A Four-Inflow Construction to Ensure Thermal Stability and Uniformity during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Rats

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative of clinical circumstances. Therefore, a good preclinical in vivo HIPEC model is needed in which temperature distributions can be well-controlled and are stable throughout treatments. Methods: We designed a setup able to generate and maintain a homogeneous flow during a 90-min HIPEC procedure using our in-house developed treatment planning tools and computer aided design (CAD) techniques. Twelve rats were treated with heated phosphate-buffered saline (PBS) using two catheter setups (one vs. four- inflows) and extensive thermometry. Simulated and measured thermal distribution and core temperatures were evaluated for the different setups. Results: Overall, the four-inflow resulted in more stable and more homogeneous thermal distributions than the one-inflow, with lower standard deviations (0.79 °C vs. 1.41 °C at the outflow, respectively) and less thermal losses. The average thermal loss was 0.4 °C lower for rats treated with the four-inflow setup. Rat core temperatures were kept stable using occasional tail cooling, and rarely exceeded 39 °C. Conclusion: Increasing the number of inflow catheters from one to four resulted in increased flow and temperature homogeneity and stability. Tail cooling is an adequate technique to prevent rats from overheating during 90-min treatments. This validated design can improve accuracy in future in vivo experiments investigating the impact of relevant parameters on the efficacy of different HIPEC protocols.

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Combination of in vivo phage therapy data with in silico model highlights key parameters for treatment efficacy

10.1101/2021.03.04.433924 ◽

2021 ◽

Author(s):

Raphaelle Delattre ◽

Jeremy Seurat ◽

Feyrouz Haddad ◽

Thu-Thuy Nguyen ◽

Baptiste Gaborieau ◽

...

Keyword(s):

Phage Therapy ◽

Biological Properties ◽

General Strategy ◽

In Vivo Experiments ◽

Bacterial Dynamics ◽

Optimal Dosing ◽

Dosing Regimens ◽

The Impact

The clinical (re)development of phage therapy to treat antibiotic resistant infections requires grasping specific biological properties of bacteriophages (phages) as antibacterial. However, identification of optimal dosing regimens is hampered by the poor understanding of phage-bacteria interactions in vivo. Here we developed a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacterial dynamics during pneumonia induced by a pathogenic strain of Escherichia coli. The model estimates some key parameters for phage therapeutic efficacy, in particular the impact of dose and route of administration on phage dynamics and the synergism of phage and the innate immune response on the bacterial clearance rate. Simulations predict a low impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage therapy clinical trials.

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Application Solid Laser-Sintered or Machined Ti6Al4V Alloy in Manufacturing of Dental Implants and Dental Prosthetic Restorations According to Dentistry 4.0 Concept

Processes ◽

10.3390/pr8060664 ◽

2020 ◽

Vol 8 (6) ◽

pp. 664 ◽

Cited By ~ 2

Author(s):

Leszek A. Dobrzański ◽

Lech B. Dobrzański ◽

Anna Achtelik-Franczak ◽

Joanna Dobrzańska

Keyword(s):

Dental Implants ◽

Computer Aided Design ◽

Bending Strength ◽

Ti6al4v Alloy ◽

Cnc Machining ◽

Live Cells ◽

Computer Aided ◽

Aided Design ◽

The Impact

This paper presents a comparison of the impact of milling technology in the computer numerically controlled (CNC) machining centre and selective laser sintering (SLS) and on the structure and properties of solid Ti6Al4V alloy. It has been shown that even small changes in technological conditions in the SLS manufacturing variant significantly affect changes from two to nearly two and a half times in tensile and bending strengths. Both the tensile and bending strength obtained in the most favourable manufacturing variant by the SLS method is over 25% higher than in the case of cast materials subsequently processed by milling. Plug-and-play SLS conditions provide about 60% of the possibilities. Structural, tribological and electrochemical tests were carried out. In vitro biological tests using osteoblasts confirm the good tendency for the proliferation of live cells on the substrate manufactured under the most favourable SLS conditions. The use of SLS additive technology for the manufacturing of dental implants and abutments made of Ti6Al4V alloy in combination with the digitisation of dental diagnostics and computer-aided design and manufacture of computer-aided design/manufacturing (CAD/CAM) following the idea of Dentistry 4.0 is the best choice of technology for manufacturing of prosthetic and implant devices used in dentistry.

