Studies of the estrogen receptor (ER) coactivator protein Mediator subunit 1 (MED1) have revealed its specific roles in pubertal mammary gland development and potential contributions to breast ...tumorigenesis, based on coamplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and to impair tumor growth, metastasis, and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.
These findings identify an estrogen receptor-binding protein as a critical mediator of HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.
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Neurofilament light chain (NfL) has been demonstrated to correlate with multiple sclerosis disease severity as well as treatment response. Nevertheless, additional serum biomarkers are still needed ...to better differentiate disease activity from disease progression. The aim of our study was to assess serum glial fibrillary acid protein (s-GFAP) and neurofilament light chain (s-NfL) in a cohort of 129 multiple sclerosis (MS) patients. Eighteen primary progressive multiple sclerosis (PPMS) and 111 relapsing remitting MS (RRMS) were included. We showed that these 2 biomarkers were significantly correlated with each other (R = 0.72, p < 0.001). Moreover, both biomarkers were higher in PPMS than in RRMS even if multivariate analysis only confirmed this difference for s-GFAP (130.3 ± 72.8 pg/ml vs 83.4 ± 41.1 pg/ml, p = 0.008). Finally, s-GFAP was correlated with white matter lesion load and inversely correlated with WM and GM volume. Our results seem to confirm the added value of s-GFAP in the context of multiple sclerosis.
Background
Chemotherapy for breast cancer is associated with a high risk of neutropenia. Pegfilgrastim reduces the risk of neutropenic fever but commonly causes bone pain.
Objective
Evaluate whether ...a reduced dose of pegfilgrastim (3 mg) reduced the frequency of bone pain without compromising efficacy.
Methods
Records reviewed from breast cancer patients who received at least one 3 mg dose of pegfilgrastim, white blood count (WBC), and absolute granulocyte counts (AGC) were collected. Musculoskeletal pain scale was collected at each visit.
Results
265 treatments from 36 women were analyzed. There was no difference in post-treatment AGC between 3 versus 6 mg. Leukocytosis (WBC > 20,000 cells/cu mm) was more likely for those treated with 6 mg (chi-square 5.265,
p
= 0.0215). There was higher change in bone pain in patients who received 6 mg doses compared to none or 3 mg.
Limitations
In this retrospective, non-randomized study, we found the majority of patients received the reduced 3 mg dose after intolerance to the 6 mg dose. It is unknown if smaller or larger doses than 3 mg would achieve similar results or whether 3 mg dose would be effective as an initial therapy or for patients receiving different chemotherapy regimens. Pain is observed despite premedication with naproxen and/or loratidine.
Conclusion
Reduced dose of pegfilgrastim 3 mg was less likely to cause bone pain. The reduced dose was not associated with a significant difference in post-treatment AGC or rate of serious infection.
Background:
Leptomeningeal enhancement (LME) is a key feature of Susac syndrome (SuS) but is only occasionally depicted on post-contrast T1-weighted images (T1-WI).
Objective:
As post-contrast ...fluid-attenuated inversion recovery (FLAIR) may be more sensitive, our aim was to assess LME in SuS on this sequence.
Methods:
From 2010 to 2020, 20 patients with definite SuS diagnosis were retrospectively enrolled in this multicentre study. Two radiologists independently assessed the number of LME on post-contrast FLAIR and T1-WI acquisitions performed before any treatment. A chi-square test was used to compare both sequences and the interrater agreement was calculated.
Results:
Thirty-five magnetic resonance imagings (MRIs) were performed before treatment, including 19 post-contrast FLAIR images in 17 patients and 25 post-contrast T1-WI in 19 patients. In terms of patients, LME was observed on all post-contrast FLAIR, contrary to post-contrast T1-WI (17/17 (100%) vs. 15/19 (79%), p < 0.05). In terms of sequences, LME was observed on all post-contrast FLAIR, contrary to post-contrast T1-WI (19/19 (100%) vs. 16/25 (64%), p < 0.005). LME was disseminated at both supratentorial (19/19) and infratentorial (18/19) levels on post-contrast FLAIR, contrary to post-contrast T1-WI (3/25 and 9/25, respectively). Interrater agreement was excellent for post-contrast FLAIR (κ = 0.95) but only moderate for post-contrast T1-WI (κ = 0.61).
Conclusion:
LME was always observed and easily visible on post-contrast FLAIR images prior to SuS treatment. In association with other MRI features, it is highly indicative of SuS.
Excessive daytime sleepiness is a frequent complaint in Parkinson's disease (PD); however the frequency and risk factors for objective sleepiness remain mostly unknown. We investigated both the ...frequency and determinants of self-reported and objective daytime sleepiness in patients with Parkinson's disease (PD) using a wide range of potential predictors.
One hundred and thirty four consecutive patients with PD, without selection bias for sleep complaint, underwent a semi-structured clinical interview and a one night polysomnography followed by a multiple sleep latency test (MSLT). Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behaviour disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness.
Of 134 patients with PD, 46.3% had subjective and only 13.4% had objective sleepiness with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness, and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behaviour disorder and nighttime sleep evaluation.
