Near-Unity Photoluminescence Quantum Yield of Core-Only InP Quantum Dots via a Simple Postsynthetic InF3 Treatment.

Indium phosphide (InP) quantum dots (QDs) are considered the most promising alternative for Cd and Pb-based QDs for lighting and display applications. However, while core-only QDs of CdSe and CdTe have been prepared with near-unity photoluminescence quantum yield (PLQY), this is not yet achieved for InP QDs. Treatments with HF have been used to boost the PLQY of InP core-only QDs up to 85%. However, HF etches the QDs, causing loss of material and broadening of the optical features. Here, we present a simple postsynthesis HF-free treatment that is based on passivating the surface of the InP QDs with InF3. For optimized conditions, this results in a PLQY as high as 93% and nearly monoexponential photoluminescence decay. Etching of the particle surface is entirely avoided if the treatment is performed under stringent acid-free conditions. We show that this treatment is applicable to InP QDs with various sizes and InP QDs obtained via different synthesis routes. The optical properties of the resulting core-only InP QDs are on par with InP/ZnSe/ZnS core-shell QDs, with significantly higher absorption coefficients in the blue, and with potential for faster charge transport. These are important advantages when considering InP QDs for use in micro-LEDs or photodetectors.

Role of Cardiovascular Magnetic Resonance in Cardiac Amyloidosis: A Narrative Review.

Amyloidosis is a rare infiltrative condition resulting from the extracellular accumulation of amyloid fibrils at the cardiac level. It can be an acquired condition or due to genetic mutations. With the progression of imaging technologies, a non-invasive diagnosis was proposed. In this study, we discuss the role of CMR in cardiac amyloidosis, focusing on the two most common subtypes (AL and ATTR), waiting for evidence-based guidelines to be published.

Frailty as a comprehensive health measure beyond seizure control in patients with epilepsy: A cross-sectional study.

OBJECTIVE: Due to the high clinical heterogeneity of epilepsy, there is a critical need for novel metrics aimed at capturing its biological and phenotypic complexity. Frailty is increasingly recognized in various medical disciplines as a useful construct to understand differences in susceptibility to adverse outcomes. Here, we develop a frailty index (FI) for patients with epilepsy (PwE) and explore its association with demographic and clinical features. METHODS: In this cross-sectional study, we consecutively enrolled 153 PwE from an outpatient epilepsy clinic. Participants were assessed for various health deficits to calculate the FI. Associations between FI and demographic/clinical features, antiseizure medications (ASMs), and patient-reported outcomes were analyzed using general linear models and Spearman correlation. RESULTS: The median age at the time of study visit was 47 years (interquartile range = 33-60), and 89 (58.2%) patients were females. Multiple linear regression revealed that the developed 33-item FI showed an independent association with age, female sex, higher body mass index, family history of epilepsy, intellectual disability, and the number of ASMs used. A robust analysis of covariance showed higher FI levels in patients using cytochrome P450 3A4-inducer ASMs. We found a moderate positive correlation between FI and psychological distress, lower quality of life, and physical frailty, measured by the Hospital Anxiety and Depression Scale, Quality of Life in Epilepsy Inventory-10, and handgrip strength, respectively. Finally, a weak association was observed between higher FI scores and an increased number of epileptic falls. SIGNIFICANCE: This study highlights the significance of frailty as a comprehensive health measure in epilepsy. It suggests that frailty in this specific population is not only a manifestation of aging but is inherently linked to epilepsy and treatment-related factors. Future research is warranted to validate and refine the FI in diverse epilepsy populations and investigate its impact on specific adverse outcomes in longitudinal studies.

Cell-free DNA levels associate with COPD exacerbations and mortality.