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Development of a framework for whole-cell models creation

10.5753/bsb_estendido.2018.8796 ◽

2019 ◽

Author(s):

Frederico Chaves Carvalho ◽

Paulo Eduardo Ambrósio

Keyword(s):

Computer Aided Design ◽

Development Process ◽

Scientific Discovery ◽

Cell Models ◽

Whole Cell ◽

Early Stages ◽

Computer Aided ◽

Aided Design

The use of whole-cell models in research has the potential to be a powerful tool for scientific discovery, allowing researchers to test hypotheses faster than using in-vitro or in vivo methods. Such models can be considered the equivalent of Computer Aided Design for Biology. However, given their complexity, it is still difficult to employ them as an instrument in investigations. In order to solve this problem, we are developing a framework with the purpose to guide and help scientists through the process of creating whole-cell models faster, enabling them to use these tools as part of their research. This paper brings details of the early stages of the framework’s development process

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Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

Molecules ◽

10.3390/molecules25051104 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1104 ◽

Cited By ~ 2

Author(s):

Kristina Søborg Pedersen ◽

Christina Baun ◽

Karin Michaelsen Nielsen ◽

Helge Thisgaard ◽

Andreas Ingemann Jensen ◽

...

Keyword(s):

Computer Aided Design ◽

Ex Vivo ◽

Design Synthesis ◽

Psma Ligand ◽

Pet Tracer ◽

Positron Emission ◽

Tumor Accumulation ◽

Aided Design

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

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Antibacterial properties of thioridazine

Farmatsevtychnyi zhurnal ◽

10.32352/0367-3057.4.19.11 ◽

2019 ◽

pp. 96-104

Author(s):

N. Hrynchuk ◽

N. Vrynchanu

Keyword(s):

Antibacterial Activity ◽

Ex Vivo ◽

Antibacterial Properties ◽

Antimicrobial Properties ◽

Antibiotic Resistant ◽

In Vivo Experiments ◽

Antistaphylococcal Activity ◽

The Impact

The emergence and spread of antibiotic-resistant strains of microorganisms reduces the effectiveness of antibiotic therapy and requires finding solutions to problems, one of which is the study of antimicrobial properties in drugs of various pharmacological groups. The purpose of the work was to summarize the data on the antibacterial activity of thioridazine and its derivatives to determine the feasibility and prospects of creating new antibacterial drugs on their basis. The paper presents literature data on the effects of thioridazine on the causative agent of tuberculosis, antistaphylococcal activity, susceptibility of plasmodium and trypanosoma. The antibacterial activity of the drug was established within in vitro studies with the determination of MIC towards gram-positive and gram-negative microorganisms, ex vivo using macrophage lines, as well as within in vivo experiments on mice. It is established that the neuroleptic thioridazine is characterized by pronounced anti-tuberculosis activity, the mechanism of action is associated with the impact on the cell membrane of M. tuberculosis, inactivation by calmodulin and inhibition of specific NADH-dehydrogenase type II. The literature data indicate that thioridazine is able to increase the activity of isoniazid against the strains of mycobacteria that are susceptible and resistant to its action. It has been established that resistance to thioridazine in antibiotic-resistant M. tuberculosis strains is not formed. The drug is characterized by its ability to inhibit the growth and reproduction of both methicylin-sensitive (MSSA) and methicilin-resistant (MRSA) strains of Staphylococcus aureus, which has been proven within in vitro experiments. The effectiveness of thioridazine has been proven within in vivo experiments in case of skin infection and sepsis caused by S. aureus. Antimicrobial effect of the drug is also observed towards to plasmodium (P. falciparum) and trypanosomes (Trypanosoma spp.). Currently, the synthesis of thioridazine derivatives is carried out to identify compounds with a pronounced antibacterial effect. Some of the first synthesized compounds are not inferior or superior to thioridazine by the inhibitory effect. Thus, these data suggest that drugs of different pharmacological groups, including drugs that affect the nervous system - thioridazine and its derivatives, can be a source of replenishment of the arsenal of antimicrobial drugs to control such threatening infections as tuberculosis and diseases caused by polyresistant strains of microorganisms.

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Hyperthermic intraperitoneal chemotherapy with recombinant mutant human TNF-α and raltitrexed in mice with colorectal-peritoneal carcinomatosis

Experimental Biology and Medicine ◽

10.1177/1535370220905047 ◽

2020 ◽

Vol 245 (6) ◽

pp. 542-551

Author(s):

Qianyi Gong ◽

Changfeng Song ◽

Xiaotong Wang ◽

Renjie Wang ◽

Guoxiang Cai ◽

...

