Machine learning models to identify lead compound and substitution optimization to have derived energetics and conformational stability through docking and MD simulations for sphingosine kinase 1.

Sphingosine kinases (SphKs) are a group of important enzymes that circulate at low micromolar concentrations in mammals and have received considerable attention due to the roles they play in a broad array of biological processes including apoptosis, mutagenesis, lymphocyte migration, radio- and chemo-sensitization, and angiogenesis. In the present study, we constructed three classification models by four machine learning (ML) algorithms including naive bayes (NB), support vector machine (SVM), logistic regression, and random forest from 395 compounds. The generated ML models were validated by fivefold cross validation. Five different scaffold hit fragments resulted from SVM model-based virtual screening and docking results indicate that all the five fragments exhibit common hydrogen bond interaction a catalytic residue of SphK1. Further, molecular dynamics (MD) simulations and binding free energy calculation had been carried out with the identified five fragment leads and three cocrystal inhibitors. The best 15 fragments were selected. Molecular dynamics (MD) simulations showed that among these compounds, 7 compounds have favorable binding energy compared with cocrystal inhibitors. Hence, the study showed that the present lead fragments could act as potential inhibitors against therapeutic target of cancers and neurodegenerative disorders.

Vanek's Tumour as a Rare Cause of Dyspeptic Syndrome in a Patient with Primary Biliary Cholangitis: A Case Report.

BACKGROUND: Inflammatory Fibroid Polyp (IFP), also known as Vanek's tumour, is a rare mesenchymal gastrointestinal tumour, potentially causing a wide range of clinical manifestations (even though it can be completely asymptomatic) primarily related to the location of the formation. The available evidence suggests a fundamentally non-neoplastic behaviour of IFP. CASE PRESENTATION: A 67-year-old female was presented with persistent dyspepsia despite symptomatic therapy. The patient's medical history included primary biliary cholangitis, managed with ursodeoxycholic acid, non-haemorrhagic uterine fibroids, and right knee arthrosis. Clinical examination revealed mild epigastric tenderness, and esophagogastroduodenoscopy identified a sessile mucosal formation. Histological analysis of biopsy samples revealed a gastric hyperplastic polyp, leading to a subsequent esophagogastroduodenoscopy for polypectomy. The excised specimen confirmed the diagnosis of gastric IFP. Post-polypectomy, the patient experienced progressive symptom amelioration, leading to complete resolution within three weeks. DISCUSSION: This case thus describes a rare cause of dyspeptic syndrome associated with the presence of a gastric IFP, promptly managed and resolved after endoscopic removal of the polyp, with no histological signs of neoplasia within the en bloc resected sample. CONCLUSION: IFP is a possible and rare cause of dyspeptic syndrome. There remain significant challenges in diagnosing this rare condition, which lacks pathognomonic or specific signs and symptoms of its presence (especially when it causes symptoms). Endoscopy, when feasible, remains a cornerstone in the resective management of such lesions.

ATP-induced fibrogenic pathway in circulating cells obtained by idiopathic pulmonary fibrotic (IPF) patients is not blocked by nintedanib and pirfenidone.

Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFß. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFß. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFß induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.

Removal of the infrapatellar fat pad and associated synovium benefits female guinea pigs in the Dunkin Hartley model of idiopathic osteoarthritis.