THE QUESTION ADDRESSED BY THE STUDY: Good biological indicators capable of predicting chronic obstructive pulmonary disease (COPD) phenotypes and clinical trajectories are lacking. Because nuclear and mitochondrial genomes are damaged and released by cigarette smoke exposure, plasma cell-free mitochondrial and nuclear DNA (cf-mtDNA and cf-nDNA) levels could potentially integrate disease physiology and clinical phenotypes in COPD. This study aimed to determine whether plasma cf-mtDNA and cf-nDNA levels are associated with COPD disease severity, exacerbations, and mortality risk. MATERIALS AND METHODS: We quantified mtDNA and nDNA copy numbers in plasma from participants enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE, n = 2,702) study and determined associations with relevant clinical parameters. RESULTS: Of the 2,128 participants with COPD, 65% were male and the median age was 64 (interquartile range, 59-69) years. During the baseline visit, cf-mtDNA levels positively correlated with future exacerbation rates in subjects with mild/moderate and severe disease (Global Initiative for Obstructive Lung Disease [GOLD] I/II and III, respectively) or with high eosinophil count (≥ 300). cf-nDNA positively associated with an increased mortality risk (hazard ratio, 1.33 [95% confidence interval, 1.01-1.74] per each natural log of cf-nDNA copy number). Additional analysis revealed that individuals with low cf-mtDNA and high cf-nDNA abundance further increased the mortality risk (hazard ratio, 1.62 [95% confidence interval, 1.16-2.25] per each natural log of cf-nDNA copy number). ANSWER TO THE QUESTION: Plasma cf-mtDNA and cf-nDNA, when integrated into quantitative clinical measurements, may aid in improving COPD severity and progression assessment.

Aluminium 8-Hydroxyquinolinate N-Oxide as a Precursor to Heterometallic Aluminium-Lanthanide Complexes.

A reaction in anhydrous toluene between the formally unsaturated fragment [Ln(hfac)3] (Ln3+ = Eu3+, Gd3+ and Er3+; Hhfac = hexafluoroacetylacetone) and [Al(qNO)3] (HqNO = 8-hydroxyquinoline N-oxide), here prepared for the first time from [Al(OtBu)3] and HqNO, affords the dinuclear heterometallic compounds [Ln(hfac)3Al(qNO)3] (Ln3+ = Eu3+, Gd3+ and Er3+) in high yields. The molecular structures of these new compounds revealed a dinuclear species with three phenolic oxygen atoms bridging the two metal atoms. While the europium and gadolinium complexes show the coordination number (CN) 9 for the lanthanide centre, in the complex featuring the smaller erbium ion, only two oxygens bridge the two metal atoms for a resulting CN of 8. The reaction of [Eu(hfac)3] with [Alq3] (Hq = 8-hydroxyquinoline) in the same conditions yields a heterometallic product of composition [Eu(hfac)3Alq3]. A recrystallization attempt from hot heptane in air produced single crystals of two different morphologies and compositions: [Eu2(hfac)6Al2q4(OH)2] and [Eu2(hfac)6(µ-Hq)2]. The latter compound can be directly prepared from [Eu(hfac)3] and Hq at room temperature. Quantum mechanical calculations confirm (i) the higher stability of [Eu(hfac)3Al(qNO)3] vs. the corresponding [Eu(hfac)3Alq3] and (ii) the preference of the Er complexes for the CN 8, justifying the different behaviour in terms of the Lewis acidity of the metal centre.

Intact mitochondrial function in the setting of telomere-induced senescence.

Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.

Structural and Comparative Analyses of Insects Suggest the Presence of an Ultra-Conserved Regulatory Element of the Genes Encoding Vacuolar-Type ATPase Subunits and Assembly Factors.

Gene and genome comparison represent an invaluable tool to identify evolutionarily conserved sequences with possible functional significance. In this work, we have analyzed orthologous genes encoding subunits and assembly factors of the V-ATPase complex, an important enzymatic complex of the vacuolar and lysosomal compartments of the eukaryotic cell with storage and recycling functions, respectively, as well as the main pump in the plasma membrane that energizes the epithelial transport in insects. This study involves 70 insect species belonging to eight insect orders. We highlighted the conservation of a short sequence in the genes encoding subunits of the V-ATPase complex and their assembly factors analyzed with respect to their exon-intron organization of those genes. This study offers the possibility to study ultra-conserved regulatory elements under an evolutionary perspective, with the aim of expanding our knowledge on the regulation of complex gene networks at the basis of organellar biogenesis and cellular organization.

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons.

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice.

Mechanistic study of ZnSe nanocrystal formation from zinc halides.

