Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild-type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin-3-gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided

Ferroelectricity and resistive switching in BaTiO3_3 thin films with liquid electrolyte top contact for bioelectronic devices

We investigate ferroelectric- and resistive switching behavior in 18-nm-thick epitaxial BaTiO$_3$ (BTO) films in a model electrolyte-ferroelectric-semiconductor (EFS) configuration. The system is explored for its potential as a ferroelectric microelectrode in bioelectronics. The BTO films are grown by pulsed laser deposition (PLD) on semiconducting Nb-doped (0.5 wt\%) SrTiO$_{3}$ (Nb:STO) single crystal substrates. The ferroelectric properties of the bare BTO films are demonstrated by piezoresponse force microscopy (PFM) measurements. Cyclic voltammetry (CV) measurements in EFS configuration, with phosphate buffered saline (PBS) acting as the liquid electrolyte top contact, indicate characteristic ferroelectric switching peaks in the bipolar current-voltage loop. The ferroelectric nature of the observed switching peaks is confirmed by analyzing the current response of the EFS devices to unipolar voltage signals. Moreover, electrochemical impedance spectroscopy (EIS) measurements indicate bipolar resisitive switching behavior of the EFS devices, which is controlled by the remanent polarization state of the BTO layer. Our results represent a constitutive step towards the realization of neuroprosthetic implants and hybrid neurocomputational systems based on ferroelectric microelectrodes

Expression of 3q oncogene SEC62 in atypical fibroxanthoma-immunohistochemical analysis of 41 cases and correlation with clinical, viral and histopathologic features

Atypical fibroxanthoma (AFX) is a rare mesenchymal tumor with predominance in older male patients located mainly in chronically UV-exposed skin. Differentiation from clinically more aggressive pleomorphic dermal sarcoma (PDS) is still under debate and immunohistochemical markers are not available yet. An immunohistochemical study, including 41 cases of AFX was conducted to investigate the expression of 3q encoded oncogene SEC62 in AFX and determine the associations with histomorphologic, clinical and viral parameters. Our cohort displayed a mean of 79.9 years at the onset of the disease. In total, 90.2% (37/41) AFXs were located in the head and neck area, whereas, four were located at the extremities (9.7%). Tumor diameter ranged between 0.06 and 40 cm2 with a mean of 5.7 cm2. SEC62 expression was markedly increased in lesional tissue compared with the adjacent healthy squamous epithelium. We found significantly higher expression of SEC62 in cases of AFX with tumor necrosis. Tendency of higher Sec62-IRS-scores were found for tumors with higher Clark levels and a tumor size >5 cm2. Sec62 is involved in endoplasmic reticulum stress tolerance and cell migration, and has been identified as a novel prognostic marker for non-small cell lung cancer as well as head and neck squamous cell carcinoma. For the first time, to the best of our knowledge, we suggest a role of 3q oncogene SEC62 in AFX and discuss a potential prognostic relevance in cases of disputable AFX with unfavorable histomorphologic features and may initiate a discussion on Sec62 serving as discriminating marker between AFX and PDS

Expression of SEC62 Oncogene in Benign, Malignant and Borderline Melanocytic Tumors—Unmasking the Wolf in Sheep’s Clothing?

SEC62 oncogene located at chromosomal region 3q26 encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is expressed at high levels in numerous human malignancies. SEC62 overexpression has been associated with worse prognosis and high risk for lymphatic and distant metastases in head and neck cancer, cervical cancer, hepatocellular cancer, and lung cancer. However, its role in the development and tumor biology of melanocytic lesions has not been investigated so far. An immunohistochemical study including 209 patients with melanocytic lesions (malignant melanoma (MM), n = 93; melanoma metastases (MET), n = 28; Spitz nevi (SN), n = 29; blue nevi (BN), n = 21; congenital nevi (CN), n = 38) was conducted and SEC62 expression was correlated with clinical data including patient survival and histopathological characteristics. SN showed the highest SEC62 expression levels followed by MET, MM, CN, and BN. High SEC62 expression correlated with a shorter overall and progression-free survival in MM patients. Additionally, high Sec62 levels correlated significantly with higher tumor size (T stage), the presence of tumor ulceration, and the presence of lymph node as well as distant metastases. Strikingly, SEC62 expression showed a strong correlation with Clark level. Taken together, these data demonstrate that SEC62 is a promising prognostic marker in MM and has the potential to predict biological behavior and clinical aggressiveness of melanocytic lesions

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events

Pressure and Flow Properties of Cannulae for Extracorporeal Membrane Oxygenation I: Return (Arterial) Cannulae

