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The route to chaos and the phase dynamics of the large scales in a rotating shallow-water model have been rigorously examined through the construction of an autonomous five-mode Galerkin truncated system employing complex variables, useful in investigating how large/meso-scales are destabilized and how their dynamics evolves and transits to chaos. This investigation revealed two distinct transitions into chaotic behaviour as the level of energy introduced into the system was incrementally increased. The initial transition manifests through a succession of bifurcations that adhere to the established Feigenbaum sequence. Conversely, the subsequent transition, which emerges at elevated levels of injected energy, is marked by a pronounced shift from quasi-periodic states to chaotic regimes. The genesis of the first chaotic state is predominantly attributed to the preeminence of inertial forces in governing nonlinear interactions. The second chaotic state, however, arises from the augmented significance of free surface elevation in the dynamical process. A novel reformulation of the system, employing phase and amplitude representations for each truncated variable, elucidated that the phase components present a temporal piece-wise locking behaviour by maintaining a constant value for a protracted interval, preceding an abrupt transition characterised by a simple rotation of ±π, even as the amplitudes display chaotic behaviour. It was observed that the duration of phase stability diminishes with an increase in injected energy, culminating in the onset of chaos within the phase components at high energy levels. This phenomenon is attributed to the nonlinear term of the equations, wherein the phase components are introduced through linear combinations of triads encompassing disparate modes. When the locking durations vary across modes, the resultant dynamics is a stochastic interplay of multiple π phase shifts, generating a stochastic dynamic within the coupled phase triads, observable even at minimal energy injections.
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Dinámicas no Lineales , Agua , Agua/química , Modelos Teóricos , RotaciónRESUMEN
BACKGROUND: Therapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC). CASE PRESENTATION: We report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response. CONCLUSIONS: Treatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células Acinares , Neoplasias Pancreáticas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Carcinoma de Células Acinares/tratamiento farmacológico , Carcinoma de Células Acinares/patología , Masculino , Antineoplásicos Inmunológicos/uso terapéutico , Persona de Mediana Edad , AncianoRESUMEN
Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.
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Neoplasias , Proteínas Nucleares , Humanos , Inestabilidad Genómica , Mutación , Tasa de Mutación , Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Microambiente Tumoral , Animales , RatonesRESUMEN
Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.
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Neoplasias de la Próstata , Canales Catiónicos TRPM , Humanos , Masculino , Andrógenos , Inflamación/genética , Factor 3 Regulador del Interferón , Proteínas de la Membrana , FN-kappa B/genética , Neoplasias de la Próstata/genética , Receptor Toll-Like 3/genética , Canales Catiónicos TRPM/genética , AnimalesRESUMEN
Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.
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Inflamasomas , Monocitos , Síndromes Mielodisplásicos , Enfermedades Cutáneas Genéticas , Adulto , Humanos , Inflamasomas/genética , Estudios Prospectivos , Células Mieloides , MutaciónRESUMEN
In recent years navigated transcranial magnetic stimulation (nTMS) has emerged as a useful tool for the preoperative mapping of brain cortical areas surrounding neoplastic tissues allowing for maximal safe tumor resection and minimizing new postoperative permanent neurological deficits. Three patients presenting with an intrinsic brain tumor (one metastasis from mammary carcinoma, one high-grade glioma, and one low-grade glioma) located within or in close relationship to the central sulcus were enrolled for this study. The MRI-based morphological and nTMS mapping of the central sulcus of the intact hemisphere was complemented by the examination of the contralateral region harboring the lesion. The findings were independently compared, in search of evidence of tumor-induced neuroplasticity and/or signs of parenchymal dislocation/infiltration caused by the tumor. An individual description of each mapping session is provided. Significant discrepancies were observed between morphological MRI and functional nTMS mapping in two patients, demonstrating a tumor-induced shift of distinct cortical areas controlling hand and/or facial movements. In the cases of gliomas, a lower MT was detected in the lesioned hemisphere, possibly due to increased electrical excitability caused by the tumor itself. The integration of MRI-based morphological mapping of the central sulcus with the detection of its somatomotor representations through nTMS can assist neurosurgeons when planning the resection of a motor-eloquent tumor, stratifying the risks of secondary neurological deficits. The combination of the two preoperative techniques is able to disclose tumor-induced neural plasticity subsequently guiding a more precise resection.