We studied the formation of zinc selenide (ZnSe) from zinc chloride (ZnCl2) and trioctylphosphine selenide (TOP=Se) in oleylamine, a chemistry originally proposed to grow ZnSe shells around InP core quantum dots. By monitoring the formation of ZnSe in reactions with and without InP seeds by quantitative absorbance and nuclear magnetic resonance (NMR) spectroscopy, we observe that the ZnSe formation rate is independent of the presence of InP cores. Similar to the seeded growth of CdSe and CdS, this observation supports a ZnSe growth mechanism through the inclusion of reactive ZnSe monomers that form homogeneously in the solution. Furthermore, by combining NMR and mass spectrometry, we identified the dominant reaction products of the ZnSe formation reaction as oleylammonium chloride and amino-substitutions of TOP, i.e., iminophosphoranes (TOP=NR), aminophosphonium chloride salts [TOP(NHR)Cl], and bis(amino)phosphoranes [TOP(NHR)2]. Based on the acquired results, we outline a reaction scheme that involves the complexation of TOP=Se by ZnCl2, followed by the nucleophilic addition of oleylamine onto the Lewis acid activated P-Se bond, thereby eliminating ZnSe monomers and forming amino-substitutions of TOP. Our work highlights the central role of oleylamine, acting as both the nucleophile and Brønsted base, in the transformation of metal halides and alkylphosphine chalcogenides into metal chalcogenides.

Bridging the Green Gap: Monochromatic InP-Based Quantum-Dot-on-Chip LEDs with over 50% Color Conversion Efficiency.

Solid-state light-emitting diodes (LEDs) emit nearly monochromatic light, yet seamless tuning of emission color throughout the visible region remains elusive. Color-converting powder phosphors are therefore used for making LEDs with a bespoke emission spectrum, yet broad emission lines and low absorption coefficients compromise the formation of small-footprint monochromatic LEDs. Color conversion by quantum dots (QDs) can address these issues, but high-performance monochromatic LEDs made using QDs free of restricted, hazardous elements remain to be demonstrated. Here, we show green, amber, and red LEDs formed using InP-based QDs as on-chip color convertor for blue LEDs. Implementing QDs with near-unity photoluminescence efficiency yields a color conversion efficiency over 50% with little intensity roll-off and nearly complete blue light rejection. Moreover, as the conversion efficiency is mostly limited by package losses, we conclude that on-chip color conversion using InP-based QDs can provide spectrum-on-demand LEDs, including monochromatic LEDs that bridge the green gap.

Intra- and Juxta-Articular Osteoid Osteoma Mimicking Arthritis: Case Series and Literature Review.

BACKGROUND: Intra- and juxta-articular osteoid osteomas are rare, representing less than 10% of all osteomas. Compared to the classic diaphyseal or metaphyseal site of long bones, they often have an atypical onset, a longest diagnostic delay, and frequent initial misdiagnoses, with pictures that can mimic inflammatory monoarthritis. We aimed to describe a case series, and to provide a literature review of this uncommon and misleading tumor location. METHODS: We performed a retrospective analysis of patients referred to three pediatric rheumatology centers, with a final diagnosis of articular osteoid osteoma. A review of the literature was additionally conducted. RESULTS: We included 10 patients with a mean age of 14 years. All patients with unusual sites (olecranon fossa, lumbar vertebra, distal phalanx of the toe, fibula) had a misdiagnosis, and cases with initial suspicion of monoarthritis had the longest diagnostic delay, up to 24 months. The literature review confirms the significant risk of misdiagnosis, and an average time from symptom onset to diagnosis ranging from 0.4 to 1.8 years. CONCLUSIONS: Articular osteoid osteoma may mimic arthritis, especially in adolescence. Knowledge of the atypical forms of presentation, and of the clinical and radiological pitfalls, reduces the risk of diagnostic error.

Laparoscopic transversus abdominis plane block is useful in pain relief after laparoscopic stapled repair of diastasis recti and ventral hernia.

