Novel Concept For Treatment Research Articles

O16 THE TOR-CONCEPT (TRAINING-OPERATION-REHABILITATION) APPLIED TO A COHORT OF POST-PARTUM WOMEN WITH SYMPTOMATIC DRA (DIASTASIS RECTI ABDOMINIS). EVALUATION OF PHYSICAL FUNCTION AND QUALITY OF LIFE ONE YEAR AFTER SURGERY

Abstract Aim Management of diastasis recti abdominis (DRA) differs regarding core training, surgical repair methods and post-operative rehabilitation. The purpose of this prospective cohort study was to evaluate the effect of a novel concept of treatment for DRA, the TOR-concept (Training, Operation and Rehabilitation). The concept includes preoperative evaluation of symptoms and instructed abdominal core training; tailored surgical repair of the DRA; and an individualized postoperative rehabilitation program. Material and Methods A cohort of seventy-five post-partum women with diagnosed DRA and training resistant core dysfunctions were evaluated and included to the study during 2018-2020. After surgery, all participants underwent an individualized supervised rehabilitation program with progressive increasing load for four months. Physical function was registered preoperatively and one year after surgery with the disability rating index (DRI) questionnaire. Quality of life (QoL) was assessed with the SF-36 questionnaire. The DRA and the surgical result were assessed with ultrasonography before and one year after surgery. Results Sixty-nine participants, 92%, completed the study. There were no DRA-recurrences at the 1-year follow-up. Early results shows that self-reported physical function, (DRI), improved in 88.8 % of patients, with a mean score improvement of 78.5 %. Quality of life, (SF-36), improved significantly compared with the preoperative scores, and reached a level similar to, or higher than, the normative Swedish female population. Conclusions In this cohort of post-partum women with DRA combined with core instability symptoms resistant to training, surgical reconstruction within the TOR-concept resulted in a significant improvement of physical function and QoL.

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in western countries. It is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. PDAC is characterized by a profound inflammatory tumor microenvironment (TME) comprising various non-neoplastic cells e.g., myofibroblasts, macrophages, T cells and endothelial cells which can exhibit different functional phenotypes. Furthermore, the microbiome is altered in the tumor and other body compartments of PDAC patients adding to the great TME heterogeneity and its impact on PDAC development, progression and therapy responses. This review summarizes the recent knowledge on the diverse phenotypes of these different stromal components. A better understanding of tumor cells as well as TME heterogeneity and considering tumor-suppressing and tumor-promoting phenotypes might provide an important step towards a more effective treatment for this highly malignant tumor.Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.

Antiarrhythmic therapy for atrial fibrillation: current guidelines of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery (ESC/EACTS)

The treatment of atrial fibrillation (AF) remains one of the most difficult tasks in modern cardiology. In 2020, the European Society of Cardiology (ESC), together with the European Association for Cardio-Thoracic Surgery (EACTS), published guidelines for the diagnosis and management of AF, which include several new directives.ESC experts have formulated a novel concept for treatment of AF patients. The first component of treatment ‘A' (Anticoagulation/ Avoid stroke) is anticoagulant therapy in patients with increased risk of thromboembolic events. The second line of treatment ‘B' (Better symptom control) is the control of arrhythmia symptoms, selection of a rhythm control strategy or ventricular rate control. The third direction ‘C' includes cardiovascular risk factors and comorbid conditions management.The most challenging tasks in AF treatment are the control of arrhythmia symptoms. As in the previous version of 2016 guidelines, the latest ones identify 2 following strategies in treatment of AF: rhythm control and ventricular rate control.According to the current ESC/EACTS guidelines (2020), antiarrhythmic therapy continues to be one of the important directions in AF management. Early prescription f antiarrhythmic and anticoagulant agents with an increased risk of thromboembolic events, catheter ablation can not only improve the quality of life, but also the prognosis of patients with AF.

