Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 20 de 267
Filtrer
2.
J Pharmacol Exp Ther ; 2024 Aug 23.
Article de Anglais | MEDLINE | ID: mdl-39179416

RÉSUMÉ

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperadine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine discrimination dose-effect function to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. Significance Statement The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

3.
J Soc Cardiovasc Angiogr Interv ; 3(1): 101205, 2024 Jan.
Article de Anglais | MEDLINE | ID: mdl-39131984

RÉSUMÉ

Percutaneous revascularization is the primary strategy for treating lower extremity venous and arterial disease. Angiography is limited by its ability to accurately size vessels, precisely determine the degree of stenosis and length of lesions, characterize lesion morphology, or correctly diagnose postintervention complications. These limitations are overcome with use of intravascular ultrasound (IVUS). IVUS has demonstrated the ability to improve outcomes following percutaneous coronary intervention, and there is increasing evidence to support its benefits in the setting of peripheral vascular intervention. At this stage in its evolution, there remains a need to standardize the use and approach to peripheral vascular IVUS imaging. This manuscript represents considerations and consensus perspectives that emerged from a roundtable discussion including 15 physicians with expertise in interventional cardiology, interventional radiology, and vascular surgery, representing 6 cardiovascular specialty societies, held on February 3, 2023. The roundtable's aims were to assess the current state of lower extremity revascularization, identify knowledge gaps and need for evidence, and determine how IVUS can improve care and outcomes for patients with peripheral arterial and deep venous pathology.

4.
Nat Cancer ; 5(8): 1176-1194, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-39009815

RÉSUMÉ

Cancer dependency maps have accelerated the discovery of tumor vulnerabilities that can be exploited as drug targets when translatable to patients. The Cancer Genome Atlas (TCGA) is a compendium of 'maps' detailing the genetic, epigenetic and molecular changes that occur during the pathogenesis of cancer, yet it lacks a dependency map to translate gene essentiality in patient tumors. Here, we used machine learning to build translational dependency maps for patient tumors, which identified tumor vulnerabilities that predict drug responses and disease outcomes. A similar approach was used to map gene tolerability in healthy tissues to prioritize tumor vulnerabilities with the best therapeutic windows. A subset of patient-translatable synthetic lethalities were experimentally tested, including PAPSS1/PAPSS12 and CNOT7/CNOT78, which were validated in vitro and in vivo. Notably, PAPSS1 synthetic lethality was driven by collateral deletion of PAPSS2 with PTEN and was correlated with patient survival. Finally, the translational dependency map is provided as a web-based application for exploring tumor vulnerabilities.


Sujet(s)
Tumeurs , Humains , Tumeurs/génétique , Animaux , Apprentissage machine , Phosphohydrolase PTEN/génétique , Souris , Lignée cellulaire tumorale , /méthodes , Génome humain , Mutations synthétiques létales/génétique , Bases de données génétiques , Régulation de l'expression des gènes tumoraux
5.
Circ Cardiovasc Interv ; 17(8): e014160, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-39034930

RÉSUMÉ

A nonthrombotic iliac vein lesion is defined as the extrinsic compression of the iliac vein. Symptoms of lower extremity chronic venous insufficiency or pelvic venous disease can develop secondary to nonthrombotic iliac vein lesion. Anatomic compression has been observed in both symptomatic and asymptomatic patients. Causative factors that lead to symptomatic manifestations remain unclear. To provide guidance for providers treating patients with nonthrombotic iliac vein lesion, the VIVA Foundation convened a multidisciplinary group of leaders in venous disease management with representatives from the American Venous Forum and the American Vein and Lymphatic Society. Consensus statements regarding nonthrombotic iliac vein lesions were drafted by the participants to address patient selection, imaging for diagnosis, technical considerations for stent placement, postprocedure management, and future research/educational needs.


