Littérature scientifique sur le sujet « Fragility cureves »

Epidermolysis bullosa (EB) and associated skin-fragility syndromes are a group of inherited skin diseases characterised by trauma-induced blistering of the skin and mucous membranes. Mutations in at least 14 distinct genes encoding molecular components of the epidermis or the dermal–epidermal junction (DEJ) can cause blistering skin diseases that differ by clinical presentation and severity of the symptoms. Despite great advances in discerning the genetic basis of this group of diseases, the molecular pathways leading to symptoms are not yet fully understood. Unravelling these pathways by molecular analysis of the structure and in vitro assessment of functional properties of the human proteins involved, combined with genetic models in lower organisms, should pave the way for specific cures for inherited skin fragility.

Background:Osteoporosis is known to be a risk factor for fragility fractures [4, 5]. On one hand, vertebral body fragility fractures often lead to additional spine deformity [2]. On the other hand, it was found that with the progression of the spinal curvature in osteoporotic patients, the fragility fractures develop more frequently. The increased incidence of these fractures could be explained with a predominance of the mechanical forces on the one side of the already weakened osteoporotic vertebrae [3].Objectives:The aim of this study is to compare the fracture risk (FRAX) for major osteoporotic fractures (MOF) and for hip fractures (HF) in women with and without scoliosis through dual-energy X-ray absorptiomentry (DXA)Methods:In the current study, 59 women underwent DXA scans. Scoliosis was defined as Cobb’s angle ≥ 5◦ according to the Chaklin’s classification [6, 7]. Cobb’s angle was measured from DXA images with DICOM software. We evaluated the following risk factors: previous fractures, parental hip fractures, secondary osteoporosis, rheumatoid arthritis, use of corticosteroids, current smoking and alcohol consumption more than 3 units daily. We estimated FRAX MOF and FRAX HF on the basis of these risk factors and on the basis of the femoral neck bone mineral density (BMD). The calculations were done through FRAX tool published on the website of the University of Sheffield [1].Results:The mean age of the women was 63 years (yrs.) ± 10 yrs. (range 43 yrs. – 89 yrs.). Subjects with scoliosis were significantly older (67 yrs.) than those without scoliosis (59 yrs.), (p = 0.004). Mean weight and height didn’t differ between the groups with- and without scoliosis. Mean lumbar spine BMD and T-score differed significantly between the groups, (p = 0.02). Women with scoliosis had lower mean BMD (0.786 g/cm2) and lower mean T-score (-2.1 standard deviations (SDs)) compared to those without scoliosis (mean BMD: 0.912 g/cm2 and mean T-score: 0.9 SDs). The mean FRAX MOF (19.3%) and FRAX HF (5.9%) of the subjects with scoliosis were significantly higher than those of the women without scoliosis (FRAX MOF: 14.9% and FRAX HF: 3.1%), (p = 0.004 for FRAX MOF and p = 0.010 for FRAX HF).Conclusion:Women with scoliosis showed significantly higher fracture risk for major osteoporotic fractures and for hip fractures compared to those without scoliosis.References:[1]https://www.sheffield.ac.uk/FRAX/index.aspx[2]Mao YF, Zhang Y, Li K, et al. Discrimination of vertebral fragility fracture with lumbar spine bone mineral density measured by quantitative computed tomography. J Orthop Translat. 2018;16:33–39. Published 2018 Oct 10. doi:10.1016/j.jot.2018.08.007.[3]Sabo A, Hatgis J, Granville M, Jacobson RE. Multilevel Contiguous Osteoporotic Lumbar Compression Fractures: The Relationship of Scoliosis to the Development of Cascading Fractures. Cureus. 2017;9(12):e1962. Published 2017 Dec 19. doi:10.7759/cureus.1962.[4]Kirilova E, Cherkezov D, Gonchev B, Zheleva Z. OSIRIS Index for the assessment of the risk for osteoporosis in menopausal women, National conference with international participation, 6-7 october 2019, Kardzhali “Science and society 2019”, RKR print OOD ISSN 1314-3425[5]Madzharova R, Kirilova E, Petranova T, Nikolova M. Assessment of the activity for self care in women with osteoporosis, Science and TechnologieVolume VIII, 2018, Number 1: MEDICAL BIOLOGY STUDIES, CLINICAL STUDIES, SOCIAL MEDICINE AND HEALTH CARE,1-6.[6]Chaklin VD, Orthopedy - Moscow: Medgiz – 1965 – C. 209[7]Chaklin VD. Pathology, clinical manifestation and treatment of the scoliosis, 1stcongress of the union of the orthopedists and traumatologists, Moscow: Medgiz, 1957 – T.2. – p 798Disclosure of Interests:None declared