A novel concept for treatment and vaccination against Covid‐19 with an inhaled chitosan‐coated DNA vaccine encoding a secreted spike protein portion

A novel concept in DNA vaccine design is the creation of an inhaled DNA plasmid construct containing a portion of the coronavirus spike protein for treatment and vaccination. The secretion of a spike protein portion will function as a competitive antagonist by interfering with the binding of coronavirus to the angiotensin‐converting enzyme 2 (ACE2) receptor. The secreted protein binding to the ACE2 receptor provides a unique mechanism of action for treatment to all strains of coronavirus in naïve patients, by blocking the ACE2 receptor site. An inhaled plasmid DNA vaccine replicates the route of lung infection taken by coronavirus with transfected cells secreting spike protein portions to induce immunity. Unlike most DNA vaccines with intracellular antigen presentation through MHC I, the current vaccine relies on the secreted proteins presentation through MHC II as well as MHC I to induce immunity. Lung specific production of vaccine particles by inhaled plasmid DNA is appealing since it may have limited systemic side effects, and may induce both humoral and cytotoxic immunity. Finally, the ease and ability to rapidly produce this plasmid construct makes this an ideal solution for managing the emerging threat of coronavirus.

Liquid buccal mucosa graft endoscopic urethroplasty: a validation animal study.

To validate a novel method of urethral stricture treatment using liquid buccal mucosal grafts (LBMG) to augment direct vision internal urethrotomy (DVIU) in an animal model. A rabbit stricture model was used to test this method. Strictures were induced in 26 rabbits using electroresection of urethral epithelium. The animals were randomized into two groups: Group-1, treated with DVIU and LBMG in fibrin glue, and Group-2, DVIU with fibrin glue only. LBMG was prepared by suspension of mechanically minced buccal mucosa micrografts in fibrin glue. This LBMG-fibrin glue mixture was later injected into the urethrotomies of Group-1 animals. All animals were killed at 24weeks after repeat retrograde urethrogram (RUG) and urethroscopy by surgeon blinded to the treatment arm. Radiographic images and histological specimens were reviewed by a radiologist and a pathologist, respectively, blinded to the treatment arm. Stricture treatment was considered a success if a diameter measured on RUG increased by ≥ 50% compared to pre-treatment RUG diameter. Histological specimens were assessed for the presence of BMG engraftment. In Group-1, 8/12(67%) animals demonstrated engraftment of LBMG, compared to none in Group-2 (p = 0.0005). 7/12(58%) in Group-1 showed radiographic resolution/improvement of strictures compared to 5/13 Group-2 rabbits (38%, p = 0.145). The median percent change for the Group-1 was 59%, compared to 41.6% for Group-2 (p = 0.29). This proof-of-concept study demonstrates feasibility of LBMG for endoscopic urethral stricture repairs. Further studies are needed to establish the role of this novel concept in treatment of urethral strictures.

Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice.

Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies. A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice. Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09-123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect. Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS.

Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo

We aimed to identify potent biliverdin reductase (BVRA) inhibitors as a novel concept for the treatment of severe unconjugated hyperbilirubinemia. 1280 FDA-approved compounds were screened in vitro for their ability to inhibit human and rat BVRA activity and 26 compounds were identified as BVRA inhibitors. Montelukast and Disulfiram were selected as potentially clinically applicable drugs and tested to reduce serum unconjugated bilirubin (UCB) levels in the Ugt1a1-deficient rat, a model for chronic unconjugated hyperbilirubinemia. Oral administration of Disulfiram was toxic in the Ugt1a1-deficient rat (weight loss, transaminase elevation). Oral Montelukast administration led to low serum concentrations and did not alter serum UCB levels. Intraperitoneal injections of Montelukast resulted in concentrations up to 110 μmol/L in serum and 400 μmol/L in the liver. Still, serum UCB levels remained unaltered. This first study on biliverdin reductase inhibition as a novel concept for treatment of unconjugated hyperbilirubinemia identified putative in vitro BVRA inhibitors. Montelukast, the clinically most suitable inhibitor, did not result in reduction of serum UCB in the Ugt1a1-deficient rat. The proposed treatment strategy will not result in amelioration of severe unconjugated hyperbilirubinemia in humans without the identification or development of more potent BVRA inhibitors.

