👤 Elie Haddad

The disruption of key mechanisms involved in amyloid beta (Aβ) clearance during the early stages of dementia may contribute to the progression of cognitive decline toward irreversible brain damage. In this study, we investigated multiple immune-related pathways implicated in the management and clearance of Aβ within circulating extracellular vesicles (cEVs) and serum from individuals with subjective cognitive decline (SCD) who later progressed to mild cognitive impairment (MCI). A cytokine panel and the levels of Aβ In SCD patients, the concentrations of Aβ Our findings support the potential value of integrating serum M-CSF levels with RAVLT performance and cEVs Aβ Show less

Intermittent hypoxia and hypercapnia (IHC), a hallmark of obstructive sleep apnea (OSA), accelerates atherosclerosis, yet the underlying mechanisms remain unclear. The gut microbiota and metabolites, specifically bile acids, change with IHC and thus the bile acid receptor farnesoid X receptor (FXR) might mediate IHC-induced atherosclerosis. In this study, Show less

This review examines the rapidly evolving landscape of myeloproliferative hypereosinophilic syndromes (HES) and related neoplasms. We aim to synthesize current understanding of their diverse molecular drivers, evaluate the efficacy of established and novel targeted therapies, and identify critical research gaps. The goal is to provide a clinically relevant update on how molecular precision is reshaping the diagnosis and management of these rare, often aggressive hematologic malignancies beyond the established standard of imatinib. The field has moved beyond generic HES diagnoses to a molecularly defined classification. While imatinib remains the standard for The management of myeloproliferative HES has transitioned from empirical therapy to a precision medicine paradigm. Early comprehensive molecular profiling is essential to guide therapy selection. While imatinib remains a cornerstone for select patients, novel agents like pemigatinib and avapritinib have filled critical therapeutic gaps. Future progress depends on the routine integration of comprehensive next-generation sequencing, the validation of minimal residual disease monitoring to guide therapy de-escalation, and international collaboration to conduct innovative trials for these rare patient populations. Show less

Few studies have compared chemoradiotherapy with primary surgery for T3 laryngeal cancers. This retrospective study compared two parallel consecutive patient cohorts: one treated surgically at the Sant'Orsola Hospital (Bologna, Italy) and the other managed with chemoradiotherapy at the Conception Hospital (Marseille, France). The study included 106 patients, 66 treated with chemoradiotherapy and 40 managed surgically. In Kaplan-Meier analysis, 2- and 5-year disease-free survival rates were 75% and 70% in the chemoradiotherapy group versus 85% at both time points in the surgery group (p = 0.22). Cox regression, adjusted for follow-up, age, sex, and cN stage, showed no significant differences in disease-free (p = 0.46), overall (p = 0.36), or disease-specific survival (p = 0.95). Tracheostomy dependence was higher after surgery (62.5% vs. 30.30%, p = 0.002), with no difference in gastrostomy dependence. Surgical and nonsurgical approaches achieved comparable oncologic outcomes with a lower rate of tracheostomy dependence in the nonsurgical group. Show less

Mammalian opsin 3 (OPN3) is a member of the opsin family of G-protein-coupled receptors with ambiguous light sensitivity. OPN3 was first identified in the brain (and named encephalopsin) and subsequently found to be expressed in other tissues. In adipocytes, OPN3 is necessary for light responses that modulate lipolysis and glucose uptake, while OPN3 in human skin melanocytes regulates pigmentation in a light-independent manner. Despite its initial discovery in the brain, OPN3 functional mechanisms in the brain remain elusive. Here, we investigated the molecular mechanism of OPN3 function in the paraventricular nucleus (PVN) of the hypothalamus. We show that Show less

The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear. In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1. A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P = 0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P = 0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P = 0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group. The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.). Show less

In 2017, an innovative partnership was established between the ENT department of La Conception Hospital in Marseille and a city-hospital network (ILHUP) to facilitate early discharge after total laryngectomy (TL) and total pharyngo-laryngectomy (TPL). The main objective was to compare the home discharge rate versus transfer to a rehabilitation facility before and after implementation of this partnership. This single-center retrospective study included 205 patients who underwent TL/TPL between January 2012 and December 2023, divided into two groups: group 1 (n = 93) and group 2 (n = 112) before and after implementation of the city-hospital network. The home discharge rate in Group 2 was significantly higher than in Group 1 (55.4% vs. 40.9%, p = 0.039). Within group 2, mean length of hospital stay (23.8 vs. 26.12 days, p = 0.295) and two-month readmission rate (4.8% vs. 10%, p = 0.321) were similar between patients discharged home and those transferred to rehabilitation facilities. Multivariate analysis showed that implementation of the city-hospital network partnership was the only factor independently associated with an increased home discharge rate (p = 0.018). Implementation of a partnership with a city-hospital network significantly increased the home discharge rate after total (pharyngo-) laryngectomy without compromising patient safety. Show less