Background: Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of sex, is the infrapatellar fat pad (IFP). We previously demonstrated that removal of the IFP had short-term beneficial effects for a cohort of male Dunkin-Hartley guinea pigs. The present project was designed to elucidate the influence of IFP removal in females of this OA-prone strain. It was hypothesized that resection of the IFP would reduce the development of OA in knees of a rodent model predisposed to the disease. Methods: Female guinea pigs (n=16) were acquired at an age of 2.5 months. Surgical removal of the IFP and associated synovium complex (IFP/SC) was executed at 3 months of age. One knee had the IFP/SC resected; a comparable sham surgery was performed on the contralateral knee. All animals were subjected to voluntary enclosure monitoring and dynamic weight-bearing, as well as compulsory treadmill-based gait analysis monthly; baseline data was collected prior to surgery. Guinea pigs were euthanized at 7 months. Knees from eight animals were evaluated via histology, mRNA expression, and immunohistochemistry (IHC); knees from the remaining eight animals were allocated to microcomputed tomography (microCT), biomechanical analyses (whole joint testing and indentation relaxation testing), and atomic absorption spectroscopy (AAS). Results: Fibrous connective tissue (FCT) replaced the IFP/SC. Mobility/gait data indicated that unilateral IFP/SC removal did not affect bilateral hindlimb movement. MicroCT demonstrated that osteophytes were not a significant feature of OA in this sex; however, trabecular thickness (TbTh) in medial femorae decreased in knees containing the FCT. Histopathology scores were predominantly influenced by changes in the lateral tibia, which demonstrated that histologic signs of OA were increased in knees containing the native IFP/SC versus those with the FCT. Similarly, indentation testing demonstrated higher instantaneous and equilibrium moduli in the lateral tibial articular cartilage of control knees with native IFPs. AAS of multiple tissue types associated with the knee revealed that zinc was the major trace element influenced by removal of the IFP/SC. Conclusions: Our data suggest that the IFP/SC is a significant component driving knee OA in female guinea pigs and that resection of this tissue prior to disease has short-term benefits. Specifically, the formation of the FCT in place of the native tissue resulted in decreased cartilage-related OA changes, as demonstrated by reduced Osteoarthritis Research Society International (OARSI) histology scores, as well as changes in transcript, protein, and cartilage indentation analyses. Importantly, this model provides evidence that sex needs to be considered when investigating responses and associated mechanisms seen with this intervention.

Interfascial planes as surgical landmarks for laparoscopic upper retroperitoneal surgery: a cadaveric and retrospectively clinical study.

Background: Radiologists currently accept the concept of "interfascial plane (IFP)" to understand retroperitoneal anatomy, replacing Meyers' classic tricompartmental theory. Despite much research on retroperitoneal anatomy, its anatomical structure, embryonic origin and developmental process still require further exploration to guide the optimization of surgical process. This study aims to explore the anatomical basis of IFP related to laparoscopic upper retroperitoneal surgery (LURS) and to compare the clinical outcomes of trans-interfascial plane procedures for LURS (TIFP-LURS) with conventional LURS (Con-LURS). Methods: The study consisted of two parts: cadaveric and clinical study. The cadaveric study involved dissecting and observing the retroperitoneal fasciae and IFP in 32 cadavers using gross anatomical and histological methods. This retrospective clinical study compared the perioperative data and complications of 229 patients who underwent TIFP-LURS and 121 patients who underwent Con-LURS for upper retroperitoneal lesions at our center. Results: The cadaveric study revealed that the retroperitoneal space was composed of multilaminar fasciae that formed potential bloodless spaces among them, that could be used as surgical landmarks and operating planes. The clinical study showed that TIFP-LURS had a significantly less estimated blood loss, lower intraoperative complication rate, lower postoperative complication rate, shorter hospital-stay and lower long-term postoperative complications rate than Con-LURS. Multivariate analysis indicated that the TIFP procedure was an independent protective factor for decreasing the risk of postoperative complications. Conclusions: The IFP are potential avascular spaces that can be used during laparoscopic surgery, and TIFP-LURS is a novel surgical approach that can improve the safety and efficacy of laparoscopic surgery for upper retroperitoneal lesions.

Regulation of IFP in solid tumours through acoustic pressure to enhance infiltration of nanoparticles of various sizes.