Osteoporosis is a bone resorptive disease characterized by the loss of bone density, causing an increase in bone fragility. In our previous study, we demonstrated that gamma aminobutyric acid-enriched fermented oyster (Crassostrea gigas) extract (FO) stimulated osteogenesis in MC3T3-E1 preosteoblast cells and vertebral formation in zebrafish. However, the efficacy of FO in prednisolone (PDS)-induced bone resorption remains unclear. In this study, we evaluated the osteogenic potential of FO in MC3T3-E1 preosteoblast cells and zebrafish larvae under both PDS-pretreated and PDS-post-treated conditions. We found that FO recovered osteogenic activity by upregulating osteoblast markers, such as alkaline phosphatase (ALP), runt-related transcription factor 2, and osterix, in both PDS-pretreated and post-treated MC3T3-E1 osteoblast cells and zebrafish larvae. In both conditions, PDS-induced decrease in calcification and ALP activity was recovered in the presence of FO. Furthermore, vertebral resorption in zebrafish larvae induced by pretreatment and post-treatment with PDS was restored by treatment with FO, along with the recovery of osteogenic markers and downregulation of osteoclastogenic markers. Finally, whether FO disturbs the endocrine system was confirmed according to the Organization for Economic Cooperation and Development guideline 455. We found that FO did not stimulate estrogen response element-luciferase activity or proliferation in MCF7 cells. Additionally, in ovariectomized mice, no change in uterine weight was observed during FO feeding. These results indicate that FO effectively prevents and treats PDS-induced osteoporosis without endocrine disturbances.

Osteoporosis is both a long-term effect (occurs during treatment and extends after treatment) and a late-effect (occurs after treatment ends) of breast cancer treatments. The worldwide prevalence of osteoporosis is estimated to be some 200 million patients. About one in three postmenopausal women will experience an osteoporotic (or fragility) fracture of the hip, spine, or wrist. breast cancer treatments, including gonadotropin-releasing hormone (GnRH) agonists, chemotherapy-induced ovarian failure (CIOF), and aromatase inhibitors (AIs), cause bone loss and increase the risks of osteoporosis. Also, breast cancer is a disease of aging, and most of the “one in eight” lifetime risks of breast cancer are in women in their sixth, seventh, and eighth decades. The majority of women diagnosed with breast cancers today will be long-term survivors and experience personal cures. It is the coalescence of osteoporosis with breast cancer, two common and age-related conditions that make osteoporosis relevant in women with breast cancer throughout the continuum from diagnosis, treatment, and survivorship. It is critical to remember that women (and men) will lose bone after age thirty years. However, only certain women will lose bone of sufficient magnitude to merit treatment with anti-osteoporosis drugs. The narrative review is intended for medical, surgical, radiation oncologists, and other mid-level providers, and provides an overview of bone loss and the prevention and treatment of osteoporosis.