We found a high frequency of self-reported EDS in PD, a finding which is however not confirmed by the gold standard neurophysiological evaluation. Current treatment options for EDS in PD are very limited; it thus remains to be determined whether decreasing pain and BMI in association with the treatment of sleep apnea syndrome would decrease significantly daytime sleepiness in PD.
Background
Symptomatic isolated carotid artery occlusions (ICAO) can lead to disability, recurrent stroke, and mortality, but natural history and best therapeutic management remain poorly known. The ...objective of this study was to describe our cohort of ICAO patients with an initial medical management.
Methods
We conducted a retrospective study including consecutive patients admitted to our Comprehensive Stroke Center for ICAO within 24 h after stroke onset between January 2016 and September 2018. Patients with immediate endovascular therapy (EVT) were excluded. Medical treatment was based on anticoagulation (delayed by 24 h if intravenous thrombolysis was performed). ‘Rescue’ EVT was considered if first-week neurological deterioration (FWND) occurred.
Results
Fifty-six patients were included, with a median National Institutes of Health Stroke Scale (NIHSS) of 3. Eleven patients (20%) had FWND during the first week, four benefited from rescue EVT. A mismatch volume > 40 cc on initial perfusion imaging and FLAIR vascular hyperintensities were associated with FWND (
p
= 0.007 and
p
= 0.009, respectively). Thirty-eight patients (69%) had a good outcome (modified Rankin Scale mRS 0–2) at 3 months, 36 (69%) had an excellent outcome (mRS 0–1). Seventeen patients (38%) had carotid patency on 3-month control imaging. Recurrences occurred in six (13%) of the survivors (mean follow-up: 13.6 months).
Conclusion
Our results suggest that the prognosis of patients with acute ICAO was favorable with a medical strategy, albeit a substantial rate of FWND and recurrence. FWND was well predicted by a core-perfusion mismatch volume > 40 cc. Randomized controlled trials are necessary to assess the benefit of EVT in ICAO.
MED1 (mediator subunit 1) co-amplifies with HER2, but its role in HER2-driven mammary tumorigenesis is still unknown. Here, we generate MED1 mammary-specific overexpression mice and cross them with ...mouse mammary tumor virus (MMTV)-HER2 mice. We observe significantly promoted onset, growth, metastasis, and multiplicity of HER2 tumors by MED1 overexpression. Further studies reveal critical roles for MED1 in epithelial-mesenchymal transition, cancer stem cell formation, and response to anti-HER2 therapy. Mechanistically, RNA sequencing (RNA-seq) transcriptome analyses and clinical sample correlation studies identify Jab1, a component of the COP9 signalosome complex, as the key direct target gene of MED1 contributing to these processes. Further studies reveal that Jab1 can also reciprocally regulate the stability and transcriptional activity of MED1. Together, our findings support a functional cooperation between these co-amplified genes in HER2+ mammary tumorigenesis and their potential usage as therapeutic targets for the treatment of HER2+ breast cancers.
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•Generation of a more clinically relevant mouse HER2+/MED1+ mammary tumor model•MED1 overexpression promotes HER2+ tumor onset, stem cell formation, and metastasis•Critical roles of MED1 overexpression in HER2+ tumor treatment resistance•Jab1 is a MED1 direct target gene mediating the aggressive phenotypes of HER2+ tumors
In this study, Yang et al. generate a more clinically relevant MMTV-HER2/MMTV-MED1 mammary tumor mouse model and discover the critical roles and molecular mechanisms of MED1 overexpression in mediating the aggressive phenotypes of HER2+ tumor progression, metastasis, cancer stem cell formation, and therapy resistance.
Background and purpose
In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS).
...Methods
To identify immune‐mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria.
Results
Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range IQR = 43–145). The median age at onset was 51.5 years (IQR = 39–58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti‐GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor‐related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti‐glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto‐/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4).
Conclusions
We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood–nerve and blood–brain barriers.
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by ...fibrillar amyloid-β (Aβ) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben).
To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients.
CSF levels of total tau, phosphorylated tau, Aβ1-42, and Aβ1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients.
A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aβ1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers.
In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri.
Primary familial brain calcification (PFBC) is a rare neurological disease characterized by deposits of calcium phosphate in the basal ganglia and other regions of the brain. Pathogenic variants in ...the XPR1/SLC53A1 gene, which encodes the only known inorganic phosphate exporter, cause an autosomal dominant form of PFBC. These variants are typically located in the SPX N-terminal domain of the protein. Here, we characterize three XPR1 variants outside of SPX in three PFBC patients with an apparently sporadic presentation: c.1375C > T p.(R459C), c.1855A > G p.(N619D) and c.1886T > G p.(I629S), with the latter identified as the first XPR1/SLC53A1 de novo mutation to occur in a PFBC proband. When tested in an in vitro physiological complementation assay, the three XPR1 variants were impaired in phosphate export function, although they were normally expressed at the cell surface and could serve as functional receptors for retrovirus entry. Moreover, peripheral blood cells from the p.N619D patient could be assayed ex vivo and displayed significantly impaired phosphate export. Our results establish for the first time the clinical and molecular characteristics of XPR1 variants located outside the SPX domain and assert a direct link between these variants, deficient phosphate export, and PFBC. Moreover, we unveiled new structural features in XPR1 C-terminal domain that play a role in phosphate export and disease.
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