-19-induced autonomic dysfunction. Treating this dysfunction can be a challenging task. To ensure the best possible outcomes for COVID-19 patients, it is essential to take a multidisciplinary approach involving providing supportive care, treating the underlying infection, managing dysfunction, monitoring for complications, and offering nutritional support. Close monitoring of the patient's condition is crucial, and prompt intervention should be taken if necessary. Furthermore, conducting thorough research on the gastrointestinal autonomic dysfunction caused by COVID-19 is vital to manage it effectively.

Effects of methoxy polyethylene glycol‐polycaprolactone block copolymers and silica nanoparticles on the mechanical, tissue affinity and antibacterial properties of n‐butyl cyanoacrylate adhesive

AbstractCyanoacrylates are widely used as surgical tissue adhesives because of their high biodegradability, but they are brittle and have poor tissue affinity. In this study, methoxy polyethylene glycol‐polycaprolactone block copolymers (MPEG‐co‐PCLs) with different PCL chain lengths were synthesized by ring‐opening polymerization. Then, a new tissue adhesive with excellent mechanical properties, tissue affinity, antibacterial properties, and coagulation performances was prepared by incorporating MPEG‐co‐PCL and silica nanoparticles (SNPs) into n‐butyl cyanoacrylate (BCA). The optimal MPEG: PCL ratio is 1:4 (MP‐3), and the optimal mass ratio of MPEG‐co‐PCL and SNPs (0.5SNPs/0.5MP‐3) is 0.5 wt.%. Compared to BCA, the adhesion strength and flexibility of 0.5SNPs/0.5MP‐3 are dramatically improved by 110% and 244%, respectively. MPEG‐co‐PCL can fully exploit the advantages of homopolymers, and therefore, improve the tissue affinity and adhesion strength of the adhesive and avoid BCA polymerization initiated by MPEG and poor compatibility of PCL with BCA. SNPs can also compensate for the lack of antibacterial properties of BCA against Gram‐negative bacteria. The E. coli inhibition circle of 0.5SNPs/0.5MP‐3 is twice as large as BCA. SNPs can also improve coagulation by promoting platelet aggregation. This work provides an effective strategy for developing adhesives with potential clinical applications.

Bioanalytical LC-QTOF/MS Method for a N-phenylpiperazine Derivate (LQFM05): An Anxiolytic- and Antidepressant-like Prototype Drug Applied to Pharmacokinetic and Biodistribution Studies.

The LQFM05 is a prototype drug designed for treatment of psychiatric disorders, such as schizophrenia, exhibiting anxiolytic- and antidepressant-like (12 or 24 µmol/kg) effects in classical behavioral tests. In order to evaluate its pharmacokinetic properties, a liquid chromatography method coupled to a quadrupole time of flight mass spectrometry system (LC-QTOF/MS) was developed and fully validated for LQFM05 analysis in rat plasma and tissue samples (brain, heart, liver, and kidneys). Liquid-liquid extraction, solid phase extraction and protein precipitation were assessed as clean-up procedures for biological samples and analyte enrichment. Plasma and tissue samples underwent protein precipitation as a preliminary step, using acetonitrile. Linearity was fully demonstrated for the dynamic range (10.0 to 900.0 ng/mL), with r2 values higher than 0.99 (RSDslope ≤ 2%, Fcal < Ftab, Ccal < Ctab). Biodistribution studies in rats revealed high brain tissue concentrations (12.4 µg/g), suggesting elevated drug affinity to the main therapeutic target tissue, showing a blood partition coefficient of 1.9. Kidneys also showed great exposure and tissue affinity, suggesting a potential extrahepatic clearance. Likewise, all examined tissues exhibited satisfactory LQFMF05 distribution. The mass fragmentation spectrum indicated the presence of its main metabolite, LQFM235, yielded by high hepatic hydroxylation route, an equally bioactive derivative. Lastly, the developed LC-QTOF/MS method was shown to be sensitive (LOQ = 10 ng/mL), precise and accurate for LQFM05 determination in tissue homogenates and plasma samples.

Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease.

Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance ( CLint ) of tacrolimus as a case example. Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CLint for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate ( eGFR ) was assessed as a covariate for CLint using the stochastic approximation of expectation and maximization method. At baseline, the median (interquartile range) eGFR was 45 (34.5-55.5) mL/min/1.73 m 2 . A significant but weak correlation was observed between tacrolimus CLint and eGFR (r = 0.2, P < 0.001). The CLint declined gradually (up to 36%) with CKD progression. Tacrolimus CLint did not differ significantly between stable and failing transplant patients. Kidney function deterioration in CKD can affect nonrenal CLint for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets.