Sujet(s)
Consensus , Veine iliaque commune , Endoprothèses , Insuffisance veineuse , Humains , Veine iliaque commune/imagerie diagnostique , Veine iliaque commune/physiopathologie , Insuffisance veineuse/thérapie , Insuffisance veineuse/imagerie diagnostique , Insuffisance veineuse/physiopathologie , Procédures endovasculaires , Résultat thérapeutique , Facteurs de risque , Valeur prédictive des tests
6.
Article de Anglais | MEDLINE | ID: mdl-38906369

RÉSUMÉ

OBJECTIVE: Iliofemoral venous obstructive disease can result in significant, potentially debilitating symptoms that can negatively affect quality of life. Unlike arterial disease, patients with deep venous disease have a significantly lower median age, therefore the need for long term stent patency becomes a matter of decades rather than years. Furthermore, iliofemoral lesions frequently require stent placement across the inguinal ligament. Such stents are subject to dynamic stress from leg movement and associated concerns for device fatigue, resulting in stent fracture. The aim of this study was to describe an in vitro 50 year stent fatigue test method designed to assess durability against dynamic stress induced device fracture. METHODS: Through literature review, cadaver studies, and computer modelling, the most challenging loading was confirmed to be hip flexion across the inguinal ligament. This occurs when the patient adjusts between a seated and standing position. Sit to stand hip flexion at the inguinal ligament was effectively simulated on the bench in this in vitro experimental study. RESULTS: When tested under challenge parameters, hip flexion was reliably found to cause fractures in non-venous nitinol stents. However, a dedicated self expanding nitinol venous stent, engineered for improved durability, underwent up to 50 years of simulated loading on the bench with 15% (3/20) of stents experiencing fractures at 50 years, compared with fractures in 35% (14/40) of non-venous stents tested to 1.4 years; no statistical testing was performed as durations do not match and the objective was to demonstrate the test method. CONCLUSION: The presented fatigue test method is a suitable approach for evaluating the durability of stents intended for venous use. Venous stents demonstrated superior fatigue resistance compared with non-venous stents via in vitro hip flexion testing.

7.
Parkinsonism Relat Disord ; 124: 107024, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38843617

RÉSUMÉ

INTRODUCTION: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). METHODS: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. RESULTS: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. CONCLUSIONS: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.


Sujet(s)
Leucine-rich repeat serine-threonine protein kinase-2 , Maladie de Parkinson , Animaux , Femelle , Mâle , alpha-Synucléine/métabolisme , Corps strié/métabolisme , Corps strié/effets des radiations , Leucine-rich repeat serine-threonine protein kinase-2/génétique , Leucine-rich repeat serine-threonine protein kinase-2/métabolisme , Maladie de Parkinson/métabolisme , Maladie de Parkinson/génétique , Protein-Serine-Threonine Kinases/génétique , Protein-Serine-Threonine Kinases/métabolisme , Suidae , Tyrosine 3-monooxygenase/métabolisme , Ubiquitin-protein ligases/génétique , Ubiquitin-protein ligases/métabolisme
8.
Mol Cancer Res ; 22(8): 689-698, 2024 08 02.
Article de Anglais | MEDLINE | ID: mdl-38747975

RÉSUMÉ

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN but not MYCL1 or non-amplified MYC cell lines exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor mivebresib (ABBV075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the antiproliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes can establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.


Sujet(s)
Tumeurs du poumon , Carcinome pulmonaire à petites cellules , Humains , Carcinome pulmonaire à petites cellules/génétique , Carcinome pulmonaire à petites cellules/traitement médicamenteux , Carcinome pulmonaire à petites cellules/anatomopathologie , Carcinome pulmonaire à petites cellules/métabolisme , Tumeurs du poumon/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Lignée cellulaire tumorale , Amplification de gène , Protéines proto-oncogènes c-myc/métabolisme , Protéines proto-oncogènes c-myc/génétique , Protéine du proto-oncogène N-Myc/génétique , Protéine du proto-oncogène N-Myc/métabolisme , Protéines contenant un bromodomaine , Protéines , Pyridones , Sulfonamides
9.
Neuro Oncol ; 26(9): 1651-1659, 2024 Sep 05.
Article de Anglais | MEDLINE | ID: mdl-38656347

RÉSUMÉ

BACKGROUND: Single-session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2 cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2 cm) to determine the safety of preoperative SRS at escalating doses. METHODS: Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy for >4-6 cm. Dose-limiting toxicity was defined as grade III or greater acute toxicity. RESULTS: A total of 35 patients/36 lesions were enrolled. For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 and 18 Gy, respectively) was reached. There were 2 DLTs in the >3-4 cm arm at 21 Gy. The maximum tolerated dose of SRS for >2-3 cm was not reached; and was 18 Gy for both >3-4 cm arm and >4-6 cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%. CONCLUSIONS: Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.


