Challenges in using anesthesia  for open chest and aorta surgery in swine

Anesthesia for aorta surgery in pigs remains challenging due to the requirements for mechanical ventilation and the need for maintaining adequate homeostasis. We report an improved anesthesia protocol in an in vivo animal model to test a novel bacterial nanocellulose (BNC) within the ‘Kardio-BNC’ trial. Forty-four 6-month-old DanBred pigs comprising 6 males and 38 females (body weight ca. 82 kg) underwent implantation of pericardium reconstructive patches (n = 8), thoracic aorta prostheses (n = 15), or both procedures (n = 17) to test the biocompatibility of the novel BNC. The primary endpoint was 90-day survival, and the secondary outcome was death for any reason before reaching the study endpoint. Univariate analysis and linear regression were used to identify variables associated with premature mortality. Of the 44 pigs that underwent surgery, 10 (23%) were lost intra-operatively because of arrhythmia (n = 1), anesthesiological causes (n = 4), or surgical complications (n = 5). Modifications to tracheal intubation, tube fixation, temperature maintenance, and vascular catheterization increased the survival rate to 91% in the last quartile of the animals that underwent surgery. Of the 34 animals that survived surgery, n = 10 (29%) were lost post-operatively because of hematoma (n = 2), pneumothorax (n = 1), or infection (n = 7). Infection was associated with the type of surgery (highest prevalence in animals undergoing the combined procedure; p = 0.02), azaperone dose (p = 0.03), intra-operative heart rate variability (p = 0.03), and crystalloid transfusion (p = 0.04). The anesthesiological strategies and modifications to surgery described here allowed safe open chest and aorta surgery in up to 91% of the procedures performed

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Uptake, Internalization and Degradation of the Novel Plasminogen Activator Reteplase (BM 06.022) in the Rat

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649973 ◽

1995 ◽

Vol 74 (06) ◽

pp. 1501-1510 ◽

Cited By ~ 7

Author(s):

J Kuiper ◽

H van de Bilt ◽

U Martin ◽

Th J C van Berkel

Keyword(s):

Plasminogen Activator ◽

Liver Cells ◽

The Novel ◽

Uptake Mechanism ◽

Liver Uptake ◽

Lysosomal Compartment ◽

Β Phase ◽

Α Phase ◽

Parenchymal Liver

SummaryThe catabolism of the novel plasminogen activator reteplase (BM 06.022) was described. For this purpose BM 06.022 was radiolabelled with l25I or with the accumulating label l25I-tyramine cellobiose (l25I-TC).BM 06.022 was injected at a pharmacological dose of 380 μg/kg b.w. and it was cleared from the plasma in a biphasic manner with a half-life of about 1 min in the α-phase and t1/2of 20-28 min in the β-phase. 28% and 72% of the injected dose was cleared in the α-phase and β-phase, respectively. Initially liver, kidneys, skin, bones, lungs, spleen, and muscles contributed mainly to the plasma clearance. Only liver and the kidneys, however, were responsible for the uptake and subsequent degradation of BM 06.022 and contributed for 75% to the catabolism of BM 06.022. BM 06.022 was degraded in the lysosomal compartment of both organs. Parenchymal liver cells were responsible for 70% of the liver uptake of BM 06.022. BM 06.022 associated rapidly to isolated rat parenchymal liver cells and was subsequently degraded in the lysosomal compartment of these cells. BM 06.022 bound with low-affinity to the parenchymal liver cells (550 nM) and the binding of BM 06.022 could be displaced by t-PA (IC50 5.6 nM), indicating that the low-density lipoprotein receptor-related protein (LRP) could be involved in the binding of BM 06.022. GST-RAP, which is an inhibitor of LRP, could in vivo significantly inhibit the uptake of BM 06.022 in the liver.It is concluded that BM 06.022 is metabolized primarily in the liver and the kidneys. These organs take up and degrade BM 06.022 in the lysosomes. The uptake mechanism of BM 06.022 in the kidneys is unknown, while LRP is responsible for a low-affinity binding and uptake of BM 06.022 in parenchymal liver cells.