To establish typical clinical and radiological profiles of primary low-grade parotid cancers in order to tailor therapeutic strategy. Retrospective study of 57 patients operated on for primary parotid cancer between 2010 and 2021, with review of preoperative MRI and histopathology according to a standardized scoring grid. To study prognostic factors and determine the preoperative clinical and radiological profile of low-grade cancers. Good prognostic factors for specific survival were: staging ≤ cT3 (p = 0.014), absence of adenopathy on cN0 MRI (p < 0.001), superficial lobe location (p = 0.033), pN0 (p < 0.001), absence of capsular rupture (p = 0.004), as well as the absence of peri-tumoral nodules (p = 0.033), intra-parotid adenopathies (p < 0.001), vascular emboli (p < 0.001), peri-neural sheathing (p = 0.016), nuclear atypia (p = 0.031), and necrosis (p = 0.002). It was not possible to define a reliable clinical and radiological profile for low-grade cancers (sensitivity 38%, specificity 79%). Our study demonstrated multiple factors of good prognosis, but it was not possible to define a clinical and radiological profile of patients likely to benefit from more limited surgery, nor to diagnose, a priori, low-grade cancers. Show less

Laryngeal surgeries using a flexible nasopharyngoscope equipped with an operative channel has gained popularity, with gradual increase in the variety of interventional office-based procedures, under local anesthesia. The purpose of this study is to analyze the tolerance of such procedures. Retrospective cohort study. 337 cases were performed during 2 years. We collected the following data: type of pathology, type of procedure and modalities of anesthesia, adverse events. 19 % of the visits were for the purpose of Biopsy, 65 % for an injection, and Trublue Laser was utilized in 12 % of the procedures. Regarding the pathologies, 27 % were vocal fold paralysis, 18 % leukoplakia or another suspicious lesion, 15 % recurrent respiratory papillomatosis, 13 % neuromuscular disorder, 9 % vocal fold scarring, 7 % vocal cord atrophy and 6 % had an inflammatory presentation. Side effects were documented in 26 visits (7.7 %) and were minor in almost all the encounters: they included strong reflexive cough, deep throat pain, discomfort, gag reflex, anxiety, vagal discomfort, malaise, hypersalivation, nose pain, labile hypertension. More severe side effects were very rare and included septal wound and epistaxis, erythematous rash, dyspnea, and transient dysarthria. 13 procedures were either aborted, or canceled at initial steps, due to inability of the patient to tolerate the procedure and were rescheduled for general anesthesia. 97 % of the cases were released home after 1 h of surveillance. Office-based flexible interventional laryngoscopy under local anesthesia is a safe and well-tolerated procedure, with abundance of various interventions feasible on ambulatory, office-based setup. Show less

High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease. Show less

Interleukin-27 (IL-27) can trigger both pro- and anti-inflammatory responses. This cytokine is elevated in the central nervous system (CNS) of multiple sclerosis (MS) patients, but how it influences neuroinflammatory processes remains unclear. As astrocytes express the receptor for IL-27, we sought to determine how these glial cells respond to this cytokine and whether such exposure alters their interactions with infiltrating activated T lymphocytes. To determine whether inflammation shapes the impact of IL-27, we compared the effects of this cytokine in non-inflamed and inflamed conditions induced by an IL-1β exposure. Transcriptomic analysis of IL-27-exposed human astrocytes showed an upregulation of multiple immune genes. Human astrocytes increased the secretion of chemokines (CXCL9, CXCL10, and CXCL11) and the surface expression of proteins (PD-L1, HLA-E, and ICAM-1) following IL-27 exposure. To assess whether exposure of astrocytes to IL-27 influences the profile of activated T lymphocytes infiltrating the CNS, we used an astrocyte/T lymphocyte co-culture model. Activated human CD4 Our results establish that IL-27 alters the immune functions of human astrocytes and shapes the profile and motility of encountered T lymphocytes, especially CD8 Show less