BackgroundOvarian cancer (OC) responds poorly to immunotherapies. Regulatory T cells (Treg) engage IL-2 by high-affinity CD25 for differentiation and function,1 and anti-tumor effector T cells (Teff) use intermediate affinity CD122. We studied IL-2 complexes (IL-2c) that selectively activate CD122 (Teff) over CD25 (Tregs).MethodsOrthotopic ID8agg-luc mouse OC burden was measured by in vivo imaging. Tumor, ascites and draining lymph nodes (TDLN) were analyzed by flow and tSNE. IL-2c was complexed using 1.5 µg/mouse IL-2 and 7.5 µg/mouse aIL-2 (clone JES6-5H4) before i.p. injection every other day x 4 starting at day 7. antiPD-L1 was given at 100ug/mouse every 3 days x 4 starting from Day 11. FIR mice2 were used to sort live Tregs.ResultsIL-2c but not antiPD-L1 potently inhibits ID8agg (figure 1). IL-2c decreased ascites Treg functional markers (e.g., CD25, granzymeB) while upregulating the same markers on Teffs (figure 2). IL-2c inhibited Treg suppression in ascites while TDLN Tregs were unaffected (figure 3). tSNE showed great similarity of TDLN Tregs treated with isotype and IL-2c while ascites Tregs after IL-2c showed a fragile phenotype (e.g., increased PD-1, T-bet, and IFNgamma with maintained FoxP3 expression [figure 4]) which is known to contribute to better response to cancer immunotherapy.3 4 We observed a complete reduction of tumor bioluminescence with IL-2c and antiPD-L1 combo treatment in nearly all subjects significantly exceeding effect of IL-2c alone (figure 5). A CD8+CXCR5+TCF-1+ T cell stem cell (TCSC) population reportedly improves immune checkpoint blockade efficacy.5 6 Since CD122 is regulated by TCF-1,7 we explored the effect of IL-2c on these TCSC. IL-2c significantly induced a CD8+TCF-1+ TCSC population in ID8agg tumors (figure 6), possibly through a positive feedback loop by further enhancing CD122 expression on TCF-1+, but not TCF-1- cells (figure 7). tSNE analysis of detailed immune phenotype of IL-2c induced TCSC revealed that these TCSC differed from those induced by antiPD-L1. In ID8agg, antiPD-L1-induced TCSC are mostly CXCR5+ and PD1+, consistent with previous reports in other cancers3 4 while IL-2c-induced TCSC were PD1- (figure 8), expressed CCR2 and CXCR3, and produced TNFalpha (figure 9).Abstract 690 Figure 1IL-2c but not aPD-L1 treats ID8aggLuciferase signal of ID8agg-luc tumors treated with isotype, ?PD-L1, or IL-2c measured by in vivo imaging. Arrows indicate treatments.Abstract 690 Figure 2IL-2c inhibits functional markers on tregs and promotes teffExpression of CD25 and granzymeB were measured by flow cytometry in indicated population from isotype or IL-2c treated ascites 3 weeks after final IL-2c dose.Abstract 690 Figure 3IL-2c reduces ascites Treg suppressive functionTregs sorted from ascites or TDLN of isotype or IL-2c treated FIR mice co-cultured with Teff cells. Percent suppression of Teff cells proliferation shown.Abstract 690 Figure 4IL-2c induces Treg fragility in ascites but not TDLN tSNE analysis on CD45+CD3+CD4+FoxP3+ cells from ascites and TDLN of isotype and IL-2c treated ID8agg-luc challenged mice. Right, representative bar graphs of flow data.Abstract 690 Figure 5IL-2c and aPD-L1 combo treatment effectively cures ID8aggLuciferase signal of ID8agg-luc tumors treated with isotype, ?PD-L1, IL-2c or combo measured by in vivo imaging. Arrows indicate treatments.Abstract 690 Figure 6IL-2c induces a CD8+TCF-1+ population in ID8aggID8agg-luc tumors analyzed by flow cytometry gated on CD45+CD3+CD8+ cells.Abstract 690 Figure 7IL-2c induces CD122 on CD8+TCF-1+ but not TCF-1- cellsCD122 expression was measured by flow cytometry in CD8+TCF-1+ and CD8+ TCF-1- cells from tumors treated with isotype or IL-2c.Abstract 690 Figure 8CD8+TCF1+ cells from ID8agg analyzed by flow cytometry plus tSNE. Cells expressing CXCR5 (blue) and PD1 (red) indicated in overlayAbstract 690 Figure 9CD8+TCF1+ cells from ID8agg analyzed by flow cytometryConclusionsWe define two novel IL-2c effects: inducing Treg fragility therefore reducing immunosuppression while promoting TCSC that could enhance effective anti-tumor immunity. Current work tests if effects are related and help efficacy, and mechanisms for IL-2c Treg effects. We also show that elicited TCSC differ by treatment and tumor, requiring additional investigations.AcknowledgementsThis work is supported by CPRIT Research Training Award (RP 170345), Ovarian Cancer Research Alliance Ann and Sol Schreiber Mentored Investigator Award to YD and R01 CA205965to TC.Ethics ApprovalAll mice studies were approved by UT Health San Antonio Institutional Animal Care and Use Committee (IACUC). Approval number 20150093AR, 20140001AR, 20170035AR, 20140039AR, 20140027AR, 20090128AR, 20120071AR, 20180021AR.ReferencesMalek TR: The biology of interleukin-2. Annu Rev Immunol 2008, 26:453–479.Fantini MC, Dominitzki S, Rizzo A, Neurath MF, Becker C: In vitro generation of CD4+ CD25+ regulatory cells from murine naive T cells. Nat Protoc 2007, 2(7):1789–1794.Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, et al: Interferon-gamma Drives Treg Fragility to Promote Anti-tumor Immunity. Cell 2017, 169(6):1130–1141e1111.Overacre-Delgoffe AE, Vignali DAA: Treg Fragility: A Prerequisite for Effective Antitumor Immunity? Cancer Immunol Res 2018, 6(8):882–887.Brummelman J, Mazza EMC, Alvisi G, Colombo FS, Grilli A, Mikulak J, Mavilio D, Alloisio M, Ferrari F, Lopci E, et al: High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors. J Exp Med 2018.Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, et al: Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018, 175(4):998–1013 e1020.Jeevan-Raj B, Gehrig J, Charmoy M, Chennupati V, Grandclement C, Angelino P, Delorenzi M, Held W: The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes. Cell Rep 2017, 20(3):613–626.

