Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases

<p>Abstract</p> <p>Background</p> <p>Alveolar sarcoma of the soft parts (ASPS) represents a very rare entity of soft tissue sarcoma with special features such as young peak age incidence and frequent metastasis to the brain. The aim of this study was a clinicopathological analysis with special reference to treatment and outcome.</p> <p>Methods</p> <p>From the database of the BG-University Hospital Bergmannsheil, 1597 soft tissue sarcoma (STS) cases were reviewed and 11 consecutive patients with ASPS were isolated. Data was acquired from patients' charts and contact to patients, their relatives or general practitioners, with special reference to treatment and clinical course. The average follow up time from the time of the definite operation for the primary tumor was 6.5 years. Kaplan-Meier method was used to calculate survival.</p> <p>Results</p> <p>Patients with localized disease who received complete resection and adjuvant radiation and who did not develop recurrence or metastatic disease within 2 years after surgery had a positive outcome. The size of the tumor, its localization, and the time of untreated growth before treatment did not influence the long-term results. All patients who developed recurrent disease also suffered from distant metastasis, reflecting the aggressive biology of the tumor. All patients with distant metastasis had the lungs and the brain affected.</p> <p>Conclusion</p> <p>Due to the limited number of patients with ASPS, prospective studies would have to span decades to gather a significant collective of patients; therefore, it is not possible to comment meaningfully on a possible benefit of neoadjuvant or adjuvant therapy.</p> <p>We recommend wide surgical excision and, in the absence of data telling otherwise, adjuvant radiation. In cases with recurrent disease or metastasis, the prognosis is bad and further treatment will be restricted to palliation in most cases.</p

New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe

Background: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms

Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency: Medical and Immunological Implications

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Development of nanowire-based-devices for neuronal interfacing