Adequate extracorporeal membrane oxygenation support in the adult requires cannulae permitting blood flows up to 6-8 L/minute. In accordance with Poiseuille's law, flow is proportional to the fourth power of cannula inner diameter and inversely proportional to its length. Poiseuille's law can be applied to obtain the pressure drop of an incompressible, Newtonian fluid (such as water) flowing in a cylindrical tube. However, as blood is a pseudoplastic non-Newtonian fluid, the validity of Poiseuille's law is questionable for prediction of cannula properties in clinical practice. Pressure-flow charts with non-Newtonian fluids, such as blood, are typically not provided by the manufacturers. A standardized laboratory test of return (arterial) cannulae for extracorporeal membrane oxygenation was performed. The aim was to determine pressure-flow data with human whole blood in addition to manufacturers' water tests to facilitate an appropriate choice of cannula for the desired flow range. In total, 14 cannulae from three manufacturers were tested. Data concerning design, characteristics, and performance were graphically presented for each tested cannula. Measured blood flows were in most cases 3-21% lower than those provided by manufacturers. This was most pronounced in the narrow cannulae (15-17 Fr) where the reduction ranged from 27% to 40% at low flows and 5-15% in the upper flow range. These differences were less apparent with increasing cannula diameter. There was a marked disparity between manufacturers. Based on the measured results, testing of cannulae including whole blood flows in a standardized bench test would be recommended.info:eu-repo/semantics/publishedVersio

Fast and Not-so-Furious: Case Study of the Fast and Faint Type IIb SN 2021bxu

We present photometric and spectroscopic observations and analysis of SN~2021bxu (ATLAS21dov), a low-luminosity, fast-evolving Type IIb supernova (SN). SN~2021bxu is unique, showing a large initial decline in brightness followed by a short plateau phase. With $M_r = -15.93 \pm 0.16\, \mathrm{mag}$ during the plateau, it is at the lower end of the luminosity distribution of stripped-envelope supernovae (SE-SNe) and shows a distinct $\sim$10 day plateau not caused by H- or He-recombination. SN~2021bxu shows line velocities which are at least $\sim1500\,\mathrm{km\,s^{-1}}$ slower than typical SE-SNe. It is photometrically and spectroscopically similar to Type IIb SNe during the photospheric phases of evolution, with similarities to Ca-rich IIb SNe. We find that the bolometric light curve is best described by a composite model of shock interaction between the ejecta and an envelope of extended material, combined with a typical SN~IIb powered by the radioactive decay of $^{56}$Ni. The best-fit parameters for SN~2021bxu include a $^{56}$Ni mass of $M_{\mathrm{Ni}} = 0.029^{+0.004}_{-0.005}\,\mathrm{M_{\odot}}$, an ejecta mass of $M_{\mathrm{ej}} = 0.57^{+0.04}_{-0.03}\,\mathrm{M_{\odot}}$, and an ejecta kinetic energy of $K_{\mathrm{ej}} = 9.3^{+0.7}_{-0.6} \times 10^{49}\, \mathrm{erg}$. From the fits to the properties of the extended material of Ca-rich IIb SNe we find a trend of decreasing envelope radius with increasing envelope mass. SN~2021bxu has $M_{\mathrm{Ni}}$ on the low end compared to SE-SNe and Ca-rich SNe in the literature, demonstrating that SN~2021bxu-like events are rare explosions in extreme areas of parameter space. The progenitor of SN~2021bxu is likely a low mass He star with an extended envelope.Comment: 18 pages, 15 figures, submitted to MNRA

Cardiac Alpha-Myosin (MYH6) Is the Predominant Sarcomeric Disease Gene for Familial Atrial Septal Defects

Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, and TTN kinase region) in 31 patients with familial ASDII using array-based resequencing. Genotyping of family relatives and control subjects as well as structural and homology analyses were used to evaluate the pathogenic impact of novel non-synonymous gene variants. Three novel missense mutations were found in the MYH6 gene encoding alpha-myosin heavy chain (R17H, C539R, and K543R). These mutations co-segregated with CHD in the families and were absent in 370 control alleles. Interestingly, all three MYH6 mutations are located in a highly conserved region of the alpha-myosin motor domain, which is involved in myosin-actin interaction. In addition, the cardiomyopathy related MYH6-A1004S and the MYBPC3-A833T mutations were also found in one and two unrelated subjects with ASDII, respectively. No mutations were found in the 11 other sarcomeric genes analyzed. The study indicates that sarcomeric gene mutations may represent a so far underestimated genetic source for familial recurrence of ASDII. In particular, perturbations in the MYH6 head domain seem to play a major role in the genetic origin of familial ASDII

DNA methylation-based classification of sinonasal tumors

The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent potentially previously misclassified adenoid cystic carcinomas. Our findings can aid in improving the diagnostic classification of sinonasal tumors and could help to change the current perception of SNUCs