Numerous nanomedicines have been developed recently that can accumulate selectively in tumours due to the enhanced permeability and retention (EPR) effect. However, the high interstitial fluid pressure (IFP) in solid tumours limits the targeted delivery of nanomedicines. We were previously able to relieve intra-tumoural IFP by low-frequency non-focused ultrasound (LFNFU) through ultrasonic targeted microbubble destruction (UTMD), improving the targeted delivery of FITC-dextran. However, the accumulation of nanoparticles of different sizes and the optimal acoustic pressure were not evaluated. In this study, we synthesised Cy5.5-conjugated mesoporous silica nanoparticles (Cy5.5-MSNs) of different sizes using a one-pot method. The Cy5.5-MSNs exhibited excellent stability and biosafety regardless of size. MCF7 tumour-bearing mice were subjected to UTMD over a range of acoustic pressures (0.5, 0.8, 1.5 and 2.0 MPa), and injected intravenously with Cy5.5-MSNs. Blood perfusion, tumour IFP and intra-tumoural accumulation of Cy5.5-MSNs were analysed. Blood perfusion and IFP initially rose, and then declined, as acoustic pressure intensified. Furthermore, UTMD significantly enhanced the accumulation of differentially sized Cy5.5-MSNs in tumour tissues compared to that of the control group, and the increase was sevenfold higher at an acoustic pressure of 1.5 MPa. Taken together, UTMD enhanced the infiltration and accumulation of Cy5.5-MSNs of different sizes in solid tumours by reducing intra-tumour IFP.

The African National Congress's factionalism and targeted killings as risks to human security in KwaZulu-Natal province.

A prevalence of political violence and political assassinations characterised post-1994 South Africa. These politically motivated killings appeared to be dominant in the controversial KwaZulu-Natal (KZN) province. Political killings in South Africa started as a form of inter-party warfare, especially during the transition to democracy, when the two rivals, the African National Congress (ANC) and the Inkatha Freedom Party (IFP), fought each other for some areas of Gauteng and KwaZulu-Natal provinces. However, following the dominance of the ANC in the KZN Province, members of the ruling party fought each other for positions in government and political party structures. Considering this, the article analyses the crisis of factionalism by examining the ANC's intra-party tensions and targeted killings, and how this poses a risk to human security in KZN. Methodologically, the article employs a qualitative literature assessment and content analysis is used to delve into the impact of intra-party tensions and targeted killings on human security in the KZN province. Contribution: In quest for curbing the crisis of factionalism in the ruling ANC, the article recommends that the ANC needs to re-visit its leadership selection as these killings have seemingly happened during leadership selection, which leads to ruthless competition of positions in government and party structures. Members of the ruling party need to identify themselves as one, as opposed to belonging to different factional groups within the party. Failure by the ruling party to address divisions within the organisation shall result in more fatal killings resulting from competition for positions and resources.

Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal.

During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.

Single cell transcriptome profiling of infrapatellar fat pad highlights the role of interstitial inflammatory fibroblasts in osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is a whole-joint disease in which the role of the infrapatellar fat pad (IFP) in its pathogenesis is unclear. Our study explored the cellular heterogeneity of IFP to understand OA and identify therapeutic targets. METHODS: Single-cell and single-nuclei RNA sequencing were used to analyze 10 IFP samples, comprising 5 from OA patients and 5 from healthy controls. Analyses included differential gene expression, enrichment, pseudotime trajectory, and cellular communication, along with comparative studies with visceral and subcutaneous fats. Key subcluster and pathways were validated using multiplex immunohistochemistry. RESULTS: The scRNA-seq performed on the IFPs of the OA and control group profiled the gene expressions of over 49,674 cells belonging to 11 major cell types. We discovered that adipose stem and progenitor cells (ASPCs), contributing to the formation of both adipocytes and synovial-lining fibroblasts (SLF). Interstitial inflammatory fibroblasts (iiFBs) were a subcluster of ASPCs that exhibit notable pro-inflammatory and proliferative characteristics. We identified four adipocyte subtypes, with one subtype showing a reduced lipid synthesis ability. Furthermore, iiFBs modulated the activities of macrophages and T cells in the IFP. Compared to subcutaneous and visceral adipose tissues, iiFBs represented a distinctive subpopulation of ASPCs in IFP that regulated cartilage proliferation through the MK pathway. CONCLUSION: This study presents a comprehensive single-cell transcriptomic atlas of IFP, uncovering its complex cellular landscape and potential impact on OA progression. Our findings highlight the role of iiFBs in OA, especially through MK pathway, opening new avenues for understanding OA pathogenesis and developing novel targeted therapies.

