Miracle-dz/UniFAR-FTUs huggingface dataset:
Idebenone as a novel therapeutic approach for Duchenne Muscular Dystrophy

Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8–18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD.
Behandlung und Nebenwirkungsmanagement des metastasierten Melanoms mit CTLA‐4‐Antikörpern

• CTLA-4-Antikörper • Nebenwirkungsmanagement • malignes Melanom • Immuntherapie • Autoimmunkolitis Zusammenfassung Immunmodulierende monoklonale Antikörper können die endogene Immunantwort gegen Tumoren induzieren und/oder verstärken. Die komplexe Interaktion zwischen Antigen-präsentierenden Zellen und T-Lymphozyten im Rahmen der Immunantwort kann durch Anti-CD152 (CTLA-4)-Antikörper maßgeblich moduliert werden. Der „Cytotoxic T-Lymphocyte Antigen-4“ (CTLA-4)Rezeptor bindet an Moleküle der B7-Familie. Dadurch wird die T-Zell-Aktivierung unterdrückt. Durch spezifische CTLA-4-Antikörper kann es dann zu einer ungehemmten T-Zell-Antwort kommen. Die Therapie mit den CTLA-4-Antikörpern Ipilimumab und Tremelimumab erfolgte in den vergangenen Jahren beim metastasierten Melanom nur im Rahmen klinischer Studien. Derzeit befindet sich die entscheidende Phase-IIIStudie zu Ipilimumab in der finalen Auswertung. Unzweifelhaft stellen die CTLA-4-Antikörper eine der hoffnungsvollsten Substanzen für die Therapie des fernmetastasierten Melanoms zum gegenwärtigen Zeitpunkt dar. Während einer CTLA-4-Antikörper-Therapie treten – aufgrund des Wirkmechanismus durchaus nicht unerwartet – Autoimmunphänomene und -erkrankungen auf, deren Management und ggf. auch Prophylaxe für die behandelnden Ärzte von großer Bedeutung sind. Die häufigste Nebenwirkung stellt unzweifelhaft die immunvermittelte Kolitis dar, bei der es je nach Schweregrad auch zu schweren und/oder auch lang anhaltenden Diarrhöen kommen kann. Daneben sind auch andere immunvermittelte Erkrankungen wie Hypophysitis, Hepatitis, Iridozyklitis und die Exazerbation einer Lupusnephritis in der Literatur beschrieben worden. Durch die frühzeitige Diagnose und Therapieeinleitung können Risiken und Folgeschäden für Patienten, die sich gegenwärtig in der Therapie befinden, reduziert werden. Interessanterweise werden autoimmunbedingte Nebenwirkungen zum Teil mit dem therapeutischen Ansprechen in Verbindung gebracht, so dass den autoimmunbedingten klinischen Symptomen vielleicht mehr als nur eine „Nebenwirkungsbedeutung“ zukommt. Diese Übersichtsarbeit gibt einen kurzen Überblick über die Wirkmechanismen und die bisherigen klinischen Ergebnisse der CTLA-4-Antikörper-Therapie beim metastasierten Melanom sowie über das Nebenwirkungsspektrum und -management. Behandlung und Nebenwirkungsmanagement des metastasierten Melanoms mit CTLA-4-Antikörpern
Discriminatory value of signs and symptoms in Cushing's syndrome revisited: what has changed in 30 years?

Flavia Magri*, Michelangelo Buonocore†, Antonella Camera*, Valentina Capelli*, Antonio Oliviero‡, Mario Rotondi*, Anna Gatti† and Luca Chiovato* *Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R. C.C. S. , University of Pavia, †Unit of Clinical Neurophysiology & Neurodiagnostic Skin Biopsy, Fondazione Salvatore Maugeri I.R. C.C. S. , Pavia, Italy, ‡FENNSI Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain E-mail: luca.chiovato@fsm.it
Distinct antiviral signatures revealed by the magnitude and round of influenza virus replication in vivo

Significance Influenza A virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. Here, we used single-cycle replication reporter viruses to analyze the early cellular response to influenza infection in vivo. This approach revealed distinct tiers of antiviral responses that were associated with the magnitude of virus replication. We also unveiled disparate protection of epithelial cell types mediated by interferon during virus spread. These results demonstrate the early landscape of virus–host interactions in vivo with the magnitude and round of replication revealing distinct antiviral signatures and responses. Influenza virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used a series of single-cycle reporter viruses. These viral probes demonstrated cells in vivo harbor a range in magnitude of virus replication. Transcriptional profiling of cells supporting different levels of replication revealed tiers of IFN-stimulated gene expression. Uninfected cells and cells with blunted replication expressed a distinct and potentially protective antiviral signature, while cells with high replication expressed a unique reserve set of antiviral genes. Finally, we used these single-cycle reporter viruses to determine the antiviral landscape during virus spread, which unveiled disparate protection of epithelial cell subsets mediated by IFN in vivo. Together these results highlight the complexity of virus–host interactions within the infected lung and suggest that magnitude and round of replication tune the antiviral response.
Ceramic Robocasting: Recent Achievements, Potential, and Future Developments