Sujet(s)
Tumeurs du cerveau , Radiochirurgie , Humains , Radiochirurgie/méthodes , Radiochirurgie/effets indésirables , Tumeurs du cerveau/secondaire , Tumeurs du cerveau/radiothérapie , Tumeurs du cerveau/chirurgie , Adulte d'âge moyen , Mâle , Femelle , Sujet âgé , Adulte , Dose maximale tolérée , Dosimétrie en radiothérapie , Études de suivi , Soins préopératoires , Sujet âgé de 80 ans ou plus
10.
PLoS One ; 19(3): e0296903, 2024.
Article de Anglais | MEDLINE | ID: mdl-38427613

RÉSUMÉ

There is a growing interest in low dose radiation (LDR) to counteract neurodegeneration. However, LDR effects on normal brain have not been completely explored yet. Recent analyses showed that LDR exposure to normal brain tissue causes expression level changes of different proteins including neurodegeneration-associated proteins. We assessed the proteomic changes occurring in radiated vs. sham normal swine brains. Due to its involvement in various neurodegenerative processes, including those associated with cognitive changes after high dose radiation exposure, we focused on the hippocampus first. We observed significant proteomic changes in the hippocampus of radiated vs. sham swine after LDR (1.79Gy). Mass spectrometry results showed 190 up-regulated and 120 down-regulated proteins after LDR. Western blotting analyses confirmed increased levels of TPM1, TPM4, PCP4 and NPY (all proteins decreased in various neurodegenerative processes, with NPY and PCP4 known to be neuroprotective) in radiated vs. sham swine. These data support the use of LDR as a potential beneficial tool to interfere with neurodegenerative processes and perhaps other brain-related disorders, including behavioral disorders.


Sujet(s)
Encéphalopathies , Exposition aux rayonnements , Suidae , Animaux , Protéomique , Irradiation corporelle totale , Mammifères , Hippocampe
11.
J Vasc Interv Radiol ; 35(5): 664-675.e5, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38336032

RÉSUMÉ

PURPOSE: To report 36-month outcomes and subgroup analysis of the ABRE study evaluating the safety and effectiveness of the Abre venous self-expanding stent system for the treatment of symptomatic iliofemoral venous outflow obstruction disease. METHODS: The ABRE study was a prospective, multicenter, nonrandomized study that enrolled and implanted Abre venous stents in 200 participants (mean age 51.5 years [SD ± 15.9], 66.5% women) with symptomatic iliofemoral venous outflow obstruction at 24 global sites. Outcomes assessed through 36 months included patency, major adverse events, stent migration, stent fracture, and quality-of-life changes. Adverse events and imaging studies were adjudicated by independent clinical events committee and core laboratories, respectively. RESULTS: Primary, primary-assisted, and secondary patency through 36 months by Kaplan-Meier estimates were 81.6%, 84.8%, and 86.3%, respectively. The cumulative incidence of major adverse events through 36 months was 10.2%, mainly driven by 12 thrombosis events. Subgroup analyses demonstrated a primary patency of 76.5% in the acute deep vein thrombosis group, 70.4% in the postthrombotic syndrome group, and 97.1% in the nonthrombotic iliac vein lesion group through 36 months. The overall mean lesion length was 112.4 mm (SD ± 66.1). There were no stent fractures or migrations in this study. Quality of life and venous functional assessments demonstrated significant improvements from baseline to 36 months across all patient subsets. CONCLUSIONS: Results from the ABRE study demonstrated sustained patency with a good safety profile after implantation of a dedicated venous stent in patients with symptomatic iliofemoral venous outflow obstruction disease.


Sujet(s)
Procédures endovasculaires , Veine fémorale , Veine iliaque commune , Conception de prothèse , Qualité de vie , Endoprothèses , Degré de perméabilité vasculaire , Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Procédures endovasculaires/instrumentation , Procédures endovasculaires/effets indésirables , Veine fémorale/imagerie diagnostique , Veine fémorale/physiopathologie , Veine iliaque commune/imagerie diagnostique , Veine iliaque commune/physiopathologie , Syndrome de May-Thurner/imagerie diagnostique , Syndrome de May-Thurner/thérapie , Syndrome de May-Thurner/physiopathologie , Syndrome post-thrombotique/imagerie diagnostique , Syndrome post-thrombotique/physiopathologie , Syndrome post-thrombotique/étiologie , Syndrome post-thrombotique/thérapie , Études prospectives , Facteurs de risque , Facteurs temps , Résultat thérapeutique , Thrombose veineuse/imagerie diagnostique , Thrombose veineuse/physiopathologie , Thrombose veineuse/thérapie
12.
Sci Total Environ ; 921: 170743, 2024 Apr 15.
Article de Anglais | MEDLINE | ID: mdl-38325484