Effect of interstitial fluid pressure on shear wave elastography: an experimental and computational study.

Objective. An elevated interstitial fluid pressure (IFP) can lead to strain-induced stiffening of poroelastic biological tissues. As shear wave elastography (SWE) measures functional tissue stiffness based on the propagation speed of acoustically induced shear waves, the shear wave velocity (SWV) can be used as an indirect measurement of the IFP. The underlying biomechanical principle for this stiffening behavior with pressurization is however not well understood, and we therefore studied how IFP affects SWV through SWE experiments and numerical modeling.Approach. For model set-up and verification, SWE experiments were performed while dynamically modulating IFP in a chicken breast. To identify the confounding factors of the SWV-IFP relationship, we manipulated the material model (linear poroelastic versus porohyperelastic), deformation assumptions (geometric linearity versus nonlinearity), and boundary conditions (constrained versus unconstrained) in a finite element model mimicking the SWE experiments.Main results. The experiments demonstrated a statistically significant positive correlation between the SWV and IFP. The model was able to reproduce a similar SWV-IFP relationship by considering an unconstrained porohyperelastic tissue. Material nonlinearity was identified as the primary factor contributing to this relationship, whereas geometric nonlinearity played a smaller role. The experiments also highlighted the importance of the dynamic nature of the pressurization procedure, as indicated by a different observed SWV-IFP for pressure buildup and relaxation, but its clinical relevance needs to be further investigated.Significance. The developed model provides an adaptable framework for SWE of poroelastic tissues and paves the way towards non-invasive measurements of IFP.

IFP35 aggravates Staphylococcus aureus infection by promoting Nrf2-regulated ferroptosis.

INTRODUCTION: Serious Staphylococcus aureus (SA) infection is one of the most life-threatening diseases. Interferon-induced protein 35 (IFP35) is a pleiotropic factor that participates in multiple biological functions, however, its biological role in SA infection is not fully understood. Ferroptosis is a new type of regulated cell death driven by the accretion of free iron and toxic lipid peroxides and plays critical roles in tissue damage. Whether ferroptosis is involved in SA-induced immunopathology and its regulatory mechanisms remain unknown. OBJECTIVES: We aimed to determine the role and underlying mechanisms of IFP35 in SA-induced lung infections. METHODS: SA infection models were established using wild-type (WT) and IFP35 knockout (Ifp35-/-) mice or macrophages. Histological analysis was performed to assess lung injury. Quantitative real-time PCR, western blotting, flow cytometry, and confocal microscopy were performed to detect ferroptosis. Co-IP and immunofluorescence were used to elucidate the molecular regulatory mechanisms. RESULTS: We found that IFP35 levels increased in the macrophages and lung tissue of SA-infected mice. IFP35 deficiency protected against SA-induced lung damage in mice. Moreover, ferroptosis occurred and contributed to lung injury after SA infection, which was ameliorated by IFP35 deficiency. Mechanically, IFP35 facilitated the ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), aggravating SA-induced ferroptosis and lung injury. CONCLUSIONS: Our data demonstrate that IFP35 promotes ferroptosis by facilitating the ubiquitination and degradation of Nrf2 to exacerbate SA infection. Targeting IFP35 may be a promising approach for treating infectious diseases caused by SA.

CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions.

The onset and progression of human inflammatory joint diseases are strongly associated with the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived mesenchymal stem/stromal cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic effects are largely exerted via their CD10-bound small extracellular vesicles (IFP-MSC sEVs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC sEVs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their sEV miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low sEVs on stimulated by inflammatory/fibrotic cues synoviocyte monocultures and cocultures with IFP-MSC-derived chondropellets. Finally, CD10High sEVs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low sEVs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in sEVs showed their involvement in the regulation of six gene groups, particularly those involving the immune system. Stimulated synoviocytes exposed to IFP-MSC sEVs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High sEV treatment of stimulated chondropellets/synoviocyte cocultures indicated significant chondroprotective effects. Therapeutically, CD10High sEV treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High sEVs possess immunomodulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for sEV-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).