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Neoplasias Encefálicas , Glioma , Humanos , Estimulación Magnética Transcraneal/métodos , Neuronavegación/métodos , Neoplasias Encefálicas/patología , Glioma/cirugía , Encéfalo/cirugía , Mapeo Encefálico/métodosRESUMEN
Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.
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Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Masculino , Humanos , Ratones , Animales , Anciano , Andrógenos/farmacología , Andrógenos/metabolismo , Próstata/patología , Hiperplasia Prostática/metabolismo , Antioxidantes/farmacología , Plasticidad de la Célula , Hiperplasia/patología , Plomo/metabolismo , Plomo/uso terapéutico , Ratones Transgénicos , Prolactina/metabolismo , Prolactina/uso terapéutico , Células Epiteliales/metabolismo , Síntomas del Sistema Urinario Inferior/metabolismo , Síntomas del Sistema Urinario Inferior/patologíaRESUMEN
BACKGROUND: Originally adopted for the cytological screening of cervical and uterine cancer, contact endoscopy (CE) is now widely used in several fields of oncological surgery. The CE method, with magnification power up to 150x, was designed to enhance visualization and identify microscopic changes indicative of precancerous and cancerous lesions at early stages. In this pilot study, we evaluated the multimodal applications of CE during different endoscopic intracranial neurosurgical procedures. METHODS: Twenty patients with skull base lesions underwent surgery using different minimally invasive endoscopic approaches (endonasal, transorbital, and supraorbital). CE was used to distinguish the pathology from the surrounding healthy tissue by positioning the endoscope either in proximity or directly onto the target tissue. Special attention was given to the visualization of the margins of the lesion to differentiate compression/displacement from infiltration of the normal surrounding tissue. RESULTS: With its unprecedented range of magnification, CE could clearly identify the microvascular pattern and cytological architecture of a tissue not detectable by simple white light endoscopy, with no reported damage due to heat transmission or iatrogenic injuries. All the lesions diagnosed as "presumed neoplastic tissue" by CE were confirmed by histopathology. The most promising results were observed in surgeries for meningioma and pituitary adenoma, as these lesions exhibit distinctive microvascular networks. CONCLUSIONS: CE represents a new and effective technique for the in vivo identification of pathological microvascular and tissue features, allowing preservation of normal tissue during different endoscopic approaches. The use of CE could improve diagnostic accuracy and assist in intraoperative decision-making, becoming a key tool in various applications in neurosurgical field.
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Neoplasias Meníngeas , Neurocirugia , Neoplasias de la Base del Cráneo , Humanos , Proyectos Piloto , Procedimientos Neuroquirúrgicos/métodos , Endoscopía/métodos , Neoplasias de la Base del Cráneo/cirugía , Endoscopía Gastrointestinal , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/cirugíaRESUMEN
Background: This review focuses on the recently published evidence on tumor treating fields (TTFields) administered alone or in combination with locoregional and systemic options for treating glioblastoma (GBM) in the past ten years. The aim is to critically summarize the novelty and results obtained with this innovative tool, which is becoming part of the armamentarium of neurosurgeons and neuro-oncologists. Methods: A comprehensive search and analysis were conducted on pivotal studies published in the past ten years. Furthermore, all completed clinical trials, whose results were published on clinicaltrials.gov, were examined and included in the present review, encompassing both recurrent (r) and newly diagnosed (n) GBM. Finally, an additional examination of the ongoing clinical trials was also conducted. Results: Recent trials have shown promising results both in patients with nGBM and rGBM/progressive (rGBM), leading to Food and Drug Administration approval in selected patients and the Congress of Neurological Surgeons to include TTFields into current guidelines on the management of GBM (P100034/S001-029). Recently, different randomized trials have demonstrated promising results of TTFields in combination with standard treatment of n- and rGBM, especially when considering progression-free and overall survival, maintaining a low rate of mild to moderate adverse events. Conclusion: Optimal outcomes were obtained in nGBM and progressive disease. A possible future refinement of TTFields could significantly impact the treatment of rGBM and the actual standard of care for GBM, given the better safety profile and survival effects.