Colloidal gold based immunochromatographic detection of Mycoplasmopsis synoviae infection and its prevalence in avian species of Karachi, Pakistan

Avian mycoplasmosis is an infection that commonly prevails in birds, particularly in poultry chickens. Among mycoplasmosis causing organisms, Mycoplasmopsis synoviae is a predominant and lethal pathogen to the aves. Considering the increased incidence of infections by M. synoviae, the prevalence of M. synoviae was deduced in poultry chickens and fancy birds of Karachi region. The lungs and tracheal samples from chicken and dead fancy birds and swab samples from live fancy birds were collected and investigated by amplifying 16 s rRNA gene of M. synoviae. Biochemical characteristics of M. synoviae was also evaluated. Furthermore, surface-associated membrane proteins, that represent key antigens for diagnosis of M. synoviae infection was extracted by Triton X- 114 method. Results showed that M. synoviae was detected more frequently in lungs than in trachea, that could be due to its invasion capacity and tissue affinity. SDS PAGE analysis of extracted membrane proteins showed two prominent hydrophobic proteins of different molecular mass including proteins of 150 and 50 kDa. Protein of 150 kDa was purified by size exclusion chromatography and it exhibited agglutinogen activity. Purified protein was used in the development of one-step immunochromatographic (ICT) assay for the detection of antibodies against M. synoviae using gold nanoparticles coated with polyclonal antibodies. Low levels of antibodies were detected by the developed ICT kit, which has 88% sensitivity with 92% specificity.

CONCEPT OF VATARAKTA IN AYURVEDA W.S.R TO GOUTY ARTHRITIS

According to the theory of Ayurveda both the body and the diseases are made of Diet. Where the wholesome diet constructs the body, but the reverse causes the diseases. Changing food habits, lack of physical activities, and different environmental factors, nowadays a number of diseases are manifesting including Vatarakata. Due to the above-mentioned factors, the metabolism of proteins takes place improperly resulting in the formation of a number of free radicals which deposit in different sites of the body according to their affinity towards the same tissue resulting in a number of serious diseases. The disease Vatarakta is described as one of the diseases of Sammurchhna of Vata and Rakta. It is a disease, that occurs due to the Avarana of Vata Dosha by the aggravated Rakta dosha. It as a Vata dosha pradhana Tridoshaja Vyadhi where the main Dushya is Rakta. Hence Vatarakta is a disease where both Vata and Rakta are afflicted by distinct etiological factors. The references of Vatarakta are found in Bruhattrayee &amp; the text of other Acharya in respective chapters. After the keen vision of etiological factors and symptomatology, Vatarakta may be correlated to gouty arthritis.[1] It is a disorder of defective purine metabolism, which is characterized by hyperuricemia &amp; deposition of monosodiumurate crystals in joints due to its affinity for elastic tissue. It is a chronic metabolic disorder of the musculoskeletal system. [2] Severe pain, tenderness, inflammation and burning sensation in affected joints are the clinical features of it. It has been called "The disease of Kings" due to its association with people having sedentary lifestyles. Due to severe morbidity, chronicity, and incurability with associated complications, management of Vatarakta always remain a challenge for the Ayurveda physician as there is no exact treatment in the allopathy system also. So, it is very much necessary to know the concept of Vatarakta before its management.[2]

Whole-Genome Sequencing Reveals Differences among Kingella kingae Strains from Carriers and Patients with Invasive Infections.