Background: There is still no consensus on perioperative pain control techniques in patients undergoing laparoscopic surgery; protocols of conventional therapy can be improved by the use of perioperative anaesthesiologic techniques, such as epidural or loco-regional analgesic administration as transversus abdominis plane (TAP) block. The aim of this evaluation was to investigate the role of laparoscopic-assisted TAP block during repair of diastasis recti associated with primary midline hernias in term of post-operative pain relief. Methods: This was a retrospective evaluation of a prospectively maintained database including patients undergoing laparoscopic repair of diastasis recti associated with primary ventral hernia. Patients were divided into two groups: Group A patients (n = 34) received laparoscopic-assisted bilateral TAP-block of 7.5 mg/ml ropivacaine for each side and Group B patients (n = 29) received conventional post-operative therapy. All patients received 24 h infusion of 20 mg morphine; pain was checked at 6, 24 and 48 h after surgery by numeric rating scale (NRS) score. A rescue analgesia by was given if NRS score was >4 or on patient request. Results: No differences in operative time, complications and post-operative stay, no complications related to TAP-block technique were found. Post-operative pain scores (determined by NRS) were found to be significantly different between groups. Group A patients showed a significant reduction in NRS score at 6, 24 and 48 h (P < 0.005) and in the number of patients requiring further analgesic drugs administration (P < 0.005) compared to Group B patients. Conclusions: Laparoscopic-guided TAP-block can be considered safe and effective in the management of post-operative pain and in the reduction of analgesic need in patients undergoing laparoscopic repair of diastasis recti and ventral hernias. The non-randomised nature of the study and the lack of a consistent series of patients require further evaluations.

Predictive models in extracorporeal membrane oxygenation (ECMO): a systematic review.

PURPOSE: Extracorporeal membrane oxygenation (ECMO) has been increasingly used in the last years to provide hemodynamic and respiratory support in critically ill patients. In this scenario, prognostic scores remain essential to choose which patients should initiate ECMO. This systematic review aims to assess the current landscape and inform subsequent efforts in the development of risk prediction tools for ECMO. METHODS: PubMed, CINAHL, Embase, MEDLINE and Scopus were consulted. Articles between Jan 2011 and Feb 2022, including adults undergoing ECMO reporting a newly developed and validated predictive model for mortality, were included. Studies based on animal models, systematic reviews, case reports and conference abstracts were excluded. Data extraction aimed to capture study characteristics, risk model characteristics and model performance. The risk of bias was evaluated through the prediction model risk-of-bias assessment tool (PROBAST). The protocol has been registered in Open Science Framework ( https://osf.io/fevw5 ). RESULTS: Twenty-six prognostic scores for in-hospital mortality were identified, with a study size ranging from 60 to 4557 patients. The most common candidate variables were age, lactate concentration, creatinine concentration, bilirubin concentration and days in mechanical ventilation prior to ECMO. Five out of 16 venous-arterial (VA)-ECMO scores and 3 out of 9 veno-venous (VV)-ECMO scores had been validated externally. Additionally, one score was developed for both VA and VV populations. No score was judged at low risk of bias. CONCLUSION: Most models have not been validated externally and apply after ECMO initiation; thus, some uncertainty whether ECMO should be initiated still remains. It has yet to be determined whether and to what extent a new methodological perspective may enhance the performance of predictive models for ECMO, with the ultimate goal to implement a model that positively influences patient outcomes.

MRI-Derived Apparent Diffusion Coefficient of Peri-Prostatic Adipose Tissue Is a Potential Determinant of Prostate Cancer Aggressiveness in Preoperative Setting: A Preliminary Report.

Background: The aim of this study was to test the association between periprostatic adipose tissue (PPAT)­apparent diffusion coefficient (ADC) value recorded at multiparametric magnetic resonance imaging (mpMRI) and determinants of prostate cancer (PCa) aggressiveness in the preoperative setting. Methods: Data from 219 consecutive patients undergoing prostate biopsy (PBx) for suspicion of PCa, between January 2020 and June 2022, at our institution were retrospectively evaluated. Only patients who had mpMRI performed before PBx were included. The distribution of demographics and clinical features among PPAT-ADC values up to vs. above the median was studied using both parametric and non-parametric tests, according to variables. Linear and logistic regression models tested the association between PPAT-ADC values and determinants of PCa aggressiveness and the presence of intermediate-high risk PCa, respectively. Results: Of 132 included patients, 76 (58%) had PCa. Median PPAT-ADC was 876 (interquartile range: 654 − 1112) × 10−6 mm2/s. Patients with PPAT-ADC up to the median had a higher rate of PIRADS (Prostate Imaging­Reporting and Data System) 5 lesions (41% vs. 23%, p = 0.032), a higher percentage of PBx positive cores (25% vs. 6%, p = 0.049) and more frequently harbored ISUP (International Society of Urological Pathology) > 1 PCa (50% vs. 28%, p = 0.048). At univariable linear regression analyses, prostate-specific antigen (PSA), PSA density, PIRADS 5, and percentage of PBx positive cores were associated with lower PPAT-ADC values. PPAT-ADC up to the median was an independent predictor for intermediate-high risk PCa (odds ratio: 3.24, 95%CI: 1.17−9.46, p = 0.026) after adjustment for age and body mass index. Conclusions: Lower PPAT-ADC values may be associated with higher biopsy ISUP grade group PCa and a higher percentage of PBx-positive cores. Higher-level studies are needed to confirm these preliminary results.