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BACKGROUND: Primary anaplastic-lymphoma-kinase (ALK)-positive large-cell lymphoma of the central nervous system (PCNS ALK-positive ALCL) is a rare entity, with a limited consensus reached regarding its management. While this pathology often presents as solitary lesions, the occurrence of multiple tumors within the brain is not uncommon. The lack of distinctive radiological features poses a diagnostic challenge, leading to delays in initiating targeted therapy. METHODS: We conducted a comprehensive literature search, identifying seventeen publications for qualitative analysis. RESULTS: The management options and reported patient outcomes in the literature varied significantly, emphasizing the need for a patient-specific approach. The emergence of ALK-specific inhibitors represents a new frontier in this field, demonstrating promising results. CONCLUSION: PCNS ALK-positive ALCL necessitates a comprehensive understanding and optimized management strategies. A tailored therapeutic approach, integrating surgical intervention with radiotherapy and chemotherapy, appears pivotal in addressing this pathology. The implementation of a therapeutic protocol is anticipated for further advancement in this field.
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Gain-of-function mutations in the PIK3CD gene result in activated phosphoinositide 3-kinase δ syndrome type 1 (APDS1). This syndrome is a life-threatening combined immunodeficiency and today there are neither optimal nor long-term therapeutic solutions for APDS1 patients. Thus, new alternative treatments are highly needed. The aim of the present study is to explore one therapeutic avenue that consists of the correction of the PIK3CD gene through gene editing. Our proof-of-concept shows that TALEN-mediated gene correction of the mutated PIK3CD gene in APDS1 T cells results in normalized phospho-AKT levels in basal and activated conditions. Normalization of PI3K signaling was correlated to restored cytotoxic functions of edited CD8+ T cells. At the transcriptomic level, single-cell RNA sequencing revealed corrected signatures of CD8+ effector memory and CD8+ proliferating T cells. This proof-of-concept study paves the way for the future development of a gene therapy candidate to cure activated phosphoinositide 3-kinase δ syndrome type 1.
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Gain-of-function mutations in stimulator of interferon gene 1 (STING1) result in STING-associated vasculopathy with onset in infancy (SAVI), a severe autoinflammatory disease. Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, which have roles in the onset and severity of SAVI and remain to be elucidated. To this end, we performed a multi-omics comparative analysis of peripheral blood mononuclear cells (PBMCs) and plasma from SAVI patients and healthy controls, combined with a dataset of healthy PBMCs treated with IFN-ß. Our data reveal a subset of disease-associated monocyte, expressing elevated CCL3, CCL4, and IL-6, as well as a strong integrated stress response, which we suggest is the result of direct PERK activation by STING. Cell-to-cell communication inference indicates that these monocytes lead to T cell early activation, resulting in their senescence and apoptosis. Last, we propose a transcriptomic signature of STING activation, independent of type I IFN response.