De par le vieillissement de la population mondiale, les maladies neurodégénératives touchent de plus en plus de personnes. Ces maladies, trouvant leur siège dans la plupart des cas au sein des neurones, restent mal comprises. Dans le but d'améliorer notre connaissance des dysfonctionnements causés lors de ce type d'agression, il est indispensable de raffiner notre analyse (neurones individuels). Les dispositifs à base de nanofils (nanosondes verticales ou transistors à NF) offrent une valeur ajoutée certaine concernant l'interfaçage de dispositifs nanoélectroniques avec les cellules vivantes. En effet, leurs sections sont beaucoup plus petites que les dimensions des cellules, les rendant peu intrusifs et leur grand rapport surface/volume permet une forte interaction NF-cellule. Dans ces travaux de thèse, nous proposons de co-intégrer ces deux types de capteurs passifs et actifs sur une même plateforme à l'aide d'un procédé basé sur une approche top-down, couplant des étapes de photolithographie conventionnelle et de gravure plasma. Afin de tirer parti de la dimension de ces capteurs, particulièrement adaptée à l'interfaçage de cellules individuelles, une approche innovante de fabrication de réseaux organisés de neurones par fonctionnalisation chimique de surface sera présentée. Basée sur l'auto-alignement de molécules d'adhésion grâce à un fort contraste hydrophile/hydrophobe de la surface de l'échantillon, elle permet de contrôler très précisément la localisation spatiale des somas et de guider la croissance des prolongements. De larges réseaux organisés de neurones ont ainsi pu être réalisés, avec un taux élevé de somas individuels (74% des sites occupés). La croissance des prolongements est également maîtrisée à l'échelle sub-micronique. Couplée aux dispositifs d'enregistrement présentés précédemment (nano-sondes passives et transistors à NF), cette maîtrise de la croissance des neurones ouvre de nombreuses perspectives pour le suivi multi-site de l'activité électrique au sein d'une culture neuronale. La chaîne d'acquisition nécessaire au transport de l'information enregistrée depuis le capteur (échelle nanométrique) jusqu'à la visualisation des signaux sera ensuite présentée. Des cultures de neurones ont été réalisées sur cette plateforme et une activité électrique spontanée (PAs et LFPs) a pu être enregistrée après 9DIV par les nanosondes passives. Ces résultats restent à ce jour, inédits avec de tels dispositifs passifs à nanofils sur des neurones de rongeurs. Plusieurs stimulations chimiques (dépolarisation KCl et potentialisation bicuculline) ont également été effectuées, permettant de valider le fonctionnement des transistors et de comparer les deux approches (passive et active). Le caractère multi-sites des enregistrements à l'aide des nanosondes a aussi été mis en évidence. Enfin, des stimulations électriques localisées à l'aide des nanosondes verticales ont été réalisées et des LFPs provenant de l'excitation des neurones voisins du capteur ont pu être enregistrés, démontrant ainsi la bidirectionnalité de l'interaction.Due to constant aging of world population, the struggle against neurodegenerative diseases is one of the major challenges in the near future and a better understanding of these pathologies goes through an improvement of basic mechanism knowledge involved in neuronal networks. In that scope, miniaturization of electronic components opens new perspectives for addressing such issues and holds great promise to improve the resolution levels. 1D-nanostructures such as NW-FET or NW-probes, offer real benefits thanks to their very small sections allowing to be less intrusive combined with their high surface-to-volume ratio leading to a higher affinity with cells. Here, we propose to co-integrate passive and active devices based on 1D nanostructures on the same platform (vertical NW probes and NW-FETs), to accurately compare advantages and drawbacks of each configuration regarding neuron electrical activity measurement. The two NW devices are fabricated with a large scale and cost effective top-down approach combining conventional lithography tools, plasma etching and sacrificial oxidation step to tune the nanostructure geometry. A core-shell-type device has been developed with a conductive part at the center, encapsulated by a conformal silicon oxide to insulate the probing nanostructures from liquid. In parallel, silicon NW-FETs are created with a planar NW channel (50 nm) connected by two highly doped low resistive regions. The device operation has been characterized in liquid environment (interface impedance of passive probes and pH sensing for transistors). Primary rat cortical neuronal cultures have been grown in-vitro with an unprecedented surface functionalization approach to precisely locate single neurons and guide the growth of their extensions. The approach allows the perfect location of somas on devices and the control of neurite growth at sub-micrometer scale. After 10 days-in-vitro, we detected for the first time spontaneous mammalian neuron action potentials using passive vertical NW-probes. Thereafter, several kinds of stimulation protocols have been implemented: (i) at the network level, with chemical stimulations such as KCl depolarization to mimic epileptic synchronization or with more refined stimulation (bicuculline). Local field potentials from few somas and action potentials from single neurons have been successfully recorded with a maximal signal-to-noise ratio of 10 for transistors compared to 40 for passive probes. (ii) At the cell level, where bi-directionality of passive probes have been used to locally trigger neuronal activity under electrical stimulation. Finally, multi-site recordings with vertical probes have been used to compare extra and intracellular probing