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Nanoformulations for Delivery of Pentacyclic Triterpenoids in Anticancer Therapies

Molecules ◽

10.3390/molecules26061764 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1764

Author(s):

Anna Kaps ◽

Paweł Gwiazdoń ◽

Ewa Chodurek

Keyword(s):

Water Solubility ◽

Biological Activities ◽

Premature Mortality ◽

Delivery Systems ◽

Pentacyclic Triterpenoids ◽

Anticancer Properties ◽

Oncological Patients ◽

Antitumor Potential ◽

Ring Structures

The search for safe and effective anticancer therapies is one of the major challenges of the 21st century. The ineffective treatment of cancers, classified as civilization diseases, contributes to a decreased quality of life, health loss, and premature mortality in oncological patients. Many natural phytochemicals have anticancer potential. Pentacyclic triterpenoids, characterized by six- and five-membered ring structures, are one of the largest class of natural metabolites sourced from the plant kingdom. Among the known natural triterpenoids, we can distinguish lupane-, oleanane-, and ursane-types. Pentacyclic triterpenoids are known to have many biological activities, e.g., anti-inflammatory, antibacterial, hepatoprotective, immunomodulatory, antioxidant, and anticancer properties. Unfortunately, they are also characterized by poor water solubility and, hence, low bioavailability. These pharmacological properties may be improved by both introducing some modifications to their native structures and developing novel delivery systems based on the latest nanotechnological achievements. The development of nanocarrier-delivery systems is aimed at increasing the transport capacity of bioactive compounds by enhancing their solubility, bioavailability, stability in vivo and ensuring tumor-targeting while their toxicity and risk of side effects are significantly reduced. Nanocarriers may vary in sizes, constituents, shapes, and surface properties, all of which affect the ultimate efficacy and safety of a given anticancer therapy, as presented in this review. The presented results demonstrate the high antitumor potential of systems for delivery of pentacyclic triterpenoids.

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513 CD26 enzymatic activity modulates efficient migration of adoptively transferred T cells to solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0513 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A549-A549

Author(s):

Megan Wyatt ◽

Stefanie Bailey ◽

Michelle Nelson ◽

Hannah Knochelmann ◽

Aubrey Smith ◽

...

Keyword(s):

T Cells ◽

Enzymatic Activity ◽

Solid Tumors ◽

Study Endpoint ◽

Melanoma Tumor ◽

Antitumor Response ◽

Migration Assay ◽

Specific Subset ◽

Donor Cells

BackgroundThe inadequate ability of adoptively transferred T cells to eradicate solid tumors limits their use in treatments for patients afflicted with those cancers. Efforts to improve ACT for solid tumors aim to identify strategies that poise T cells for optimal response. We have previously identified a specific subset of CD4 T cells which express high levels of the ubiquitous ectoenzyme dipeptidyl peptidase-4 (DPP-4), also known as CD26, that produce a tremendous antitumor response in solid tumor models. We therefore sought to investigate the importance of CD26 on T cells destined for ACT.MethodsWe adoptively transferred tumor specific CD26+ T cells into melanoma tumor-bearing CD26-/- mice, and continuously blocked the CD26 enzymatic activity of the donor cells in vivo with sitagliptin, an established competitive inhibitor of CD26.ResultsTumors in sitagliptin-treated mice eventually reached study endpoint, while tumors untreated mice were regressed for 130+ days. Tumor infiltration of donor cells and host CD8 and CD4 cells was diminished with sitagliptin treatment. A 32-plex cytokine array of blood plasma revealed a diminished profile of cytokines and chemokines, indicating that the inflammatory response of the T cells was dampened with sitagliptin treatment. Further experiments characterized the ability of CD26+ T cells to respond to tumor trafficking signals with a transwell migration assay and found that sitagliptin treatment significantly impaired their migratory capacity. However, sitagliptin did not impair the ability of T cells to functionally respond to antigen.ConclusionsThese data suggest that the enzymatic activity of CD26 is important for the ability of T cells to migrate to the tumor site in order to mount an effective antitumor response. Further investigations into the mechanism behind the role of CD26 are ongoing.Ethics ApprovalThis study was approved by the Medical University of South Carolina’s IACUC, protocol #00488

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Characterization of the SARS-CoV-2 coronavirus X4-like accessory protein

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-021-00160-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Olanrewaju Ayodeji Durojaye ◽

Nkwachukwu Oziamara Okoro ◽

Arome Solomon Odiba

Keyword(s):

Rapid Development ◽

Protein A ◽

The Novel ◽

Quality Model ◽

A Value ◽

Model Protein ◽

Novel Coronavirus ◽

Global Threat

Abstract Background The novel coronavirus SARS-CoV-2 is currently a global threat to health and economies. Therapeutics and vaccines are in rapid development; however, none of these therapeutics are considered as absolute cure, and the potential to mutate makes it necessary to find therapeutics that target a highly conserved regions of the viral structure. Results In this study, we characterized an essential but poorly understood coronavirus accessory X4 protein, a core and stable component of the SARS-CoV family. Sequence analysis shows a conserved ~ 90% identity between the SARS-CoV-2 and previously characterized X4 protein in the database. QMEAN Z score of the model protein shows a value of around 0.5, within the acceptable range 0–1. A MolProbity score of 2.96 was obtained for the model protein and indicates a good quality model. The model has Ramachandran values of φ = − 57o and ψ = − 47o for α-helices and values of φ = − 130o and ψ = + 140o for twisted sheets. Conclusions The protein data obtained from this study provides robust information for further in vitro and in vivo experiment, targeted at devising therapeutics against the virus. Phylogenetic analysis further supports previous evidence that the SARS-CoV-2 is positioned with the SL-CoVZC45, BtRs-BetaCoV/YN2018B and the RS4231 Bat SARS-like corona viruses.