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Interferón Tipo I , Enfermedades Vasculares , Humanos , Monocitos/metabolismo , Leucocitos Mononucleares/metabolismo , Enfermedades Vasculares/genética , Enfermedades Vasculares/metabolismo , Interferón Tipo I/metabolismo , ARNRESUMEN
PURPOSE: Pediatric liver transplant surgery is burdened by arterial complications whose endovascular treatment is not standardized. We report the outcomes of a cohort of pediatric recipients with hepatic artery complications treated by endoluminal procedures. MATERIALS AND METHODS: From December 2019 to December 2022, consecutive transplanted pediatric patients who underwent endovascular treatment of hepatic artery complications were reviewed. The analysis included: type of complication (occlusion, stenosis, pseudoaneurysm); onset (acute = < 15 days, subacute = 15-90 days, late = > 90 days); endovascular technique (angioplasty, stenting); complications and outcomes. Technical success was defined as the opacification of the hepatic artery at the final angiogram with < 50% residual stenosis and no pseudoaneurysms. Clinical success was defined by graft's and patient's survival. RESULTS: Seventeen patients (8 males; median age 33 months, IQR 9-103) underwent 21 hepatic arteriography procedures for predominantly acute or subacute occlusions (n = 7) or stenosis (n = 11) with concurrent pseudoaneurysms (n = 4). Primary and secondary technical success was achieved in 13/18 and 3/3 procedures, respectively, with overall technical success of 76%. Angioplasty alone was successful in 5/21 procedures; stent-retriever thrombectomy was performed in one occlusion with thrombosis; stenting was required in 9/17 (53%) patients. Clinical success was obtained in 14/17 (82%) patients with hepatic artery patency after a median of 367 days (IQR 114.5-500). Clinical failure occurred in 3 permanent occlusions, with 2 deaths and 1 re-transplantation. Procedure-related complications included minor events in 3/17 (18%) patients and 1/17 (6%) death. CONCLUSION: In liver transplanted children with hepatic artery complications, endovascular treatment may provide clinical success, with stenting often required in acute and subacute conditions. LEVEL OF EVIDENCE: Level 4.
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Aneurisma Falso , Procedimientos Endovasculares , Trasplante de Hígado , Masculino , Humanos , Niño , Preescolar , Constricción Patológica , Arteria Hepática/diagnóstico por imagen , Arteria Hepática/cirugíaRESUMEN
The upper portions of the Earth's atmospheric layer, e.g., the ionospheric plasma layer, can be significantly affected by perturbations generated in the lower layers. In fact, all perturbations formed within the troposphere can easily propagate, not only horizontally within the layer but also vertically reaching the highest regions of the atmosphere far from the Earth's surface, as depicted by the Wentzel-Kramers-Brillouin (WKB) approximation of atmospheric waves. Because all perturbations generated in the atmospheric boundary layer must take into account the effects of the medium's nonlinearity and thus the effects of atmospheric turbulence, in this work the impact of a strong seismic event and the disturbances generated in the flow are analyzed by means of a fully nonlinear model which incorporates a simple parametrization of the seismic event and is based on the classical shallow water. A strict dependence was observed between the model control parameters and the vertical nonvanishing modes from the WKB approximation, and only few specific bands of excited modes are nonvanishing and can eventually propagate to the ionosphere. Moreover, the flow disturbance, generated by a seismic event, presents a multiscale nature characterized by two fixed wavelengths, and the excited modes are harmonics of such distinctive scales.
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INTRODUCTION: About 30-50 % of stage IV HER2+ breast cancers (BC) will present brain metastases (BMs). Their management is based on both local treatment and systemic therapy. Despite therapeutic advances, BMs still impact on survival and quality of life and the development of more effective systemic therapies represents an unmet clinical need. MATERIALS AND METHODS: A thorough analysis of the published literature including ongoing clinical trials has been performed, investigating concepts spanning from the pathophysiology of tumor microenvironment to clinical considerations with the aim to summarize the current and future locoregional and systemic strategies. RESULTS: Different trials have investigated monotherapies and combination treatments, highlighting how the blood-brain barrier (BBB) represents a major problem hindering diffusion and consequently efficacy of such options. Trastuzumab has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab, and trastuzumab emtansine, as well as more recently neratinib, tucatinib, and trastuzumab deruxtecan, have been introduced in clinical practice after showing promising results in randomized controlled trials. CONCLUSIONS: We ultimately propose an evidence-based treatment algorithm for clinicians treating HER2 + BCs patients with BMs.