Développement de nanosystèmes à base de nanofils pour l'interfaçage neuronal

De par le vieillissement de la population mondiale, les maladies neurodégénératives touchent de plus en plus de personnes. Ces maladies, trouvant leur siège dans la plupart des cas au sein des neurones, restent mal comprises. Dans le but d'améliorer notre connaissance des dysfonctionnements causés lors de ce type d'agression, il est indispensable de raffiner notre analyse (neurones individuels). Les dispositifs à base de nanofils (nanosondes verticales ou transistors à NF) offrent une valeur ajoutée certaine concernant l'interfaçage de dispositifs nanoélectroniques avec les cellules vivantes. En effet, leurs sections sont beaucoup plus petites que les dimensions des cellules, les rendant peu intrusifs et leur grand rapport surface/volume permet une forte interaction NF-cellule. Dans ces travaux de thèse, nous proposons de co-intégrer ces deux types de capteurs passifs et actifs sur une même plateforme à l'aide d'un procédé basé sur une approche top-down, couplant des étapes de photolithographie conventionnelle et de gravure plasma. Afin de tirer parti de la dimension de ces capteurs, particulièrement adaptée à l'interfaçage de cellules individuelles, une approche innovante de fabrication de réseaux organisés de neurones par fonctionnalisation chimique de surface sera présentée. Basée sur l'auto-alignement de molécules d'adhésion grâce à un fort contraste hydrophile/hydrophobe de la surface de l'échantillon, elle permet de contrôler très précisément la localisation spatiale des somas et de guider la croissance des prolongements. De larges réseaux organisés de neurones ont ainsi pu être réalisés, avec un taux élevé de somas individuels (74% des sites occupés). La croissance des prolongements est également maîtrisée à l'échelle sub-micronique. Couplée aux dispositifs d'enregistrement présentés précédemment (nano-sondes passives et transistors à NF), cette maîtrise de la croissance des neurones ouvre de nombreuses perspectives pour le suivi multi-site de l'activité électrique au sein d'une culture neuronale. La chaîne d'acquisition nécessaire au transport de l'information enregistrée depuis le capteur (échelle nanométrique) jusqu'à la visualisation des signaux sera ensuite présentée. Des cultures de neurones ont été réalisées sur cette plateforme et une activité électrique spontanée (PAs et LFPs) a pu être enregistrée après 9DIV par les nanosondes passives. Ces résultats restent à ce jour, inédits avec de tels dispositifs passifs à nanofils sur des neurones de rongeurs. Plusieurs stimulations chimiques (dépolarisation KCl et potentialisation bicuculline) ont également été effectuées, permettant de valider le fonctionnement des transistors et de comparer les deux approches (passive et active). Le caractère multi-sites des enregistrements à l'aide des nanosondes a aussi été mis en évidence. Enfin, des stimulations électriques localisées à l'aide des nanosondes verticales ont été réalisées et des LFPs provenant de l'excitation des neurones voisins du capteur ont pu être enregistrés, démontrant ainsi la bidirectionnalité de l'interaction.Due to constant aging of world population, the struggle against neurodegenerative diseases is one of the major challenges in the near future and a better understanding of these pathologies goes through an improvement of basic mechanism knowledge involved in neuronal networks. In that scope, miniaturization of electronic components opens new perspectives for addressing such issues and holds great promise to improve the resolution levels. 1D-nanostructures such as NW-FET or NW-probes, offer real benefits thanks to their very small sections allowing to be less intrusive combined with their high surface-to-volume ratio leading to a higher affinity with cells. Here, we propose to co-integrate passive and active devices based on 1D nanostructures on the same platform (vertical NW probes and NW-FETs), to accurately compare advantages and drawbacks of each configuration regarding neuron electrical activity measurement. The two NW devices are fabricated with a large scale and cost effective top-down approach combining conventional lithography tools, plasma etching and sacrificial oxidation step to tune the nanostructure geometry. A core-shell-type device has been developed with a conductive part at the center, encapsulated by a conformal silicon oxide to insulate the probing nanostructures from liquid. In parallel, silicon NW-FETs are created with a planar NW channel (50 nm) connected by two highly doped low resistive regions. The device operation has been characterized in liquid environment (interface impedance of passive probes and pH sensing for transistors). Primary rat cortical neuronal cultures have been grown in-vitro with an unprecedented surface functionalization approach to precisely locate single neurons and guide the growth of their extensions. The approach allows the perfect location of somas on devices and the control of neurite growth at sub-micrometer scale. After 10 days-in-vitro, we detected for the first time spontaneous mammalian neuron action potentials using passive vertical NW-probes. Thereafter, several kinds of stimulation protocols have been implemented: (i) at the network level, with chemical stimulations such as KCl depolarization to mimic epileptic synchronization or with more refined stimulation (bicuculline). Local field potentials from few somas and action potentials from single neurons have been successfully recorded with a maximal signal-to-noise ratio of 10 for transistors compared to 40 for passive probes. (ii) At the cell level, where bi-directionality of passive probes have been used to locally trigger neuronal activity under electrical stimulation. Finally, multi-site recordings with vertical probes have been used to compare extra and intracellular probing

Improvement of electronic lithography process using proximity effect correction

National audienc

Laser-induced cell printing: a versatile tool for applications in biology

International audienc