RESUMEN
We recently identified TMEM230 as a master regulator of the endomembrane system of cells. TMEM230 expression is necessary for promoting motor protein dependent intracellular trafficking of metalloproteins for cellular energy production in mitochondria. TMEM230 is also required for transport and secretion of metalloproteinases for autophagy and phagosome dependent clearance of misfolded proteins, defective RNAs and damaged cells, activities that decline with aging. This suggests that aberrant levels of TMEM230 may contribute to aging and regain of proper levels may have therapeutic applications. The components of the endomembrane system include the Golgi complex, other membrane bound organelles, and secreted vesicles and factors. Secreted cellular components modulate immune response and tissue regeneration in aging. Upregulation of intracellular packaging, trafficking and secretion of endosome components while necessary for tissue homeostasis and normal wound healing, also promote secretion of pro-inflammatory and pro-senescence factors. We recently determined that TMEM230 is co-regulated with trafficked cargo of the endomembrane system, including lysosome factors such as RNASET2. Normal tissue regeneration (in aging), repair (following injury) and aberrant destructive tissue remodeling (in cancer or autoimmunity) likely are regulated by TMEM230 activities of the endomembrane system, mitochondria and autophagosomes. The role of TMEM230 in aging is supported by its ability to regulate the pro-inflammatory secretome and senescence-associated secretory phenotype in tissue cells of patients with advanced age and chronic disease. Identifying secreted factors regulated by TMEM230 in young patients and patients of advanced age will facilitate identification of aging associated targets that aberrantly promote, inhibit or reverse aging. Ex situ culture of patient derived cells for identifying secreted factors in tissue regeneration and aging provides opportunities in developing therapeutic and personalized medicine strategies. Identification and validation of human secreted factors in tissue regeneration requires long-term stabile scaffold culture conditions that are different from those previously reported for cell lines used as cell models for aging. We describe a 3 dimensional (3D) platform utilizing non-biogenic and non-labile poly ε-caprolactone scaffolds that supports maintenance of long-term continuous cultures of human stem cells, in vitro generated 3D organoids and patient derived tissue. Combined with animal component free culture media, non-biogenic scaffolds are suitable for proteomic and glycobiological analyses to identify human factors in aging. Applications of electrospun nanofiber technologies in 3D cell culture allow for ex situ screening and the development of patient personalized therapeutic strategies and predicting their effectiveness in mitigating or promoting aging.
Asunto(s)
Envejecimiento , Organoides , Humanos , Organoides/metabolismo , Envejecimiento/metabolismo , Proteínas de la Membrana/metabolismo , Senescencia Celular , Femenino , Andamios del Tejido/química , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/citologíaRESUMEN
High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.
Asunto(s)
Glioblastoma , Glioma , Enfermedad de Parkinson , Humanos , Glioblastoma/genética , Proteínas de la Membrana/genética , Células Endoteliales , Angiogénesis , Glioma/genética , Neuroglía , Neovascularización Patológica/genéticaRESUMEN
BACKGROUND: Suction drainage is commonly applied after total knee arthroplasty (TKA) and unicompartmental knee arthroplasty (UKA) to reduce hematoma, swelling and to favor surgical wound healing. However, its efficacy remains controversial; thus, the purpose of this study is to evaluate drainage efficiency in the management of postoperative bleeding in TKA and UKA. METHODS: The cohort comprised 134 clinical records of patients affected by knee osteoarthritis (OA) who underwent either TKA or UKA. All the patients were subdivided into 2 groups: the first one with drainage and the second one without drainage (respectively 61 and 73 patients). For each group, hemoglobin levels in the preoperative, first, second and third postoperative day were collected. Postoperative complications such as swelling, bleeding from the surgical wound or the need for blood transfusion, were also recorded. RESULTS: Our results did not show any significant difference of hemoglobin levels in the first (p = 0.715), second (p = 0.203) and third post-operative day (p = 0.467) between the two groups. Moreover, no significant correlation between knee swelling or transfusion rate and the drainage was observed (p = 0.703 and p = 0.662 respectively). Besides, a significant correlation was found between bleeding from the surgical wound and the absence of drainage (p = 0.006). CONCLUSIONS: The study demonstrates how the routine use of suction drainage does not provide substantial benefits in the postoperative blood loss management after TKA or UKA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04508101 , 09/08/2020, Retrospectively registered LEVEL OF EVIDENCE: III.
Asunto(s)
Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Rodilla , Artroplastia de Reemplazo de Rodilla/efectos adversos , Humanos , Osteoartritis de la Rodilla/cirugía , Hemorragia Posoperatoria/epidemiología , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/terapia , Estudios Retrospectivos , SucciónRESUMEN
BACKGROUND: The SARS-CoV-2 pandemic drastically changed daily life activities and medical practice, leading to a reorganization of healthcare activities. People spent two months in home-isolation, changing their daily habits and undertaking a more sedentary lifestyle. Change in lifestyle is related to important consequences in knee pathologies. The aim of this study was to evaluate the outpatient activity for knee pathologies before and after lockdown in terms of incidence, severity, diagnosis, and treatment. METHODS: Medical records of patients with knee pathology in outpatient follow-up at IRCCS Istituto Ortopedico Galeazzi in Milan (Italy) were analyzed in the time frame 4 May-4 September 2020 and compared with patients examined between 4 May and 4 September 2019. RESULTS: A significant increase of knee diagnoses associated to patellofemoral disorders in 2020 was found (p = 0.004). In addition, physiotherapy was significantly more prescribed in 2020 than in 2019 (p = 0.012). CONCLUSIONS: The SARS-CoV-2 pandemic lockdown did not drastically change knee pathology, but it may have had an impact on it, highlighting a summary worsening of patellofemoral disorders associated with other knee diagnoses. Further studies are required to validate this result.
RESUMEN
The debate over the relative merits of substituting or retaining the posterior cruciate ligament in total knee arthroplasty is still ongoing. This article discusses the differences between the two procedures, considering the biomechanics and the surgical techniques involved.