Inflammatory fibroid polyp of the renal pelvis: first report at an extra-gastrointestinal site with molecular confirmation.

Inflammatory fibroid polyps (IFP) are rare and benign mesenchymal tumours of the gastrointestinal tract. They are submucosal spindle cell lesions with an eosinophilic-rich inflammatory infiltrate and mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. In this report, we present the case of a 74-year-old female with a solid tumour of the kidney, which presented as a bland proliferation of spindle cells with thin-walled blood vessels and an inflammatory infiltrate with eosinophilic granulocytes. Immunohistochemistry revealed a positivity for vimentin and a weak staining for CD99 and CD34 in the spindle cells. Because of the morphological similarity to IFPs of the gastrointestinal tract, a molecular pathology analysis was performed. This identified an oncogenic mutation in exon 18 of the PDGFRA gene, which is characteristic for inflammatory fibroid polyps of the gastrointestinal tract. To the best of our knowledge, this is the first case of an IFP in the urogenital tract.

Comparison of the yields and properties of dedifferentiated fat cells and mesenchymal stem cells derived from infrapatellar fat pads.

Introduction: Infrapatellar fat pad (IFP)-derived mesenchymal stem cells (MSCs) have high chondrogenic potential and are attractive cell sources for cartilage regeneration. During ceiling culture to acquire the characteristics of MSCs, mature adipocytes from fat tissue are known to undergo dedifferentiation, generating dedifferentiated fat (DFAT) cells. The purpose of the present study was to compare the yields and biological properties of IFP-derived MSCs and IFP-derived DFAT cells. Methods: IFPs were harvested from the knees of 8 osteoarthritis (OA) patients. DFAT cells were obtained using a ceiling culture of adipocytes isolated from the floating top layer of IFP digestion. MSCs were obtained by culturing precipitated stromal vascular fraction cells. We compared the P0 cell yields, surface antigen profile, colony formation ability, and multipotency of DFAT cells and MSCs. Results: The P0 cell yields per flask and the estimated total cell yields from 1 g of IFP were much greater for MSCs than for DFAT cells. Both MSCs and DFAT cells were positive for MSC markers. No obvious difference was observed in colony formation ability. In differentiation assays, DFAT cells produced greater amounts of lipid droplets, calcified tissue, and glycosaminoglycan than MSCs did. Adipogenic and chondrogenic gene expressions were upregulated in DFAT cells. Conclusions: IFP-derived DFAT cells showed higher adipogenic and chondrogenic potentials than IFP-derived MSCs, but they had a poor cell yield.

Ileo-ileal intussusception due to inflammatory fibroid polyp: a rare cause of small bowel obstruction in adults.

Intussusception in adults is a relatively uncommon occurrence for a cause of bowel obstruction, which can present acutely, chronically or in an acute on chronic fashion. It is clinically concerning because of the possibility of cancer acting as a lead point. Small bowel tumours are rare, mostly detected incidentally with small bowel obstruction. Inflammatory fibroid polyp (IFP) is a rare benign tumour of the small bowel, either detected incidentally on imaging or endoscopy carried out for other reasons, or presents with acute features. We present a case of small bowel intussusception caused by IFP within the distal third of the ileum as a leading point. The patient presented acutely with small bowel obstruction, on a background of recurrent non-specific abdominal pain over the preceding month, and the computed tomography scan revealed an intussusception that was timely managed with a laparoscopy-assisted small bowel segmental resection.

Infiltration of the Hoffa's fat pad with stromal vascular fraction in patients with osteoarthritis of the knee -Results after one year of follow-up.