Trends of Phase I Clinical Trials in the Latest Ten Years across Five European Countries.

BACKGROUND: Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies. METHODS: The main data and characteristics of phase 1 clinical studies registered on the ClinicalTrials.gov database for France, Germany, Italy, Spain and the United Kingdom have been investigated and subsequently compared. The above-mentioned countries were selected based on similarities in terms of demographic and Gross Domestic Product (GDP) data available on official government websites. (3) Results: A total number of 6878 phase 1 clinical trials were registered for the five selected countries in the ClinicalTrials.gov database during the ten years analyzed; the studies were predominantly randomized (39.33%) and for-profit (76.64%). The most represented area of investigations was oncology (52.15%), followed by hematology (24.99%) and immunology (12.04%). The variability observed between the analyzed countries showed that the UK, Germany and France presented the highest reduction in the number of phase 1 clinical trials, while for Spain and Italy, a stable/increased trend was observed, although with a lower number of trials registered on the ClinicalTrials.gov database. (4) Conclusions: Italy displayed the lowest number of registered phase 1 clinical trials, even though it showed a stable trend over the years. In this regard, the Italian regulatory framework must urgently be adapted to that of other European countries (Spain has been the first country to implement the new Regulation (EU) No 536/2014) and streamline the process of clinical trial application to increase the attractiveness of the country. Moreover, nonprofit phase 1 clinical trials (which represent 19.81% of the total number of phase 1 clinical trials registered in Italy vs. 80.19% of profit phase 1 clinical studies) should be promoted and supported by the institutions, even from a financial point of view, to allow independent researchers to develop new therapeutic drugs.

Mitochondrial oxygen sensing of acute hypoxia in specialized cells - Is there a unifying mechanism?

Acclimation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation and thus oxygen supply to the tissues. Acute oxygen sensing by these cells triggers hyperventilation and hypoxic pulmonary vasoconstriction which limits pulmonary blood flow through areas of low alveolar oxygen content. Oxygen sensing of acute hypoxia by specialized cells thus is a fundamental pre-requisite for aerobic life and maintains systemic oxygen supply. However, the primary oxygen sensing mechanism and the question of a common mechanism in different specialized oxygen sensing cells remains unresolved. Recent studies unraveled basic oxygen sensing mechanisms involving the mitochondrial cytochrome c oxidase subunit 4 isoform 2 that is essential for the hypoxia-induced release of mitochondrial reactive oxygen species and subsequent acute hypoxic responses in both, the carotid body and pulmonary vasculature. This review compares basic mitochondrial oxygen sensing mechanisms in the pulmonary vasculature and the carotid body.

Full-Spectrum InP-Based Quantum Dots with Near-Unity Photoluminescence Quantum Efficiency.

Photoluminescent color conversion by quantum dots (QDs) makes possible the formation of spectrum-on-demand light sources by combining blue LEDs with the light generated by a specific blend of QDs. Such applications, however, require a near-unity photoluminescence quantum efficiency since self-absorption magnifies disproportionally the impact of photon losses on the overall conversion efficiency. Here, we present a synthesis protocol for forming InP-based QDs with +90% quantum efficiency across the full visible spectrum from blue/cyan to red. The central features of our approach are as follows: (1) the formation of InP core QDs through one-batch-one-size reactions based on aminophosphine as the phosphorus precursor, (2) the introduction of a core/shell/shell InP/Zn(Se,S)/ZnS structure, and (3) the use of specific interfacial treatments, most notably the saturation of the ZnSe surface with zinc acetate prior to ZnS shell growth. Moreover, we adapted the composition of the Zn(Se,S) inner shell to attain the intended emission color while minimizing line broadening induced by the InP/ZnS lattice mismatch. The protocol is established by analysis of the QD composition and structure using multiple techniques, including solid-state nuclear magnetic resonance spectroscopy and Raman spectroscopy, and verified for reproducibility by having different researchers execute the same protocol. The realization of full-spectrum, +90% quantum efficiency will strongly facilitate research into light-matter interaction in general and luminescent color conversion in particular through InP-based QDs.