Additive manufacturing (AM) of ceramic materials has attracted tremendous attention in recent years, due to its potential to fabricate suitable advanced ceramic structures for various engineering applications. Robocasting, a subset of ceramic AM, is an ideal technique for constructing fine and dense ceramic structures with geometrically complex morphology. With the freedom and convenience to deposit various materials within any 3D spatial position, ceramic robocasting opens up unlimited opportunities, which are otherwise hardly attainable from other AM techniques. Here, a summary of the recent progress on the fabrication of single and multi‐ceramic structures by robocasting is provided, as well as the prospects of achieving shapeable ceramic structures. The current challenges in ceramic robocasting and an outlook on its development, especially toward the fabrication of self‐shaping ceramic structures, are also discussed.
Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

Significance Planar cell polarity (PCP) signaling coordinates cell polarization along an axis orthogonal to its apical–basal axis and is essential for both tissue development and function. In inner ear sensory epithelia, intercellular and cell-intrinsic PCP signaling controls the orientation and V shape of hair bundles atop sensory hair cells essential for hearing. Here we demonstrate that the conserved PDZ-domain scaffold protein Par3 plays an essential role in establishing PCP of sensory hair cells. Genetic mosaic analysis indicates that Par3 has both cell-autonomous and cell-nonautonomous functions in kinocilium positioning and hair bundle orientation. Mechanistically, Par3 interacts with and regulates localization of Rac guanine nucleotide exchange factors Tiam1 and Trio to activate Rac GTPases, thereby mediating both intercellular and cell-intrinsic PCP signaling. In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3–GEF–Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.
On the assessment of lower-limb muscular power capability

Purpose: This study assessed the reliability and validity of different methods used to estimate lower-limb muscular power capability based on mechanical variables. For this purpose, vertical jumping was compared with isokinetic knee extensions and with power tests used by practitioners. Methods: Four groups of subjects (N = 106) were tested in different conditions. Group-1 performed countermovement vertical jumps (CMJ) on a force plate followed by left and right knee extensions on an isokinetic device at 120, 180 and 240 deg.s -1 . Group-II performed CMJ trials followed by 20-m sprints, hand-reach jumps and 1RM leg-press testing. Group-III carried out squat jumps (SJ) in addition to CMJ trials. Finally, Group-IV performed the CMJ test and was retested twice after a short inter-session interval (1-4 days) and after a long one (4.5-5 months). The Pearson correlation was used to assess the validity and reliability of CMJ (p ≤ 0.01, **). Results: Mean peak power during CMJ was correlated with sprint time (r = -0.882**) and leg-press 1 RM (r = 0.797**), but less with peak hand-reach height (r = 0.695; p < 0.05). Isokinetic knee extension power showed also a significant correlation with CMJ power, but its strength depended on the angular velocity (Isok-120 r = 0.702**; Isok-180 r = 0.737**; Isok-240 r = 0.599**). Test-retests showed a strong correlation after a short interval (r = 0.915**) and after a long one (r = 0.890**). Using the SJ technique did not have any effect on reliability (r = 0.914**). Conclusions: CMJ matches other methods used for testing lower-limb power capability. It is highly reliable and it allows a valid assessment of muscular power. Since CMJ is also simple and accurate to perform, it is the recommended method.
A Case of Perianal Abscess Due to Prostatic Abscess

Abscess, is a condition that often occurs in the anorectal region. Anorectal abscesses are more frequently seen in men than women (2:1 or 3:1) and often seen in 3th -5th decades. Prostatic abscess, which is a rare condition today, has been thought th at originated from prostatitis. A 50 year old male patient, was admitted to our urology clinic with the complaints of urinary frequency a nd dysuria for last two months. There is no prominent feature other than diabe tes in the patient's history and asymmetric growth found on the left lobe in rectal examination of the prostate. The patients presenting with clinically anorectal abscess should be assessed properly with history, physical examination, laboratory, and imagi ng findings and also rarely underlying causes of inflammation of adjacent organs such as the prostate abscess should be kept in mind.
A case of invasive carcinoma derived from intraductal papillary‐mucinous carcinoma of the pancreas producing a signet ring‐type appearance on pancreatic duct brushing cytology