Polysialinsäure zur Immunmodulation im Tiermodell der feuchten altersabhängigen Makuladegeneration (AMD)

Background Chronic activation of the innate immune system is a hallmark of retinal degenerative diseases, including age-related macular degeneration (AMD). Overt microglia and macrophage reactivity, as well as dysregulation of the alternative complement system, trigger and sustain retinal degeneration. It is now accepted that there exists a vicious cycle of mononuclear phagocyte reactivity, abnormal intrinsic complement activation, damage of Bruch's membrane, dysfunction of the retinal pigment epithelium, photoreceptor degeneration and choroidal neovascularization (CNV). Targeting the innate immune system may, therefore, be a complementary approach to anti-angiogenic therapy. This article presents data from polysialic acid treatment experiments in the laser-induced mouse model of wet AMD. Material and Methods The laser-CNV mouse model was used to simulate events of neovascular AMD. Polysialic acid was applied by intravitreal injection and microglia activity was assessed with Iba1 staining of retinal and RPE/choroidal flat mounts. Neovascular leakage was determined by fluorescein angiography. Results Intravitreal injection of polysialic acid reduced retinal and RPE/choroidal lesion-associated microglia activity in the laser-induced mouse model of AMD. Polysialic acid treatment also diminished vascular leakage at laser spots in this model. Conclusion Local retinal immunomodulation with polysialic acid presents a novel concept for treatment of inflammatory conditions related to neovascular AMD.

767. A Novel Humanized Mouse Model for Testing Anti-HIV T-Cell Gene Therapy Strategies

Despite major advances in the therapeutic treatment of individuals infected with HIV using anti-retroviral therapies (ART), patients are not cured. Deviation from standard drug administration can lead to rapid rebound of viremia, and the emergence of drug-resistant variants. New approaches for treatment of HIV include a range of techniques from gene therapies to vaccine studies. Many of these methods utilize animal models to test the efficacy of treatment prior to advancing to clinical settings. Humanized mouse models have been invaluable for such strategies. Immune compromised mice can engraft with human hematopoietic stem cells (HSC), give rise to a functional human immune system, and maintain an HIV infection. A novel concept for treatment involves engineering a specific immune response against infected cells using chimeric antigen receptors (CAR) to viral epitopes on infected cells. These CAR modified T cells have been used in the preliminary treatment of some cancers, where modified cells lead to the elimination of target cancer cells. A similar approach is being investigated now for HIV. While progress has been made on creating engineered receptors, there has not been a good pre-clinical animal model to test them in. We address this problem by building on the well characterized NOD-scid-gamma (NSG) animal model of HIV treatment, and adapted it to test the functionality of T cell-based immunotherapies. To better model the clinical setting, we use adult apheresis HSCs from healthy mobilized donors as the source for engraftment instead of cord blood or fetal tissue. Neonatal NSG mice injected with these harvested HSCs give rise to over 90% CD3 T-cells in the human fraction circulating in the blood unlike other models which don't readily develop T-cells. Instead of using additional sources for T-cell collection, we harvested CD3 cells directly from the mice, cultured, expanded, and transduced them using GFP expressing lentiviral vectors, and re-infused them back into the mice. The modified CD3 cells were detected in the peripheral blood with frequencies reaching 50% of total CD3 cells without the symptoms of graft-vs-host disease. These cells persisted for over two months and were also found in all lymphoid tissues analyzed at necropsy. To assess safety of vector modified cells, we utilized integration site (IS) analysis to measure the clonal repertoire of injected cells. While over 500 unique clones were detected, we did not observe indications of clonal outgrowth in animals over the course of the experiment. Mice receiving the engrafted HSCs and transduced CD3 cells were capable of sustaining HIV infection with titers between 105-107 viral copies/mL and demonstrated significant CD4 depletion in both blood and lymphoid tissues. With the establishment of this clinically relevant model for testing the effectiveness of T-cell based therapies to treat HIV, we are beginning to test anti-HIV engineered cells. By building upon the existing animal models and combining T-cell gene therapy approaches with IS to monitor for vector safety, we have established a novel method for testing new anti-HIV cure therapies.