As a result of the increasing use of sensitive nucleic acid amplification tests, Kingella kingae is being recognized as a common pathogen of early childhood, causing medical conditions ranging from asymptomatic oropharyngeal colonization to bacteremia, osteoarthritis, and life-threatening endocarditis. However, the genomic determinants associated with the different clinical outcomes are unknown. Employing whole-genome sequencing, we studied 125 international K. kingae isolates derived from 23 healthy carriers and 102 patients with invasive infections, including bacteremia (n = 23), osteoarthritis (n = 61), and endocarditis (n = 18). We compared their genomic structures and contents to identify genomic determinants associated with the different clinical conditions. The mean genome size of the strains was 2,024,228 bp, and the pangenome comprised 4,026 predicted genes, of which 1,460 (36.3%) were core genes shared by >99% of the isolates. No single gene discriminated between carried and invasive strains; however, 43 genes were significantly more frequent in invasive isolates, compared to asymptomatically carried organisms, and a few showed a significant differential distribution among isolates from skeletal system infections, bacteremia, and endocarditis. The gene encoding the iron-regulated protein FrpC was uniformly absent in all 18 endocarditis-associated strains but was present in one-third of other invasive isolates. Similar to other members of the Neisseriaceae family, the K. kingae differences in invasiveness and tropism for specific body tissues appear to depend on combinations of multiple virulence-associated determinants that are widely distributed throughout the genome. The potential role of the absence of the FrpC protein in the pathogenesis of endocardial invasion deserves further investigation. IMPORTANCE The wide range of clinical severities exhibited by invasive Kingella kingae infections strongly suggests that isolates differ in their genomic contents, and strains associated with life-threatening endocarditis may harbor distinct genomic determinants that result in cardiac tropism and severe tissue damage. The results of the present study show that no single gene discriminated between asymptomatically carried isolates and invasive strains. However, 43 putative genes were significantly more frequent among invasive isolates than among pharyngeal colonizers. In addition, several genes displayed a significant differential distribution among isolates from bacteremia, skeletal system infections, and endocarditis, suggesting that the virulence and tissue tropism of K. kingae are multifactorial and polygenic, depending on changes in the allele content and genomic organization. Further analysis of these putative genes may identify genomic determinants of the invasiveness of K. kingae and its affinity for specific body tissues and potential targets for a future protective vaccine.

Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of HPV-Associated Cancers.

The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.

Hydrogel transformed from sandcastle-worm-inspired powder for adhering wet adipose surfaces

Normally, hydrogel adhesives do not perform well on adipose matters that are covered with bodily fluids. Besides, the maintenance of high extensibility and self-healing ability in fully swollen state still remains challenging. Based on these concerns, we reported a sandcastle-worm-inspired powder, which was made of tannic acid-functionalized cellulose nanofiber (TA-CNF), polyacrylic acid (PAA) and polyethyleneimine (PEI). The obtained powder can rapidly absorb diverse bodily fluids and transform into a hydrogel, displaying fast (＜3 s), self-strengthening and repeatable wet adhesion to adipose tissues. Due to the dense physically cross-linked network, the formed hydrogel still showed excellent extensibility (∼14 times) and self-healing ability after being immersed in water. Moreover, excellent hemostasis, antibacterial ability and biocompatibility make it suitable for numerous biomedical applications. With combined advantages of powders and hydrogels, such as good adaptability to irregular sites, efficient drug loading capacity and tissue affinity, the sandcastle-worm-inspired powder offers significant promise as tissue adhesive and repair materials. This work may open new avenues for designing high-performance bioadhesives with efficient and robust wet adhesiveness to adipose tissues.

Revealing the three-dimensional murine brain microstructure by contrast-enhanced computed tomography.

To improve our understanding of the brain microstructure, high-resolution 3D imaging is used to complement classical 2D histological assessment techniques. X-ray computed tomography allows high-resolution 3D imaging, but requires methods for enhancing contrast of soft tissues. Applying contrast-enhancing staining agents (CESAs) ameliorates the X-ray attenuating properties of soft tissue constituents and is referred to as contrast-enhanced computed tomography (CECT). Despite the large number of chemical compounds that have successfully been applied as CESAs for imaging brain, they are often toxic for the researcher, destructive for the tissue and without proper characterization of affinity mechanisms. We evaluated two sets of chemically related CESAs (organic, iodinated: Hexabrix and CA4+ and inorganic polyoxometalates: 1:2 hafnium-substituted Wells-Dawson phosphotungstate and Preyssler anion), for CECT imaging of healthy murine hemispheres. We then selected the CESA (Hexabrix) that provided the highest contrast between gray and white matter and applied it to a cuprizone-induced demyelination model. Differences in the penetration rate, effect on tissue integrity and affinity for tissue constituents have been observed for the evaluated CESAs. Cuprizone-induced demyelination could be visualized and quantified after Hexabrix staining. Four new non-toxic and non-destructive CESAs to the field of brain CECT imaging were introduced. The added value of CECT was shown by successfully applying it to a cuprizone-induced demyelination model. This research will prove to be crucial for further development of CESAs for ex vivo brain CECT and 3D histopathology.