Differential diagnosis in Rosai-Dorfman disease: A rare case of isolated hepatic presentation mimicking a metastatic tumor with positive 18-FDG uptake.

Rosai-Dorfman disease (RDD) is also called sinus histiocytosis with massive lymphadenopathy, and it is caused by a histiocytic disorder with unclear etiology. It usually involves cervical lymph nodes, but it may also present with extranodal involvement. We report a rare condition of isolated hepatic RDD without nodal involvement, clinically manifested with three-month abdominal pain and tenderness of the right hypochondrium. CT- and PET-CT scans were compatible with a secondary lesion from an unknown primary tumor. Therefore, the patient underwent an atypical liver resection. Immunohistochemistry and histological results were compatible with a diagnosis of RDD. RDD is characterized by phenomena of emperipolesis, histiocytic proliferation and positive immunostaining for CD14, CD68 and S-100 protein. Cases of isolated gastrointestinal localization of RDD are particularly rare, especially in the liver. Instrumental exams might confuse RDD with other malignancies. RDD is a rare entity, which might be misdiagnosed using PET-CT due to its similarities with malignant tumors. An accurate multidisciplinary approach may help to clear diagnostic clues of this uncommon disease.

Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD.

Cigarette smoke (CS) is the most common risk factor for chronic obstructive pulmonary disease (COPD). The present study aimed to elucidate whether mtDNA is released upon CS exposure and is detected in the plasma of former smokers affected by COPD as a possible consequence of airway damage. We measured cell-free mtDNA (cf-mtDNA) and nuclear DNA (cf-nDNA) in COPD patient plasma and mouse serum with CS-induced emphysema. The plasma of patients with COPD and serum of mice with CS-induced emphysema showed increased cf-mtDNA levels. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased oxidative stress, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles (EVs). Mitochondrial DNA release into EVs occurred concomitantly with increased expression of markers that associate with DNA damage responses, including DNase III, DNA-sensing receptors (cGAS and NLRP3), proinflammatory cytokines (IL-1ß, IL-6, IL-8, IL-18, and CXCL2), and markers of senescence (p16 and p21); the majority of the responses are also triggered by cytosolic DNA delivery in vitro. Exposure to a lethal CSE dose preferentially induced mtDNA and nDNA release in the cell debris. Collectively, the results of this study associate markers of mitochondrial stress, inflammation, and senescence with mtDNA release induced by CSE exposure. Because high cf-mtDNA is detected in the plasma of COPD patients and serum of mice with emphysema, our findings support the future study of cf-mtDNA as a marker of mitochondrial stress in response to CS exposure and COPD pathology.

Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active.

Plants and other organisms, but not insects or vertebrates, express the auxiliary respiratory enzyme alternative oxidase (AOX) that bypasses mitochondrial respiratory complexes III and/or IV when impaired. Persistent expression of AOX from Ciona intestinalis in mammalian models has previously been shown to be effective in alleviating some metabolic stresses produced by respiratory chain inhibition while exacerbating others. This implies that chronic AOX expression may modify or disrupt metabolic signaling processes necessary to orchestrate adaptive remodeling, suggesting that its potential therapeutic use may be confined to acute pathologies, where a single course of treatment would suffice. One possible route for administering AOX transiently is AOX-encoding nucleic acid constructs. Here we demonstrate that AOX-encoding chemically-modified RNA (cmRNA), sequence-optimized for expression in mammalian cells, was able to support AOX expression in immortalized mouse embryonic fibroblasts (iMEFs), human lung carcinoma cells (A549) and primary mouse pulmonary arterial smooth muscle cells (PASMCs). AOX protein was detectable as early as 3 h after transfection, had a half-life of ~4 days and was catalytically active, thus supporting respiration and protecting against respiratory inhibition. Our data demonstrate that AOX-encoding cmRNA optimized for use in mammalian cells represents a viable route to investigate and possibly treat mitochondrial respiratory disorders.