Objectives: Cell therapy using multipotential stromal cells (MSCs) is being used in a variety of clinical settings to induce tissue regeneration. Promising results have also been achieved in the therapy of osteoarthritis. MSCs have been demonstrated to be safe (Borakati et al., 2018). They can be used in a one step procedure as minimally manipulated mesenchymal stem cells or after in vitro expansion. The in vitro step allows for the selection of a more homogeneous cell population, meeting the standard criteria for MSC identification (Lv et al., 2014). In vitro expansion of MSCs is cost intensive, time consuming and furthermore associated with gradual accumulation of senescent cells (Wagner et al., 2008), telomere erosion (Baxter et al., 2004), and changing phenotypes (Jones et al., 2010; Halfon et al., 2011). These disadvantages could be surpassed by the use of "minimally manipulated mesenchymal stem cells" from bone marrow or adipose tissue (Di Matteo et al., 2019) such as the adipogenic stromal-vascular fraction (SVF).The study investigates whether infiltration of the Hoffa fat pad with autologous SVF is an effective and safe treatment option for patients with gonarthrosis. Furthermore, the number and vitality of the injected cells as well as the clinical efficacy will be evaluated. Materials and methods: We conduct a prospective study. Patients with osteoarthritis of the knee receive infiltration of SVF into the Hoffa fat pad. The number and vitality of the cells are measured with a cell counter. The clinical outcome is checked using VAS, KOOS and SF12 questionnaires with a follow-up period of 1 year. Results: A total of 33 patients and 36 knees were included in this Study. An average of 45 million cells were injected with a standard deviation of 2,5 million Cells. After 6 months a significant improvement of the VAS and the respective subscales of the KOOS could be observed compared to the baseline. After one year of follow-up, a significant improvement in all KOOS subscales compared to baseline was still observed. A significant correlation between reduced knee pain on the VAS and the number of injected cells could be observed as well. Thus, patients injected with a higher number of cells seem to have a better outcome. The average viability of the cells was 64,4% with a standard deviation of 15,9%. A correlation between higher cell viability and better outcome on the QOL subscale of the KOOS was observed. There were no major complications or side effects. Discussion: These initial results indicate that treatment with SVF is a safe therapeutic option that has the potential to relieve joint pain and significantly improved function. The cell number and vitality of the injected cells appear to be important factors influencing the success of the therapy.

Case Report: Ileo-Ileal Intussusception Secondary to Inflammatory Fibroid Polyp: A Rare Cause of Intestinal Obstruction.

Introduction: Intussusception is a telescoping of a bowel segment into another and it can be a surgical urgency. Most adult intussusceptions arise from a lead point which can be benign or malignant. For this reason, intussusception in adults should undergo surgery. Here we describe a case of ileal inflammatory fibroid polyp (IFP), presenting with ileo-ileal intussusception and obstruction. Case report: A 54-year-old Caucasian woman presented for acute abdominal pain. A radiography and a CT of the abdomen were performed, which showed signs of occlusion due to an ileo-ileal intussusception. An urgent laparoscopy was performed, the intussusception was extracorporeally reduced, the ileal segment involved was resected, and an ileo-ileal anastomosis was performed. The intussusception seemed to be caused by a 3-cm intra-mural lesion. Discussion: Intussusception is a surgical concern. While most cases are idiopathic in children, 90% of adult intussusceptions are caused by underlying diseases. Therefore, intussusception in adults should undergo surgery. Radiology is necessary for the diagnosis: the CT scan helps localizing the lesion and shows pathognomonic signs. This case report analyzes an intussusception caused by an inflammatory fibroid polyp. Accurate diagnosis of IFP is only possible with histopathological examination, helped by immunohistochemistry. The differential diagnosis is important because some lesions are malignant. Conclusion: We reported a case of intussusception caused by an IFP. The diagnosis was made with a CT scan together with intraoperative findings and histopathological examination, which excluded potential differential diagnoses. The patient underwent an explorative laparoscopy, with an ileal resection and anastomosis. Due to the risk of malignancy, surgery is mandatory.

Towards principled design of cancer nanomedicine to accelerate clinical translation.