Ruminal tissue uptake of amino acids in Holstein cows when supply of nutrients within the rumen differs

Characterisation of amino acid (AA) use by the ruminal vein-drained viscera (RDV) has not been assessed in vivo in dairy cattle, and thus, the extent of ruminal AA use from arterial and postabsorptive blood supplies is unclear. Understanding the complete use of AA by the splanchnic bed may lead to alternative feeding programmes that maximise animal N efficiency. The objective of this work was to determine how different nutritional manipulations affect RDV net appearance and apparent affinity for arterial AA in lactating dairy cattle. Data from two arterio-venous (A-V) difference studies, that used a common set of multicatheterised lactating Holstein cows, assigned to different nutritional treatments, were used to assess ruminal metabolism. Study 1 consisted of three dietary treatments at calving [an alfalfa-glucogenic diet, a glucogenic diet (GLCG), or a ketogenic diet (KETO)] to investigate the effects of dietary nutrients and increasing intake postpartum on RDV metabolism of AA at −14, +4, +15, and +29 days relative to calving (DRTC). Study 2 consisted of two dietary levels of CP (17 or 13%) and three ruminal buffers (ammonia, butyrate, and control) to investigate the level of dietary CP and ruminal fermentation products on RDV metabolism of AA. Blood was collected at 9, 20, and 30 min after buffer administration. Regardless of dietary nutrients or fermentation products present in ruminal fluid, net RDV uptake was positive for most AA, excepting Asp, Cys, Glu, and Ser, which were consistently negative. The general positive net uptakes indicate that any AA potentially absorbed from the rumen were not adequate to meet apparent needs. Ruminal plasma flow and net RDV uptake of Trp, Ala, Gly, and Pro increased linearly with increased DRTC. Feeding KETO or GLCG diets increased ruminal plasma flow, and net RDV uptake of Thr and Gly. Feeding high CP diets increased ruminal uptake of Leu, Phe, and Val. The increased AA uptakes were partially driven by increased plasma flow, however, tissue affinity as reflected in clearance rates also increased or tended to for Met, Trp, Ala, Gly, Pro, and Tyr suggesting that changes in RDV uptake were regulated and not due solely to mass action. In conclusion, splanchnic tissue bed responses to dietary and washed rumen conditions were in part driven by changes in RDV nutrient demand and metabolic activity. The adaptive responses alter the fraction of absorbed AA utilised for non-productive purposes and thus the efficiency of conversion of those AA to product.

Radioligand therapy with &lt;sup&gt;177&lt;/sup&gt;Lu-DOTA-PSMA in metastatic castration-resistant prostate cancer. Pharmacokinetics, safety, antitumour efficacy

INTRODUCTION: The results of studies of clinical potential of a new domestic radiopharmaceutical 177Lu-DOTA-PSMA in patients with metastatic castration-resistant prostate cancer are presented in this article.OBJECTIVE: The pharmacokinetics, safety and tolerability of radiopharmaceutical were studied. Tolerability of increasing activities — 5.0, 7.5 and 10.0 GBq was investigated.MATERIALS AND METHODS: The study included 12 patients with metastatic castration-resistant prostate cancer, who progressed after previous treatment. The first 4 patients was treated by 5 GBq of 177Lu DOTA-PSMA, the next 4 patients of the second group was treated by 7.5 GBq, and the 4 patients of the third group was treated by 10 GBq. Radiopharmacokinetics was studied by whole-body scintigraphy, SPECT/CT, blood and urine radiometry. The radiation-absorbed dose (RAD) of metastases and organs at risk was studied by clinical dosimetry. Safety assessment also was studied by hematological status. All patients was taken a complete blood count, a biochemical blood test before course of therapy treatable and during the case study.RESULTS: Study data showed high accumulation of 177Lu-DOTA-PSMA the in pathological focus, the distribution in the body conformed to the previous data of PET/CT study. Blood radiometry showed that 177Lu-DOTA-PSMA rapidly excreted from the bloodstream (during the first hours after injection). Urine radiometry showed that, more than half of the injected dose was excreted during 2 days (from 34.4% to 88.8%).DISCUSSION: During the study was solicited increasing of pain syndrome, dry mouth. Most patients had moderate myelosuppression. Changes in hematological parameters had a transistor character, the adverse event resolved without consequences in 5 week. 4th grade of NCI CTCAE hematological toxicity criteria wasn’t identified. Serious adverse events weren’t identified too.CONCLUSIONS: Radiopharmaceutical demonstrated high affinity for tumor tissue and safety in the clinical use. Data, which demonstrating a high potential anti-tumor efficacy of radiopharmaceutical, were obtained. Dosimetric studies showed radiation safety of work with radiopharmaceutical for the personnel.