RÉSUMÉ

The US pesticide registration and review process requires regular re-assessment of the risk of pesticide use to species listed under the Endangered Species Act (ESA), yet current assessment methods are inefficient when applied to hundreds of pesticides potentially impacting multiple species across a continent. Thus, many pesticides remain on the market without complete review. We assessed the value of using high resolution pesticide usage data in the risk assessment process to rapidly improve process efficiency. By using data available only in California, we found that high resolution data increased the number of species deemed not likely to be adversely affected by pesticides from <5 % to nearly 50 %. Across the contiguous US, we predicted that 48 % of species would be deemed not likely to be adversely affected using high resolution data, compared to 20 % without. However, if such data were available in just 11 states, 68 % of the available gains in efficiency could be obtained. Overall, using existing high-resolution data in California and a focused collection of such information from 11 other states could reduce risk assessment burden across the contiguous U.S. by one-quarter.


Sujet(s)
Pesticides , Animaux , Pesticides/analyse , Espèce en voie de disparition , Appréciation des risques/méthodes , Agriculture
13.
J Vasc Interv Radiol ; 35(3): 335-348, 2024 Mar.
Article de Anglais | MEDLINE | ID: mdl-38206255

RÉSUMÉ

Percutaneous revascularization is the primary strategy for treating lower extremity venous and arterial disease. Angiography is limited by its ability to accurately size vessels, precisely determine the degree of stenosis and length of lesions, characterize lesion morphology, or correctly diagnose postintervention complications. These limitations are overcome with use of intravascular ultrasound (IVUS). IVUS has demonstrated the ability to improve outcomes following percutaneous coronary intervention, and there is increasing evidence to support its benefits in the setting of peripheral vascular intervention. At this stage in its evolution, there remains a need to standardize the use and approach to peripheral vascular IVUS imaging. This manuscript represents considerations and consensus perspectives that emerged from a roundtable discussion including 15 physicians with expertise in interventional cardiology, interventional radiology, and vascular surgery, representing 6 cardiovascular specialty societies, held on February 3, 2023. The roundtable's aims were to assess the current state of lower extremity revascularization, identify knowledge gaps and need for evidence, and determine how IVUS can improve care and outcomes for patients with peripheral arterial and deep venous pathology.


Sujet(s)
Expertise , Maladies vasculaires , Humains , Machine à vecteur de support , Échographie , Maladies vasculaires/thérapie , Échographie interventionnelle/méthodes , Coronarographie
14.
J Vasc Surg Venous Lymphat Disord ; 12(1): 101685, 2024 Jan.
Article de Anglais | MEDLINE | ID: mdl-37703944

RÉSUMÉ

BACKGROUND: Vein ablation is a common and effective treatment for patients with chronic venous insufficiency. The overuse of vein ablation despite the existence of evidence-based guidelines has resulted in insurance companies developing restrictive policies for coverage that create barriers to appropriate care. This study compares the insurance coverage by single-state carriers (SSCs) and multistate carriers (MSCs), highlighting the variations and inconsistencies in the various policies. METHODS: The American Venous Forum Venous Policy Navigator was reviewed for the various policies available in the United States. The policies were divided into SSCs and MSCs. The characteristics of the policies, including the anatomic and hemodynamic criteria for specific veins, duration of conservative treatment, disease severity, symptoms, and types of procedures covered, were compared between the two groups. SAS, version 9.4 (SAS Institute Inc) was used for statistical analysis. RESULTS: A total of 122 policies were analyzed and divided between SSCs (n = 85; 69.7%) and MSCs (n = 37; 30.3%). A significant variation was found in the size requirement for great saphenous vein ablation. Although 48% of the policies did not specify a size criterion, the remaining policies indicated a minimal size, ranging from 3 to 5.5 mm. However, no significant differences were found between SSCs and MSCs. Similar findings were encountered for the small and anterior accessory saphenous veins. MSCs were more likely to define a saphenous reflux time >500 ms compared with SSCs (81.1% vs 58.8%; P = .04). A significant difference was found between the SSCs and MSCs in the criteria for perforator ablation in terms of size and reflux time. MSCs were significantly more likely to provide coverage for mechanochemical ablation than were SSCs (24.3% vs 8.2%; P = .03). SSCs were more likely to require ≥12 weeks of compression stocking therapy than were MSCs (76.5% vs 48.7%; P = .01). No significant differences were found in the clinical indications between the two groups; however, MSCs were more likely to mention major hemorrhage than were SSCs. CONCLUSIONS: The results of this study highlight the variations in policies for venous ablation, in particular, the striking inconsistencies in size criteria. MSCs were more likely to cover mechanochemical ablation and require a shorter duration of conservative therapy before intervention compared with SSCs. Evidence-based guidance is needed to develop more coherent policies for venous ablation coverage.