We aimed to assess differences in (1) first-pass intubation success, (2) frequency of a hypoxic event, and (3) time from decision to intubate to successful intubation among direct laryngoscopy (DL) versus video laryngoscopy (VL) intubations in emergency department (ED) patients with traumatic injuries. This retrospective cohort study was performed at a Level I trauma center ED where trauma activations are video recorded. All patients requiring a Level I trauma activation and intubation from 2016 through 2019 were included. Multivariable logistic regression was used to assess the association between initial method of intubation and first-pass success. Differences in frequency of a hypoxic event and time to successful intubation were assessed using bivariate tests. Of 164 patients, 68 (41.5%) were initially intubated via DL and 96 (58.5%) were initially intubated via VL. First-pass success for DL and VL were 63.2% and 79.2%, respectively. In multivariable regression analysis, VL was associated with higher odds of first-pass intubation success compared with DL (odds ratio: 2.28; 95% confidence interval: 1.04, 4.98), independent of mechanism of injury, presence of airway hemorrhage or obstruction, and experience of intubator. Frequency of a hypoxic event during intubation was not significantly different (13.2% for DL and 7.3% VL; Video laryngoscopy, compared with direct laryngoscopy, was associated with higher odds of first-pass intubation success among a sample of ED trauma patients. Frequency of a hypoxic event during intubation and time to successful intubation was not significantly different between the 2 intubation methods. Show less

Triple-negative breast cancer (TNBCs) account for 15-20% of all breast cancers and represent the most aggressive subtype of this malignancy. Early tumor relapse and progression are linked to the enrichment of a sub-fraction of cancer cells, termed breast tumor-initiating cells (BTICs), that undergo epithelial to mesenchymal transition (EMT) and typically exhibit a basal-like CD44 Show less

Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated Show less

Adenylate cyclases (ADCYs) catalyze the conversion of ATP to cAMP, an important co-factor in energy homeostasis. Giving ADCYs role in obesity, diabetes and inflammation, we questioned whether calcium-stimulated ADCY isoforms may be variably detectable in human plasma. We report the results of a cross-sectional study assessing circulating levels of functional ADCY1, -3 and -8 in patients with T2D vs. non-diabetic (ND) controls in association with obesity. ADCY1 levels exhibited no significant change between ND and T2D groups. ADCY3 levels were lower in obese individuals, albeit not statistically significantly. In contrast, ADCY8 plasma levels were significantly higher in obese and T2D patients compared to controls ( Show less

Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was to determine their serum levels in MCI (mild cognitive impairment) and Alzheimer's disease (AD) patients, to analyze their effects on the neurotrophic and inflammatory factors, on neurodegenerative markers in neuronal cells and in neuronal derived-extracellular vesicles (nEVs). Our results show that MG and GO levels in serum, determined by HPLC, were higher in MCI. ROC (receiver-operating characteristic curves) analysis showed that the levels of MG in serum have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. Cells and nEVs levels of BDNF, PRGN, NSE, APP, MMP-9, ANGPTL-4, LCN2, PTX2, S100B, RAGE, Aβ peptide, pTau T181 and alpha-synuclein were quantified by luminex assay. Treatment of neuronal cells with MG or GO reduced the cellular levels of NSE, PRGN, APP, MMP-9 and ANGPTL-4 and the nEVs levels of BDNF, PRGN and LCN2. Our findings suggest that targeting MG and GO may be a promising therapeutic strategy to prevent or delay the progression of AD. Show less

The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM₀₀₀₂₅₈.2:c.170C>A, NP₀₀₀₂₄₉.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Human-induced pluripotent stem cells (iPSCs) were derived from the heterozygous VUS MYL3 The heterozygous VUS MYL3 Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrier-specific manner in a dish. As such, this platform represents a promising VUS risk-assessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field. Show less

Recent reports have demonstrated that adult tissue cells can be induced to pluripotency, the iPS cells, mostly with the addition of genes delivered using viruses. Also, several publications both in mouse and in human have demonstrated that spermatogonial stem cells (SSCs) from testes can convert back to embryonic stem (ES)-like cells without the addition of genes. Furthermore, these pluripotent ES-like cells can differentiate into all three germ layers and organ lineages. Thus, SSCs have great potential for cell-based, autologous organ regeneration therapy for various diseases. We obtained testes from organ donors and using 1 g pieces of tissue (biopsy size) we demonstrate that testis germ cells (putative SSCs and/or their progenitors) reprogram to pluripotency when removed from their stem cell niche and when appropriate growth factors and reagents in embryonic stem cell medium are added. In addition, our method of obtaining pluripotent ES-like cells from germ cells is simpler than the described methods and may be more suitable if this procedure is developed for the clinic to obtain pluripotent cells to cure disease. Show less