Nanotechnology in medical applications, especially in oncology as drug delivery systems, has recently shown promising results. However, although these advances have been promising in the pre-clinical stages, the clinical translation of this technology is challenging. To create drug delivery systems with increased treatment efficacy for clinical translation, the physicochemical characteristics of nanoparticles such as size, shape, elasticity (flexibility/rigidity), surface chemistry, and surface charge can be specified to optimize efficiency for a given application. Consequently, interdisciplinary researchers have focused on producing biocompatible materials, production technologies, or new formulations for efficient loading, and high stability. The effects of design parameters can be studied in vitro, in vivo, or using computational models, with the goal of understanding how they affect nanoparticle biophysics and their interactions with cells. The present review summarizes the advances and technologies in the production and design of cancer nanomedicines to achieve clinical translation and commercialization. We also highlight existing challenges and opportunities in the field.

D-Tagatose-Based Product Triggers Sweet Immunity and Resistance of Grapevine to Downy Mildew, but Not to Gray Mold Disease.

The use of natural bio-based compounds becomes an eco-friendly strategy to control plant diseases. Rare sugars would be promising compounds as inducers of plant "sweet immunity". The present study aimed to investigate the induced resistance of grapevine leaves against Plasmopara viticola and Botrytis cinerea by a rare sugar-based product (IFP48) and its active ingredient D-tagatose (TAG), in order to elucidate molecular mechanism involved in defense-related metabolic regulations before and after pathogen challenge. Data showed that spraying leaves with IFP48 and TAG lead to a significant reduction of downy mildew, but not of gray mold disease. The induced protection against P. viticola relies on IFP48's and to a lesser extent TAG's ability to potentiate the activation of salicylic acid- and jasmonic acid/ethylene-responsive genes and stilbene phytoalexin accumulation. Most of defense responses remained upregulated in IFP48-treated plants after infection with P. viticola, but inconsistent following challenge with B. cinerea. The beneficial effects of IFP48 were associated with an enhanced accumulation of tagatose inside leaf tissues compared to TAG treatment. Meanwhile, the amounts of sugars, glucose, fructose, maltose, galactose and trehalose remained unchanged or decreased in IFP48-treated leaves after P. viticola infection, although only a few genes involved in sugar transport and metabolism showed transcriptional regulation. This suggests a contribution of sugar homeostasis to the IFP48-induced sweet immune response and priming plants for enhanced resistance to P. viticola, but not to B. cinerea.

Phenotypic and functional properties of dedifferentiated fat cells derived from infrapatellar fat pad.

INTRODUCTION: Mature adipocyte-derived dedifferentiated fat cells (DFATs) are mesenchymal stem cell (MSC)-like cells with high proliferative ability and multilineage differentiation potential. In this study, we first examined whether DFATs can be prepared from infrapatellar fat pad (IFP) and then compared phenotypic and functional properties of IFP-derived DFATs (IFP-DFATs) with those of subcutaneous adipose tissue (SC)-derived DFATs (SC-DFATs). METHODS: Mature adipocytes isolated from IFP and SC in osteoarthritis patients (n = 7) were cultured by ceiling culture method to generate DFATs. Obtained IFP-DFATs and SC-DFATs were subjected to flow cytometric and microarray analysis to compare their immunophenotypes and gene expression profiles. Cell proliferation assay and adipogenic, osteogenic, and chondrogenic differentiation assays were performed to evaluate their functional properties. RESULTS: DFATs could be prepared from IFP and SC with similar efficiency. IFP-DFATs and SC-DFATs exhibited similar immunophenotypes (CD73+, CD90+, CD105+, CD31-, CD45-, HLA-DR-) and tri-lineage (adipogenic, osteogenic, and chondrogenic) differentiation potential, consistent with the minimal criteria for defining MSCs. Microarray analysis revealed that the gene expression profiles in IFP-DFATs were very similar to those in SC-DFATs, although there were certain number of genes that showed different levels of expression. The proliferative activity in IFP-DFATs was significantly (p < 0.05) higher than that in the SC-DFATs. IFP-DFATs showed higher chondrogenic differentiation potential than SC-DFATs in regard to production of soluble galactosaminogalactan and gene expression of type II collagen. CONCLUSIONS: IFP-DFATs showed higher cellular proliferative potential and higher chondrogenic differentiation capacity than SC-DFATs. IFP-DFAT cells may be an attractive cell source for chondrogenic regeneration.