Prolactin and the evolution of male pregnancy

Prolactin (PRL) is a multifunctional hormone of broad physiological importance, and is involved in many aspects of fish reproduction, including the regulation of live birth (viviparity) and both male and female parental care. Previous research suggests that PRL also plays an important reproductive role in syngnathid fishes (seahorses, pipefish and seadragons), a group with a highly derived reproductive strategy, male pregnancy - how the PRL axis has come to be co-opted for male pregnancy remains unclear. We investigated the molecular evolution and expression of the genes for prolactin and its receptor (PRLR) in an evolutionarily diverse sampling of syngnathid fishes to explore how the co-option of PRL for male pregnancy has impacted its evolution, and to clarify whether the PRL axis is also involved in regulating reproductive function in species with more rudimentary forms of male pregnancy. In contrast to the majority of teleost fishes, all syngnathid fishes tested carry single copies of PRL and PRLR that cluster genetically within the PRL1 and PRLRa lineages of teleosts, respectively. PRL1 gene expression in seahorses and pipefish is restricted to the pituitary, while PRLRa is expressed in all tissues, including the brood pouch of species with both rudimentary and complex brooding structures. Pituitary PRL1 expression remains stable throughout pregnancy, but PRLRa expression is specifically upregulated in the male brood pouch during pregnancy, consistent with the higher affinity of pouch tissues for PRL hormone during embryonic incubation. Finally, immunohistochemistry of brood pouch tissues reveals that both PRL1 protein and PRLRa and Na+/K+ ATPase-positive cells line the inner pouch epithelium, suggesting that pituitary-derived PRL1 may be involved in brood pouch osmoregulation during pregnancy. Our data provide a unique molecular perspective on the evolution and expression of prolactin and its receptor during male pregnancy, and provide the foundation for further manipulative experiments exploring the role of PRL in this unique form of reproduction.

Green Electrospinning of Biodegradable Cellulose Acetate Nanofibrous Membranes with Tunable Porosity

The electrospinning of polymer nanofibers has received significant attention owing to their high surface-area-to-volume ratio, high porosity, adjustable pore size and texture, and highly interconnected porous structure. In particular, the electrospinning of biodegradable cellulose acetate (CA) nanofibers has sparked interest in diverse applications, including drug delivery systems, scaffolding for tissue engineering, air filtration, and affinity membrane systems. However, the electrospinning process has been mostly performed using toxic and hazardous solvents and additives. We developed electrospun CA nanofibers using a green solvent system comprising dimethyl carbonate and cyclopentanone. The use of green additives, namely, tetrabutylammonium bromide salts and sophorolipid-based biosurfactants, obtained from honey yeast, substantially improved the spinnability of the CA solution. Moreover, the nanofiber diameter and porous texture were tunable by adjusting the solvent ratio. Pore generation was induced using volatile dimethyl carbonate, which quickly evaporated from the fiber jet. Molecular dynamics simulations demonstrated that the electrospinning process can be divided into three stages. The addition of the biosurfactant facilitated the evaporation process and improved the uniformity of the nanofibers. Furthermore, the nanofibers can be degraded using esterase and cellulase enzymes. To summarize, the electrospinning of ultrafine CA porous nanofibers with tunable morphology was achieved using green solvents and additives.

Cancer cell membrane coated PLGA nanoparticles as biomimetic drug delivery system for improved cancer therapy

Based on the immune escape and homologous adhesion ability of cancer cells, a drug delivery system (DDS) could overcome the dilemma of immune clearance and non-specific binding by coating the cancer cell membrane (CCM). In this study, a biomimetic DDS based on CCM and poly lactic acid-glycolic acid (PLGA) nanoparticles was successfully constructed for tumor active and homologous targeting therapy. The doped CCM on the surface of the nanoparticle enabled the DDS to achieve immune escape and had an affinity for tumor tissues. The cellular uptake and in vivo distribution tests showed a superior cellular affinity of CCM coated PLGA nanoparticles (CCMNPs) than that of PLGA nanoparticles (PLGANPs). All of those results proved that CCMNPs endowed with drug-loaded nanoparticles had the abilities of immune escape and homologous targeting through the biological functional proteins retained on the coated CCM. In addition, the tumor inhibition rate of CCMNPs in tumor-bearing nude mice was 1.3 and 2.0-fold compared to PLGANPs and PTX injection, which showed the capacity to efficiently and accurately deliver drugs to cancer sites improved the therapeutic effect of tumor and achieved accurately targeted therapy.