Sujet(s)
Ablation par cathéter , Varices , Insuffisance veineuse , Humains , États-Unis , Insuffisance veineuse/imagerie diagnostique , Insuffisance veineuse/chirurgie , Résultat thérapeutique , Veine saphène/imagerie diagnostique , Veine saphène/chirurgie , Veine fémorale/chirurgie , Ablation par cathéter/effets indésirables , Varices/chirurgie , Études rétrospectives
15.
Int J Radiat Oncol Biol Phys ; 118(3): 650-661, 2024 Mar 01.
Article de Anglais | MEDLINE | ID: mdl-37717787

RÉSUMÉ

PURPOSE: Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). METHODS AND MATERIALS: Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. RESULTS: The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P = .004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n = 162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P = .003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis. CONCLUSIONS: Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212).


Sujet(s)
Tumeurs du cerveau , Lésions radiques , Radiochirurgie , Humains , Tumeurs du cerveau/radiothérapie , Tumeurs du cerveau/chirurgie , Tumeurs du cerveau/anatomopathologie , Études de cohortes , Fractionnement de la dose d'irradiation , Lésions radiques/étiologie , Radiochirurgie/effets indésirables , Radiochirurgie/méthodes , Études rétrospectives , Résultat thérapeutique , Essais cliniques de phase III comme sujet , Essais contrôlés randomisés comme sujet
16.
J Proteome Res ; 23(1): 397-408, 2024 01 05.
Article de Anglais | MEDLINE | ID: mdl-38096401

RÉSUMÉ

Repeated blast-traumatic brain injury (blast-TBI) has been hypothesized to cause persistent and unusual neurological and psychiatric symptoms in service members returning from war zones. Blast-wave primary effects have been supposed to induce damage and molecular alterations in the brain. However, the mechanisms through which the primary effect of an explosive-driven blast wave generate brain lesions and induce brain consequences are incompletely known. Prior findings from rat brains exposed to two consecutive explosive-driven blasts showed molecular changes (hyperphosphorylated-Tau, AQP4, S100ß, PDGF, and DNA-polymerase-ß) that varied in magnitude and direction across different brain regions. We aimed to compare, in an unbiased manner, the proteomic profile in the hippocampus of double blast vs sham rats using mass spectrometry (MS). Data showed differences in up- and down-regulation for protein abundances in the hippocampus of double blast vs sham rats. Tandem mass tag (TMT)-MS results showed 136 up-regulated and 94 down-regulated proteins between the two groups (10.25345/C52B8VP0X). These TMT-MS findings revealed changes never described before in blast studies, such as increases in MAGI3, a scaffolding protein at cell-cell junctions, which were confirmed by Western blotting analyses. Due to the absence of behavioral and obvious histopathological changes as described in our previous publications, these proteomic data further support the existence of an asymptomatic blast-induced molecular altered status (ABIMAS) associated with specific protein changes in the hippocampus of rats repeatedly expsosed to blast waves generated by explosive-driven detonations.


Sujet(s)
Traumatismes par explosion , Lésions traumatiques de l'encéphale , Explosifs , Rats , Animaux , Traumatismes par explosion/complications , Traumatismes par explosion/anatomopathologie , Protéomique , Lésions traumatiques de l'encéphale/anatomopathologie , Hippocampe/anatomopathologie , Modèles animaux de maladie humaine
17.
Sci Rep ; 13(1): 19256, 2023 11 07.
Article de Anglais | MEDLINE | ID: mdl-37935813

RÉSUMÉ

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients with local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improve lymphocyte recovery should be investigated.