Keyword(s):

Colorectal Cancer ◽

Experimental Data ◽

Peritoneal Carcinomatosis ◽

Intraperitoneal Chemotherapy ◽

Hyperthermic Intraperitoneal Chemotherapy ◽

Antitumor Effect ◽

Tnf Α ◽

Colorectal Cancer Cells

Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. In vitro, we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. In vivo, we established xenograft models of CRC-PC and assessed the antitumor effect by in vivo imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly in vitro, and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited in vivo. Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application. Impact statement Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both in vitro and vivo. The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.

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Harnessing tumor immunity with chemotherapy: Mathematical modeling for decision-making in combinatorial regimen with immune-oncology drugs.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e14095 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e14095-e14095

Author(s):

Vesna Cuplov ◽

Guillaume Sicard ◽

Dominique Barbolosi ◽

Joseph Ciccolini ◽

Fabrice Barlesi

Keyword(s):

Mathematical Modeling ◽

T Cells ◽

In Silico ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells ◽

Model Parameters ◽

In Vivo Experiments ◽

The Impact

e14095 Background: Combining chemotherapy and immune checkpoint inhibitors (ICI) is challenging due to the near-infinite choice of dosing, scheduling and sequencing between drugs. The aim of this work is to develop a phenomenological model that describes the synergistic effect between cytotoxics and immune check point inhibitors in patients with cancer. Methods: Inspired from literature, we have developed an integrative mathematical model that includes tumor cells, cytotoxic T cells (CTLs) and regulatory T cells (TREGs) plus pharmacokinetics (PK) inputs. Loss in tumor mass is due to combined effect of direct chemotherapy-induced cytotoxicity and CTLs immune response, which is in turn inhibited by the tumor and mitigated by TREGs in the tumor micro-environment. The model describes as well the impact of chemotherapy-induced lymphodepletion on immune tolerance, whereas ICIs protect CTLs against tumor inhibition. Identification of model’s parameters and simulations of various scheduling were performed using Mlxplore software and a Python standalone code. In vitro and in vivo experiments using lung cancer models generate experimental data to adjust model parameters. Results: Complex interplays between cytotoxics and immune cells were best described by a 10-parameters model so as to ensure better identifiability. PK/PD relationships were integrated using compartmental modeling. In silico simulations show how changes in dosing and scheduling impact efficacy endpoints, an observation in line with data from the literature. Ongoing in vitro and in vivo experiments with pemetrexed-cisplatin doublet and anti-PD1 pembrolizumab help optimizing the model’s parameters in a self-learning loop. Conclusions: This work is at the frontier between mathematical modeling and experimental therapeutics with ICIs. In silico modeling and simulations could help narrow down the treatment choices and define optimal combinations prior to running clinical trials. Such model will help identify optimal dosing and scheduling, so as to achieve better synergism and efficacy.

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Variation in Clinical Application of Hyperthermic Intraperitoneal Chemotherapy: A Review

Cancers ◽

10.3390/cancers11010078 ◽

2019 ◽

Vol 11 (1) ◽

pp. 78 ◽

Cited By ~ 22

Author(s):

Roxan Helderman ◽

Daan Löke ◽

H. Kok ◽

Arlene Oei ◽

Pieter Tanis ◽

...

Keyword(s):

Intraperitoneal Chemotherapy ◽

Hyperthermic Intraperitoneal Chemotherapy ◽

Experimental Studies ◽

Effective Treatment Option ◽

Curative Intent ◽

Rapid Disease Progression ◽

Drug Concentrations

Peritoneal metastasis (PM) originating from gastrointestinal and gynecological malignancies are associated with a poor prognosis and rapid disease progression. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment option with curative intent. Hyperthermia enhances the cytotoxicity of chemotherapeutic drugs, thereby killing microscopic tumors and reducing the risk of tumor recurrence. Eight parameters potentially have an impact on the efficacy of HIPEC: the type of drug, drug concentrations, carrier solution, volume of the perfusate, temperature of the perfusate, duration of the treatment, the technique of delivery, and patient selection. In this review, a literature search was performed on PubMed, and a total of 564 articles were screened of which 168 articles were included. Although HIPEC is a successful treatment, there is no standardized method for delivering HIPEC: the choice of parameters is presently largely determined by institutional preferences. We discuss the current choice of the parameters and hypothesize about improvements toward uniform standardization. Quantifying the effect of each parameter separately is necessary to determine the optimal way to perform HIPEC procedures. In vivo, in vitro, in silico, and other experimental studies should shed light on the role of each of the eight parameters.