The Upjohn oxazolidinones, U-100592 and U-100766, are orally bioavailable synthetic antimicrobial agents with spectra of activity against antibiotic-susceptible and -resistant gram-positive pathogens. In several mouse models of methicillin-resistant Staphylococcus aureus infection, U-100592 and U-100766 yielded oral 50% effective doses (ED50) ranging from 1.9 to 8.0 mg/kg of body weight, which compared favorably with vancomycin subcutaneous ED50 values of 1.1 to 4.4 mg/kg. Similarly, both compounds were active versus a Staphylococcus epidermidis experimental systemic infection. U-100592 and U-100766 effectively cured an Enterococcus faecalis systemic infection, with ED50 values of 1.3 and 10.0 mg/kg, and versus a vancomycin-resistant Enterococcus faecium infection in immunocompromised mice, both drugs effected cures at 12.5 and 24.0 mg/kg. Both compounds were exceptionally active in vivo against penicillin- and cephalosporin-resistant Streptococcus pneumoniae, with ED50 values ranging from 1.2 to 11.7 mg/kg in systemic infection models. In soft tissue infection models with S. aureus and E. faecalis, both compounds exhibited acceptable curative activities in the range of 11.0 to 39.0 mg/kg. U-100766 was also very active versus the Bacteroides fragilis soft tissue infection model (ED50 = 46.3 mg/kg). In combination-therapy studies, both U-100592 and U-100766 were indifferent or additive in vivo against a monomicrobic S. aureus infection in combination with other antibiotics active against gram-positive bacteria and combined as readily as vancomycin with gentamicin in the treatment of a polymicrobic S. aureus-Escherichia coli infection. U-100592 and U-100766 are potent oxazolidinones active against antibiotic-susceptible and -resistant gram-positive pathogens in experimental systemic and soft tissue infections.

Background:Osteogenesis imperfecta (OI), is a rare hereditary disease characterized by bone fragility and low bone mass. The clinical presenatation is various with varying severity skeletal signs and inconstant extra-skeletal signs. Type 1 is the most common form (60% of cases).Objectives:Our objective is to describe the various clinical features observed over a period of 15 years.Methods:This is a retrospective descriptive study including 12 patients followed for OI, hospitalized in the Rheumatology Department at Fattouma Bourguiba Hospital Monastir TUNISIA between 2006 and 2019. Files were collected and analyzed.Results:They are 9 boys and 3 girls with an average age of 14.9 ± 8.6 years. Consanguinity was reported in 25% of cases. The reason leading to consultation was, recurrent fractures (75%), blue sclera (16.7), and bone deformity (8.3%). The number of previous fractures was on average of 5, all of which were caused by a low energy trauma. Similar family cases were noted in 41.6%. The mean age of the first fracture was 4.41 ± 3.2 years. The most frequent fracture sites were respectively: femur (7/12), leg (6/12), tibia (3/12), humerus (4/12), ankle (2/12), and forearm (2/12). A deformity was noted in 58.3% of the cases: lumbar kyphosis (2), exaggerated dorsal kyphosis (2), femurs in parenthesis (2), and an anarchic deformity of 2 lower limbs (1). Imperfect dentinogenesis was found in 8.3% of cases, while ENT examination revealed conductive and sensorineural hearing loss in 2 patients each. The main radiological abnormalities were diffuse bone demineralization (9 patients), cortical thinning (5 patients), vertebral compression (3 patients), and fracture (2 patients). The bone densitometry showed a mean Z score of 3.49±1.4 in the lumbar spine. The average serum calcium level was 2.38±1.15, alkaline phosphatases were elevated in all cases with an average of 756±624.9. The vitamin D level was deficient in all cases with an average of 22.75±5.3. All patients received in addition to the vitamin-calcium supplementation, pamidronate intravenously at a dose of 9mg/kg/year with a mean number of 6 cures. The main side effects observed during the infusion were abdominal pain, polyarthralgia and asthenia (1 patient), chest pain (1 patient) and fever and chills (1 patient). The control bone densitometry showed a mean Z score of 1.81±1.2 in the lumbar spine.Conclusion:Despite advances in the OI diagnosis and treatment, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice.References:[1]https://doi.org/10.1097/med.0000000000000367Disclosure of Interests:None declared

Tesi presentata e approvata dalla Facoltà di Architettura, Ingegneria Civile e Scienze Ambientali Technische Universität Braunschweig e dal Dipartimento di Ingegneria Civile e Ambientale dell'Università degli Studi di Firenze per candidarsi al titolo di Doktor-Ingenieur (Dr.-Ing.) / Dottore di Ricerca in Ingegneria Civile e Ambientale*) *) Può essere utilizzata la forma tedesca o italiana del titolo. Dissertation submitted to and approved by the Faculty of Architecture, Civil Engineering and Environmental Sciences Technische Universität Braunschweig and the Department of Civil and Environmental Engineering University of Florence in candidacy for the degree of a Doktor-Ingenieur (Dr.-Ing.) / Dottore di Ricerca in Civil and Environmental Engineering*) *) Either the German or the Italian form of the title may be used.