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Chemically-Boosted Corneal Cross-Linking for the Treatment of Keratoconus through a Riboflavin 0.25% Optimized Solution with High Superoxide Anion Release

Journal of Clinical Medicine ◽

10.3390/jcm10061324 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1324

Author(s):

Cosimo Mazzotta ◽

Marco Ferrise ◽

Guido Gabriele ◽

Paolo Gennaro ◽

Alessandro Meduri

Keyword(s):

Superoxide Anion ◽

Hydroxypropyl Methylcellulose ◽

Anterior Segment ◽

Preclinical Study ◽

Cross Linking ◽

Specular Microscopy ◽

The Novel ◽

Power Setting ◽

Contralateral Eye

The purpose of this study was to evaluate the effectiveness and safety of a novel buffered riboflavin solution approved for corneal cross-linking (CXL) in progressive keratoconus and secondary corneal ectasia. Following the in vivo preclinical study performed on New Zealand rabbits comparing the novel 0.25% riboflavin solution (Safecross®) containing 1% hydroxypropyl methylcellulose (HPMC) with a 0.25% riboflavin solution containing 0.10% EDTA, accelerated epithelium-off CXL was performed on 10 patients (10 eyes treated, with the contralateral eye used as control) through UV-A at a power setting of 9 mW/cm2 with a total dose of 5.4 J/cm2. Re-epithelialization was evaluated in the postoperative 7 days by fluorescein dye test at biomicroscopy; endothelial cell count and morphology (ECD) were analyzed by specular microscopy at the 1st and 6th month of follow-up and demarcation line depth (DLD) measured by anterior segment optical coherence tomography (AS-OCT) one month after the treatment. We observed complete re-epithelization in all eyes between 72 and 96 h after surgery (88 h on average). ECD and morphology remained unchanged in all eyes. DLD was detected at a mean depth of 362 ± 50 µm, 20% over solutions with equivalent dosage. SafeCross® riboflavin solution chemically-boosted corneal cross-linking seems to optimize CXL oxidative reaction by higher superoxide anion release, improving DLD by a factor of 20%, without adverse events for corneal endothelium.

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Advanced Functional Materials Based on Nanocellulose for Pharmaceutical/Medical Applications

Pharmaceutics ◽

10.3390/pharmaceutics13081125 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1125

Author(s):

Raluca Nicu ◽

Florin Ciolacu ◽

Diana E. Ciolacu

Keyword(s):

Rapid Development ◽

Cellulose Nanofibrils ◽

Functional Materials ◽

Medical Applications ◽

Bacterial Nanocellulose ◽

Green Materials ◽

Wide Range ◽

In Vivo Cytotoxicity

Nanocelluloses (NCs), with their remarkable characteristics, have proven to be one of the most promising “green” materials of our times and have received special attention from researchers in nanomaterials. A diversity of new functional materials with a wide range of biomedical applications has been designed based on the most desirable properties of NCs, such as biocompatibility, biodegradability, and their special physicochemical properties. In this context and under the pressure of rapid development of this field, it is imperative to synthesize the successes and the new requirements in a comprehensive review. The first part of this work provides a brief review of the characteristics of the NCs (cellulose nanocrystals—CNC, cellulose nanofibrils—CNF, and bacterial nanocellulose—BNC), as well as of the main functional materials based on NCs (hydrogels, nanogels, and nanocomposites). The second part presents an extensive review of research over the past five years on promising pharmaceutical and medical applications of nanocellulose-based materials, which have been discussed in three important areas: drug-delivery systems, materials for wound-healing applications, as well as tissue engineering. Finally, an in-depth assessment of the in vitro and in vivo cytotoxicity of NCs-based materials, as well as the challenges related to their biodegradability, is performed.