Synthesis and characterization of calcium phosphate loaded with Ho-166 and Sm-153: a novel biomaterial for treatment of spine metastases

Spine metastases are a common and painful complication of cancer. A novel concept of treatment combines the in situ vertebroplasty with radiotherapy employing radioactive bone cement into the human vertebrae. Thus, investigations concerning possible bioactive and radioactive cements become a relevant theme. In this work, we have synthesized calcium phosphate bioceramics incorporated with Ho and Sm nuclides using sol-gel technique. Characterizations were performed using X-ray diffractometry, infrared spectroscopy, scanning electron microscopy, instrumental neutron activation analysis, and gamma spectroscopy. Results showed bioceramics composed by multiphasic calcium phosphates along with holmium and samarium phosphates, with 8.9 and 13.7 % of Sm and Ho in weight, respectively. After neutron activation, the Ho-166 and Sm-153 beta-emitters were identified and quantified on the bioceramics with activities estimated at 32.5 and 14.5 MBq/mg of Sm-153 and Ho-166 bioceramic powder, respectively. These radioactive calcium phosphate bioceramics can compose suitable radioactive cements to radiovertebroplasty.

Boosting the hypoxia-induced adaptive response in inflammatory bowel disease: A novel concept of treatment

As cells critically depend on oxygen for function and survival, inadequate cellular oxygenation is a major factor in the pathogenesis of a number of life-threatening diseases. Not surprisingly, cells share adaptive mechanisms to protect them against low-oxygen conditions. The recent discovery of a new family of oxygen-dependent hydroxylases has markedly increased the understanding of these adaptive processes, which in turn has led to the identification of new therapeutic targets for the treatment of conditions associated with enhanced hypoxia, such as a number of vascular and inflammatory diseases. This mini-review focuses on inhibition of hydroxylases as a potential novel treatment option for inflammatory bowel disease. Current knowledge, as well as future directions, are summarized and discussed.

Targeted PLGA microparticles as a novel concept for treatment of lactose intolerance

Background Peroral β-galactosidase preparations for the management of lactose intolerance need to be administered in large doses (1500 to 6000 U) immediately before or together with a lactose-containing meal. Aim Therefore, this work aimed at developing an innovative long-acting formulation. For this purpose, biodegradable polymeric microcarriers were functionalized with β-galactosidase and targeted with wheat germ agglutinin (WGA) for bioadhesion and thus prolonged residence time in the small intestine. Methods Spray-dried poly( d, l-lactide-co-glycolide) (PLGA) particles with 2.78 ± 1.05 µm in diameter were functionalized with β-galactosidase from Kluyveromyces lactis and WGA using different types of spacers (polyethyleneimine, hexamethylene diamine, 6-aminocaproic acid) and coupling methods (carbodiimide and glutaraldehyde). The particle-bound enzyme activity was determined, and the bioadhesive characteristics were assessed by interaction with mucin coatings and Caco-2 cell monolayers. Results Up to 1470 U β-galactosidase per gram PLGA were immobilized. The best results were obtained with hexamethylene diamine as a spacer applying the carbodiimide method. Thereby, a nearly 6-fold increase in enzyme activity was obtained as compared to particles without spacer. Upon targeting with WGA, binding to artificial human intestinal epithelium was increased considerably. Conclusions For the delivery of β-galactosidase WGA-targeted PLGA microparticles were prepared, which represent promising candidates for a convenient biomimetic treatment regimen of lactose intolerance.

Targeted PLGA-Microparticles as a Novel Concept for Treatment of Lactose Intolerance

Background: Lactose intolerance is the inability to metabolize lactose because of the absence of the enzyme lactase. It is estimated that 75–90% of birth lactase levels are lost by most people after weaning. [...]

Chronic inflammation in asthma: a contest of persistence vs resolution

Recent investigations have highlighted that endogenous anti-inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th-2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro-inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter-regulatory mechanisms that co-determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti-inflammatory pathways, rather than solely antagonising the various pro-inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti-inflammatory mediators in clinical and experimental asthma.

A novel concept of treatment of diffuse or multiple pleural tumors by boron neutron capture therapy (BNCT)

Two patients, one with malignant pleural mesothelioma and one with a malignant short spindle cell tumor, received boron neutron capture therapy (BNCT). In each case, the tumors regressed or remained stable in size for 3–6 months following BNCT. No acute or late adverse events higher than grade 2 were observed.

Off-line bioartificial liver: a novel concept of treatment and its potency of liver regeneration

Off-line bioartificial liver: a novel concept of treatment and its potency of liver regeneration