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Antimicrobial Properties of Apis mellifera’s Bee Venom

Toxins ◽

10.3390/toxins12070451 ◽

2020 ◽

Vol 12 (7) ◽

pp. 451 ◽

Cited By ~ 3

Author(s):

Hesham El-Seedi ◽

Aida Abd El-Wahed ◽

Nermeen Yosri ◽

Syed Ghulam Musharraf ◽

Lei Chen ◽

...

Keyword(s):

Antimicrobial Properties ◽

Bee Venom ◽

Biological Functions ◽

Volatile Metabolites ◽

In Vivo Experiments ◽

Anticancer Effects ◽

Bioactive Ingredients ◽

The Impact

Bee venom (BV) is a rich source of secondary metabolites from honeybees (Apis mellifera L.). It contains a variety of bioactive ingredients including peptides, proteins, enzymes, and volatile metabolites. The compounds contribute to the venom’s observed biological functions as per its anti-inflammatory and anticancer effects. The antimicrobial action of BV has been shown in vitro and in vivo experiments against bacteria, viruses, and fungi. The synergistic therapeutic interactions of BV with antibiotics has been reported. The synergistic effect contributes to a decrease in the loading and maintenance dosage, a decrease in the side effects of chemotherapy, and a decrease in drug resistance. To our knowledge, there have been no reviews on the impact of BV and its antimicrobial constituents thus far. The purpose of this review is to address the antimicrobial properties of BV and its compounds.

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Cryptococcus neoformans Secretes Small Molecules That Inhibit IL-1β Inflammasome-Dependent Secretion

Mediators of Inflammation ◽

10.1155/2020/3412763 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20

Author(s):

Pedro Henrique Bürgel ◽

Clara Luna Marina ◽

Pedro H. V. Saavedra ◽

Patrícia Albuquerque ◽

Stephan Alberto Machado de Oliveira ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Fungal Infections ◽

Virulent Strain ◽

Acanthamoeba Castellanii ◽

Conditioned Media ◽

Inflammasome Activation ◽

In Vivo Experiments ◽

The Impact

Cryptococcus neoformans is an encapsulated yeast that causes disease mainly in immunosuppressed hosts. It is considered a facultative intracellular pathogen because of its capacity to survive and replicate inside phagocytes, especially macrophages. This ability is heavily dependent on various virulence factors, particularly the glucuronoxylomannan (GXM) component of the polysaccharide capsule. Inflammasome activation in phagocytes is usually protective against fungal infections, including cryptococcosis. Nevertheless, recognition of C. neoformans by inflammasome receptors requires specific changes in morphology or the opsonization of the yeast, impairing proper inflammasome function. In this context, we analyzed the impact of molecules secreted by C. neoformans B3501 strain and its acapsular mutant Δcap67 in inflammasome activation in an in vitro model. Our results showed that conditioned media derived from B3501 was capable of inhibiting inflammasome-dependent events (i.e., IL-1β secretion and LDH release via pyroptosis) more strongly than conditioned media from Δcap67, regardless of GXM presence. We also demonstrated that macrophages treated with conditioned media were less responsive against infection with the virulent strain H99, exhibiting lower rates of phagocytosis, increased fungal burdens, and enhanced vomocytosis. Moreover, we showed that the aromatic metabolite DL-Indole-3-lactic acid (ILA) and DL-p-Hydroxyphenyllactic acid (HPLA) were present in B3501’s conditioned media and that ILA alone or with HPLA is involved in the regulation of inflammasome activation by C. neoformans. These results were confirmed by in vivo experiments, where exposure to conditioned media led to higher fungal burdens in Acanthamoeba castellanii culture as well as in higher fungal loads in the lungs of infected mice. Overall, the results presented show that conditioned media from a wild-type strain can inhibit a vital recognition pathway and subsequent fungicidal functions of macrophages, contributing to fungal survival in vitro and in vivo and suggesting that secretion of aromatic metabolites, such as ILA, during cryptococcal infections fundamentally impacts pathogenesis.

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