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Mycobacterium chimaera genomics with regard to epidemiological and clinical investigations conducted for the open-chest post-surgical Mycobacterium chimaera infections outbreak

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab192 ◽

2021 ◽

Author(s):

Emmanuel Lecorche ◽

Côme Daniau ◽

Kevin La ◽

Faiza Mougari ◽

Hanaa Benmansour ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Isolates ◽

Whole Genome ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Healthcare Facilities ◽

Open Chest

Abstract Background Post-surgical infections due to Mycobacterium chimaera appeared as a novel nosocomial threat in 2015, with a worldwide outbreak due to contaminated heater-cooler units used in open chest surgery. We report the results of investigations conducted in France including whole genome sequencing comparison of patient and HCU isolates. Methods We sought M. chimaera infection cases from 2010 onwards through national epidemiological investigations in healthcare facilities performing cardiopulmonary bypass together with a survey on good practices and systematic heater-cooler unit microbial analyses. Clinical and HCU isolates were subjected to whole genome sequencing analyzed with regards to the reference outbreak strain Zuerich-1. Results Only two clinical cases were shown to be related to the outbreak, although 23% (41/175) heater-cooler units were declared positive for M. avium complex. Specific measures to prevent infection were applied in 89% (50/56) healthcare facilities although only 14% (8/56) of them followed the manufacturer maintenance recommendations. Whole genome sequencing comparison showed that the clinical isolates and 72% (26/36) of heater-cooler unit isolates belonged to the epidemic cluster. Within clinical isolates, 5 to 9 non-synonymous single nucleotide polymorphisms were observed, among which an in vivo mutation in a putative efflux pump gene observed in a clinical isolate obtained for one patient under antimicrobial treatment. Conclusions Cases of post-surgical M. chimaera infections were declared to be rare in France, although heater-cooler units were contaminated as in other countries. Genomic analyses confirmed the connection to the outbreak and identified specific single nucleotide polymorphisms, including one suggesting fitness evolution in vivo.

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In vitro and in vivo evaluation of a sustained-release once-a-day formulation of the novel antihypertensive drug MT-1207

Pharmaceutical Development and Technology ◽

10.1080/10837450.2021.1872087 ◽

2021 ◽

Vol 26 (3) ◽

pp. 349-361

Author(s):

Napoleon-Nikolaos Vrettos ◽

Peng Wang ◽

Yan Zhou ◽

Clive J. Roberts ◽

Jinyi Xu ◽

...

Keyword(s):

Sustained Release ◽

Antihypertensive Drug ◽

The Novel ◽

In Vivo Evaluation

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The Anticancer Action of a Novel 1,2,4-Triazine Sulfonamide Derivative in Colon Cancer Cells

Molecules ◽

10.3390/molecules26072045 ◽

2021 ◽

Vol 26 (7) ◽

pp. 2045

Author(s):

Agnieszka Gornowicz ◽

Anna Szymanowska ◽

Mariusz Mojzych ◽

Robert Czarnomysy ◽

Krzysztof Bielawski ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Cells ◽

Cathepsin B ◽

Beclin 1 ◽

Special Role ◽

The Novel ◽

Colon Cancer Cells ◽

Sulfonamide Derivative

Cancer therapy is one of the most important challenges of modern medical and chemical sciences. Among the many methods of combating cancer, chemotherapy plays a special role. Imperfect modern chemotherapy justifies continuing the search for new, more effective, and safe drugs. Sulfonamides are the classic group of chemotherapeutic drugs with a broad spectrum of pharmacological activity. Recent literature reports show that sulfonamide derivatives have anti-tumor activity in vitro and in vivo. The aim of the study was to synthesize a novel 1,2,4-triazine sulfonamide derivative and check its anticancer potential in DLD-1 and HT-29 colon cancer cells. The biological studies included MTT assay, DNA biosynthesis, cell cycle analysis, Annexin V binding assay, ethidium bromide/acridine orange staining, and caspase-8, -9, and -3/7 activity. The concentrations of important molecules (sICAM-1, mTOR, Beclin-1, cathepsin B) involved in the pathogenesis and poor prognosis of colorectal cancer were also evaluated by ELISA. We demonstrated that the novel compound was able to induce apoptosis through intrinsic and extrinsic pathways and was capable of decreasing sICAM-1, mTOR, cathepsin B concentrations, whereas increased Beclin-1 concentration was detected in both colon cancer cell lines. The novel compound represents promising multi-targeted potential in colorectal cancer, but further in vivo examinations are needed to confirm the claim.

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Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response

International Journal of Molecular Sciences ◽

10.3390/ijms22073728 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3728

Author(s):

Masahiro Hatasa ◽

Sumiko Yoshida ◽

Hirokazu Takahashi ◽

Kenichi Tanaka ◽

Yoshihito Kubotsu ◽

...

Keyword(s):

Risk Factor ◽

Periodontal Disease ◽

Alveolar Bone ◽

Basic Research ◽

Epidemiological Studies ◽

Cross Sectional ◽

Periodontopathic Bacteria ◽

In Vivo Animal Model ◽

The Relationship

Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, Porphyromonas gingivalis lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD.

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