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Antineoplásicos , Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Calidad de Vida , Receptor ErbB-2 , Trastuzumab/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/secundario , Microambiente TumoralRESUMEN
PURPOSE: To report procedural data and outcomes of a novel image guidance technique, CT renal arteriography (CTRA), performed to target and ablate small intraparenchymal renal tumors. MATERIALS AND METHODS: We retrospectively analyzed data of 2 patients undergoing CTRA-guided ablation for 3 renal intraparenchymal tumors, from February to March 2023. We previously evaluated tumor visibility with US/CEUS, and in all cases conspicuity was poor, whereas contrast-enhanced CT (CECT) clearly depicted all hypervascular nodules. Our primary endpoint was CTRA-guidance feasibility for renal ablation, defined as the precise probe deployment inside the target tumor. The secondary endpoint was CTRA-guided ablation technical success, intended as the inclusion of the whole tumor inside the necrotic volume, with 5 mm safety margins. RENAL scores, complications, procedural time, dose length product (DLP), serum creatinine variation and hospital stay length were also recorded. RESULTS: A confident deployment of the probe tip inside the nodule was accomplished in all 3 cases, with a 100% of correct targeting. We observed immediate technical success after all 3 ablations. The 3 nodules had a RENAL score <7 points, and we encountered no complications due to line placement or ablation. The average time from preablative to postablative CTRA was 54 min (50-58min), with a DLP of 3632mGy*cm (2807-4458mGy*cm). Serum creatinine didn't show a significant variation after the procedures; both patients were hospitalized for 2 days. CONCLUSION: Preliminary data showed that CTRA-guidance might provide unique advantages over conventional CECT-guidance to assist the ablation of small renal intraparenchymal tumor not visualized on US/CEUS.
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Ablación por Catéter , Neoplasias Renales , Humanos , Creatinina , Estudios Retrospectivos , Ultrasonografía Intervencional , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Tomografía Computarizada por Rayos X , Angiografía , Ablación por Catéter/métodos , Resultado del TratamientoRESUMEN
OBJECTIVE: The objective of this study was to compare the clinical outcome of minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) versus standard revision diskectomy for recurrent lumbar disk herniation (RLDH). BACKGROUND: RLDH is the most common cause of redo surgery after a microdiscectomy. Commonly, in patients without evidence of spinal instability, many surgeons would simply redo microdiscectomy, while others proceed to a redo microdiscectomy with arthrodesis. According to the literature, there is no evidence of what the best management of an RLDH would be. METHODS: This study involved 90 patients who underwent lumbar microdiscectomy in the past and were now experiencing a new lumbar disk herniation for the first time. The patients were divided into two groups, each with 45 patients: group A received standard revision microdiscectomy, whereas group B received revision microdiscectomy with MIS TLIF.The Japanese Orthopaedic Association score, operating time, blood loss, duration of hospital stay, costs, and complications were all prospectively recorded in a database and examined. Back and leg discomfort were measured using the visual analog scale. RESULTS: The mean total postoperative Japanese Orthopaedic Association score across the groups exhibited no statistically significant difference, nor did the preoperative clinical and epidemiological data. Although postoperative leg pain was comparable in both groups, postoperative lower back pain in group A was much worse than that in group B. Additional revision surgery was necessary for six individuals in group A. Group A had higher rates of dural rupture and postoperative neurological impairment. Group A experienced much less intraoperative blood loss, longer operation times, and postoperative hospital stays. CONCLUSION: In patients with RLDH, revision microdiscectomy is effective. In comparison with conventional microdiscectomy, MIS TLIF reduces intraoperative risk of dural rupture or neural injury, postoperative incidence of mechanical instability or recurrence, and postoperative lower back pain. STUDY DESIGN: Prospective, randomized, multicenter, comparative study.
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Desplazamiento del Disco Intervertebral , Dolor de la Región Lumbar , Fusión Vertebral , Humanos , Discectomía , Desplazamiento del Disco Intervertebral/cirugía , Dolor de la Región Lumbar/cirugía , Vértebras Lumbares/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos , Dolor Postoperatorio , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.
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Síndrome de Plaquetas Grises , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Plaquetas/metabolismo , Proteínas Sanguíneas/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Síndrome de Plaquetas Grises/genética , Síndrome de Plaquetas Grises/metabolismoRESUMEN
BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.