Intraductal papillary-mucinous neoplasm (IPMN) is considered to be a tumour that is localized in pancreatic ducts, and grows in a papillary fashion, producing mucin. IPMNs include IPMN with invasive carcinoma, the so-called invasive carcinoma derived from intraductal papillary-mucinous carcinoma (IPMC) of the pancreas . In this paper, we report a patient who was diagnosed pathologically with invasive carcinoma derived from IPMC of the pancreas.
Reversing established sepsis with antagonists of endogenous high-mobility group box 1

Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1β] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1β. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 μg per mouse) or the DNA-binding A box (600 μg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.
Uspješnost liječenja kroničnog hepatitisa C kombinacijom pegiliranog interferona alfa-2 i ribavirina u bolesnika s niskom viremijom i genotipom 1

Trajni virusolo{ki odgovor nakon 48 tjedana lije~enja kombinacijom pegiliranog interferona alfa-2 i ribavirina u bolesnika s kroni~nim hepatitisom C inficiranih genotipom 1 posti`e se u oko 55 % bolesnika. Prethodne studije pokazale su da je kra}a, 24-tjedna terapija u bolesnika s niskom po~etnom viremijom (<600 000 IU/mL) jednako u~inkovita, ali uz pra}enje rane virusne kinetike. Na{a studija pokazuje da su bolesnici s niskom po~etnom viremijom veoma heterogena skupina bolesnika kod kojih trajni virusolo{ki odgovor na lije~enje nije bolji u odnosu na bolesnike s visokom viremijom (niska viremija SVR 53,2 % (n = 94), visoka viremija SVR 50,8 % (n = 122)). Bolesnici s niskom po~etnom viremijom u kojih nije postignut trajni virusolo{ki odgovor imali su statisti~ki zna~ajno vi{i stupanj fibroze (stadij fibroze po Ishaku 3,47 u non-SVR grupi prema 2,94 u SVR+ grupi, p = 0,004) i bili su zna~ajno starije ̀ ivotne dobi (46,4 godina u non-SVR grupi prema 39,6 godina u SVR+ grupi, p = 0,008). Od bolesnika s niskom po~etnom viremijom i cirozom jetre (n = 6) nitko nije postigao trajni virusolo{ki odgovor, dok su oni sa stadijem fibroze 4/6 po Ishaku u 48 % slu~ajeva bili non-responderi, tako da se stadij fibroze 4 nije pokazao kao zna~ajan prediktivni faktor. Na{i rezultati govore da su osim visine viremije na po~etku lije~enja, zna~ajni prediktivni faktori za uspjeh lije~enja i stadij fibroze, naro~ito prisustvo ciroze, te starija ̀ ivotna dob.
Preferential Inactivation of Tissue Inhibitor of Metalloproteinases-1 That Is Bound to the Precursor of Matrix Metalloproteinase 9 (Progelatinase B) by Human Neutrophil Elastase (*)

The precursor of matrix metalloproteinase 9 (pro-MMP-9) forms a complex with the tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule, and the N-terminal domain of TIMP-1 in the complex interacts and inhibits active MMPs. We have reported that a catalytic amount of MMP-3 (stromelysin 1) activates pro-MMP-9 (Ogata, Y., Enghild, J. J., and Nagase, H.(1992) J. Biol. Chem. 267, 3581-3584). To activate pro-MMP-9 in the complex, however, an excess molar amount of MMP-3 is required to saturate the TIMP-1 in the complex. The aim of this study was to test the hypothesis that the requirement for excess MMP-3 can be circumvented by specific destruction of TIMP-1 by non-target proteinases. We have tested trypsin, plasmin, cathepsin G, neutrophil elastase, and chymotrypsin as possible inactivators of TIMP-1 and found that neutrophil elastase inactivates TIMP-1 in the complex without significant destruction of pro-MMP-9. Once TIMP-1 is inactivated, pro-MMP-9 can be readily activated by a catalytic amount of MMP-3. These results suggest that neutrophil elastase may participate in connective tissue destruction at the inflammatory sites not only by its direct action on matrix macromolecules but also by rendering pro-MMP-9 in the pro-MMP-9TIMP-1 complex activable by MMP-3 as well as activating pro-MMP-3.
The Glycosaminoglycan Binding Site Governs Ligand Binding to the Somatomedin B Domain of Vitronectin*

The ligand binding functions of vitronectin (Vn) are regulated by its conformational state/degree of multimerization. In the native plasma form of Vn, the C-terminal glycosaminoglycan (GAG) binding domain is believed to be cryptic. Here, evidence is provided that the addition of fucoidan or dextran sulfate to unfractionated plasma results in the formation of covalently and non-covalently stabilized Vn multimers. These multimers express conformationally sensitive antibody epitopes and ligand binding sites located in the N terminus of the Vn molecule. While heparin forms complexes with monomeric plasma Vn and induces conformational changes, a reduction in ionic strength is required for induction of multimerization. In addition, heparin serves as a template for the assembly of type 1 plasminogen activator inhibitor-induced disulfide-linked Vn multimers. These results support a new model for the structure of native Vn. The C-terminal GAG binding domain is predicted to be exposed in the native conformation, whereas the N terminus is cryptic. Ligand binding to the GAG binding site unfolds the N terminus, thereby exposing cryptic ligand binding sites.
Steatohepatitis, Spontaneous Peroxisome Proliferation and Liver Tumors in Mice Lacking Peroxisomal Fatty Acyl-CoA Oxidase

Peroxisomal β-oxidation system consists of four consecutive reactions to preferentially metabolize very long chain fatty acids. The first step of this system, catalyzed by acyl-CoA oxidase (AOX), converts fatty acyl-CoA to 2-trans-enoyl-CoA. Herein, we show that mice deficient in AOX exhibit steatohepatitis, increased hepatic H2O2 levels, and hepatocellular regeneration, leading to a complete reversal of fatty change by 6 to 8 months of age. The liver of AOX−/− mice with regenerated hepatocytes displays profound generalized spontaneous peroxisome proliferation and increased mRNA levels of genes that are regulated by peroxisome proliferator-activated receptor α (PPARα). Hepatic adenomas and carcinomas develop in AOX−/− mice by 15 months of age due to sustained activation of PPARα. These observations implicate acyl-CoA and other putative substrates for AOX, as biological ligands for PPARα; thus, a normal AOX gene is indispensable for the physiological regulation of PPARα.
The Clinical Anatomy of the Cranial Nerves: The Nerves of "On Old Olympus Towering Top"

The cranial nerves are an endlessly fascinating family of twelve nerves that have a dramatic impact on our daily lives. A dysfunction of the cranial nerves can cause loss of vision or double vision, loss of smell, poor balance, or loss of muscle function, and can also be an indicator of underlying neurological disorders. The Clinical Anatomy of the Cranial Nerves: The Nerves of "On Old Olympus Towering Top is an engaging and accessible book on the anatomy and clinical importance of these unique nerves. Thetext opens with a brief introduction of key neuroanatomical concepts that relate the clinical and anatomical sections that follow. Additionally, this book uniquely provides a detailed description of the bones of the head and face in order for the reader to understand the routes taken by the cranial nerves through the skull. Chapters then detail each nerve and its unique impact in relationship to our senses, motor function, and health. Vividly illustrated and supported by real-life clinical cases, the book will appeal to anyone wishing to gain a better understanding of the cranial nerves. Merging anatomical and clinical information with intriguing clinical cases, The Clinical Anatomy of the Cranial Nerves: The Nerves of "On Old Olympus Towering Top introduces readers to the anatomy and diverse function of this intriguing family of nerves.
Homodimer of Two F-box Proteins βTrCP1 or βTrCP2 Binds to IκBα for Signal-dependent Ubiquitination*

We found previously that overexpression of an F-box protein βTrCP1 and the structurally related βTrCP2 augments ubiquitination of phosphorylated IκBα (pIκBα) induced by tumor necrosis factor-α (TNF-α), but the relationship of the two homologous βTrCP proteins remains unknown. Herein we reveal that deletion mutants of βTrCP1 and βTrCP2 lacking the F-box domain suppressed ubiquitination and destruction of pIκBα as well as transcriptional activation of NF-κB. The ectopically expressed βTrCP1 and βTrCP2 formed both homodimer and heterodimer complexes without displaying the trimer complex. Dimerization of βTrCP1 and/or βTrCP2 takes place at their conserved NH2-terminal regions, termed a “D-domain” (for dimerization domain), located upstream of the F-box domain. The D-domain was necessary and sufficient for the dimer formation. Intriguingly, the βTrCP homodimer, but not the heterodimer, was selectively recruited to pIκBα induced by TNF-α. These results indicate that not only βTrCP1 but also βTrCP2 participates in the ubiquitination-dependent destruction of IκBα by forming SCFβTrCP1-βTrCP1 and SCFβTrCP2-βTrCP2 ubiquitin-ligase complexes.