Sujet(s)
Radiochirurgie , Sarcomes , Humains , Résultat thérapeutique , Granulocytes neutrophiles , Études rétrospectives , Sarcomes/radiothérapie , Sarcomes/chirurgie , Lymphocytes , Microenvironnement tumoral
18.
Sci Rep ; 13(1): 21142, 2023 11 30.
Article de Anglais | MEDLINE | ID: mdl-38036591

RÉSUMÉ

Brain radiation has been medically used to alter the metabolism of cancerous cells and induce their elimination. Rarely, though, brain radiation has been used to interfere with the pathomechanisms of non-cancerous brain disorders, especially neurodegenerative disorders. Data from low-dose radiation (LDR) on swine brains demonstrated reduced levels of phosphorylated-tau (CP13) and amyloid precursor protein (APP) in radiated (RAD) versus sham (SH) animals. Phosphorylated-tau and APP are involved in Alzheimer's disease (AD) pathogenesis. We determined if the expression levels of hyperphosphorylated-tau, 3R-tau, 4R-tau, synaptic, intraneuronal damage, and DNA damage/oncogenic activation markers were altered in RAD versus SH swine brains. Quantitative analyses demonstrated reduced levels of AT8 and 3R-tau in hippocampus (H) and striatum (Str), increased levels of synaptophysin and PSD-95 in frontal cortex (FCtx), and reduced levels of NF-L in cerebellum (CRB) of RAD versus SH swine. DNA damage and oncogene activation markers levels did not differ between RAD and SH animals, except for histone-H3 (increased in FCtx and CRB, decreased in Str), and p53 (reduced in FCtx, Str, H and CRB). These findings confirm the region-based effects of sLDR on proteins normally expressed in larger mammalian brains and support the potential applicability of LDR to beneficially interfere against neurodegenerative mechanisms.


Sujet(s)
Maladie d'Alzheimer , Protéines tau , Animaux , Suidae , Protéines tau/métabolisme , Maladie d'Alzheimer/métabolisme , Encéphale/métabolisme , Précurseur de la protéine bêta-amyloïde/génétique , Précurseur de la protéine bêta-amyloïde/métabolisme , Altération de l'ADN , Peptides bêta-amyloïdes/métabolisme , Phosphorylation , Mammifères/métabolisme
19.
Semin Vasc Surg ; 36(4): 550-559, 2023 Dec.
Article de Anglais | MEDLINE | ID: mdl-38030329

RÉSUMÉ

Venous compression syndromes have been described, yet the role of sex is poorly understood. Although iliac vein compression has been discussed more often with the advent of newer technologies, research has fallen short on defining epidemiology, best practices for evaluation and treatment, and differences in responses to treatment between men and females. The authors report on iliac vein compression, nonthrombotic renal vein compression, and other venous compression syndromes in females. Literature searches of PubMed were performed using the following keywords: females/females and May Thurner, venous stenting, venous outcomes, deep venous disease, deep venous compression, venous stenting, renal vein compression, renal vein surgery/stent, popliteal vein entrapment, venous thoracic vein entrapment, and popliteal vein entrapment. The articles prompted the authors to research further as the referenced articles were reviewed. Sex representation has not been addressed adequately in the research of venous compression syndromes, making the discussion of best treatment options and long-term outcomes difficult. More specific understanding of epidemiology and response to interventions will only come from research that addresses these issues directly, understanding that some of these syndromes occur rarely.


Sujet(s)
Syndrome de May-Thurner , Maladies vasculaires , Mâle , Humains , Femelle , Syndrome de May-Thurner/imagerie diagnostique , Syndrome de May-Thurner/thérapie , Résultat thérapeutique , Maladies vasculaires/diagnostic , Maladies vasculaires/épidémiologie , Maladies vasculaires/chirurgie , Veine poplitée , Veine iliaque commune/imagerie diagnostique , Endoprothèses , Études rétrospectives
20.
PLoS One ; 18(9): e0291029, 2023.
Article de Anglais | MEDLINE | ID: mdl-37751459

RÉSUMÉ

Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the FosB proto-oncogene (FOSB) and ERCC excision repair 1 (ERCC1) genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants.


Sujet(s)
Maladie d'Alzheimer , Cellules souches pluripotentes induites , Humains , Maladie d'Alzheimer/métabolisme , Polymorphisme de nucléotide simple , Génotype , Neurones
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE