Novel Hypertrophic Cardiomyopathy Diagnosis Index Using Deep Features and Local Directional Pattern Techniques

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that exhibits a wide spectrum of clinical presentations, including sudden death. Early diagnosis and intervention may avert the latter. Left ventricular hypertrophy on heart imaging is an important diagnostic criterion for HCM, and the most common imaging modality is heart ultrasound (US). The US is operator-dependent, and its interpretation is subject to human error and variability. We proposed an automated computer-aided diagnostic tool to discriminate HCM from healthy subjects on US images. We used a local directional pattern and the ResNet-50 pretrained network to classify heart US images acquired from 62 known HCM patients and 101 healthy subjects. Deep features were ranked using Student's t-test, and the most significant feature (SigFea) was identified. An integrated index derived from the simulation was defined as 100.log(10 )(SigFea /root 2) in each subject, and a diagnostic threshold value was empirically calculated as the mean of the minimum and maximum integrated indices among HCM and healthy subjects, respectively. An integrated index above a threshold of 0.5 separated HCM from healthy subjects with 100% accuracy in our test dataset

Role of Four-Chamber Heart Ultrasound Images in Automatic Assessment of Fetal Heart: A Systematic Understanding

The fetal echocardiogram is useful for monitoring and diagnosing cardiovascular diseases in the fetus in utero. Importantly, it can be used for assessing prenatal congenital heart disease, for which timely intervention can improve the unborn child's outcomes. In this regard, artificial intelligence (AI) can be used for the automatic analysis of fetal heart ultrasound images. This study reviews nondeep and deep learning approaches for assessing the fetal heart using standard four-chamber ultrasound images. The state-of-the-art techniques in the field are described and discussed. The compendium demonstrates the capability of automatic assessment of the fetal heart using AI technology. This work can serve as a resource for research in the field

Final Efficacy and Safety Results of Pemetrexed Continuation Maintenance Therapy in the Elderly from the PARAMOUNT Phase III Study

Introduction:The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non–small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (<70 years) patients.Methods:Final efficacy and safety data from the PARAMOUNT study were analyzed post hoc using subgroup analyses for elderly and non-elderly patients.Results:The median age was 73 years in the elderly subgroup (n = 92) and 60 years in the non-elderly subgroup (n = 447). Subgroups had similar baseline characteristics, except for a higher percentage of males and patients with a performance status of one in the elderly subgroup. For elderly patients, the median PFS was 6.4 months for pemetrexed and 3.0 months for placebo; the median OS was 13.7 months for pemetrexed and 12.1 months for placebo. For non-elderly patients, the median PFS was 4.0 months for pemetrexed and 2.8 months for placebo; the median OS was 13.9 months for pemetrexed and 10.8 months for placebo. Elderly patients experienced similar levels of low-grade toxicities, but had a higher percentage of grade 3/4 anemia and neutropenia than non-elderly patients, although importantly, this did not translate into increased febrile neutropenia.Conclusions:Continuation maintenance pemetrexed had comparable survival and toxicity profiles in the elderly and non-elderly subgroups. However, grade 3/4 anemia and neutropenia were numerically higher for elderly patients

A rationally designed peptide enhances homologous recombination in vitro and resistance to DNA damaging agents in vivo

The RecA family of proteins is essential in homologous recombination, a critical step in DNA repair. Here, we report that a rationally-designed small peptide based on the crystal structure of Escherichia coli RecA–DNA complex can promote homologous recombination through the enhancement of both RecA-mediated strand assimilation and three-strand exchange activity. Among 17 peptides tested, peptide #3 with the amino acid sequence of IRFLTARRR has the most potent activity in promoting the RecA-mediated D-loop formation by ∼7.2-fold at 37°C. Other peptides such as IRFLTAKKK and IRLLTARRR also have similar, albeit lower, activities. Therefore, hydrophobicity and poly-positive charges, and the space between them in those small peptides are crucial features for such activities. The enhancement of recombination by these peptides appears to be a general phenomenon as similar results were seen by using different plasmids. Remarkably, peptide #3 alone without RecA can also promote the D-loop formation at elevated temperature. Cell viability assays showed that the peptide elevates mammalian cell resistance to two cytotoxic DNA drugs, cisplatin and doxorubicin. The rescue of viability may result from increased DNA repair efficiency. Such peptides may find future biological applications

Mug20, a novel protein associated with linear elements in fission yeast meiosis

In the fission yeast, Schizosaccharomyces pombe, homologous chromosomes efficiently pair and recombine during meiotic prophase without forming a canonical synaptonemal complex (SC). Instead, it features simpler filamentous structures, the so-called linear elements (LinEs), which bear some resemblance to the axial/lateral element subunits of the SC. LinEs are required for wild-type recombination frequency. Here, we recognized Mug20, the product of a meiotically upregulated gene, as a LinE-associated protein. GFP-tagged Mug20 and anti-Mug20 antibody co-localized completely with Rec10, one of the major constituents of LinEs. In the absence of Mug20, LinEs failed to elongate beyond their initial state of nuclear dots. Foci of recombination protein Rad51 and genetic recombination were reduced. Since meiotic DNA double-strand breaks (DSBs), which initiate recombination, are induced at sites of preformed LinEs, we suggest that reduced recombination is a consequence of incomplete LinE extension. Therefore, we propose that Mug20 is required to extend LinEs from their sites of origin and thereby to increase DSB proficient regions on chromosomes

Local Preserving Class Separation Framework to Identify Gestational Diabetes Mellitus Mother Using Ultrasound Fetal Cardiac Image

In the presence of gestational diabetes mellitus (GDM), the fetus is exposed to a hyperinsulinemia environment. This environment can cause a wide range of metabolic and fetal cardiac structural alterations. Fetal myocardial hypertrophy predominantly affecting the interventricular septum possesses a morphology of disarray similar to hypertrophic cardiomyopathy, and may be present in some GDM neonates after birth. Myocardial thickness may increase in GDM fetuses independent of glycemic control status and fetal weight. Fetal echocardiography performed on fetuses with GDM helps in assessing cardiac structure and function, and to diagnose myocardial hypertrophy. There are few studies in the literature which have established evidence for morphologic variation associated with cardiac hypertrophy among fetuses of GDM mothers. In this study, fetal ultrasound images of normal, pregestational diabetes mellitus (preGDM) and GDM mothers were used to develop a computer aided diagnostic (CAD) tool. We proposed a new method called local preserving class separation (LPCS) framework to preserve the geometrical configuration of normal and preGDM/GDM subjects. The generated shearlet based texture features under LPCS framework showed promising results compared with deep learning algorithms. The proposed method achieved a maximum accuracy of 98.15% using a support vector machine (SVM) classifier. Hence, this paradigm can be helpful to physicians in detecting fetal myocardial hypertrophy in preGDM/GDM mothers

SIFAP2: a new versatile configuration at the TNG for the MPPC based photometer

The quality of SiFAP (Silicon Fast Astronomical Photometer) at the TNG has already shown its ability to easily detect optical pulses from transitional millisecond pulsars and from other slower neutron stars. Up to now the photometer based on Silicon Photo Multipliers manufactured by Hamamatsu Photonics (MPPC, Multi Pixel Photon Counter) was mounted (on and manually aligned with) a MOS mask at the F/11 focal plane of the telescope. In order to have a more versatile instrument with the possibility to remotely center and point several targets during the night we have decided to build a new mechanical support for the MPPCs and mount it on the Namsyth Interface (NI), where originally OIG and later GIANO were hosted. The MPPC module devoted to observe the target will be placed at the center of the FoV (on-axis), while the reference signal will be collected from a peripheral star in the FoV (Field of view) by means of the MPPC module that will be set at this position by a combination of a linear stage movement and a derotator angle. At the same time we have introduced the option for a polarimetric mode, with a 3rd MPPC module and a polarizing cube beam-splitter that separates the states between this and the on axis MPPC. SiFAP has been developed with 3 independent custom electronic chains for data acquisition, exploiting the 3 different outputs (analog, digital, USB pre-processed) provided by the MPPCs modules. The electronic chain fed by the analog output is able to tag a single photon ToA (Time of Arrival) with a time resolution of 25 ns, while the remaining electronic chains can integrate the signal into time bins from 100 ms down to 20 μs. The absolute time is provided by a GPS unit with a time resolution of 25 ns at 50% of the rising edge of the 1PPS (1 Pulse Per Second) signal which is linked to the UTC (Universal Time Coordinated). Apart from the versatility with the remotely controlled on sky configuration of the MPPCs, the mounting of SiFAP2 at the NI allows for a permanent hosting of the instrument, readily available for observations. The new polarimetric mode will then offer other scientific opportunities that have not been explored so far in high-temporal resolution astronomy

Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD

Plasticity of BRCA2 Function in Homologous Recombination: Genetic Interactions of the PALB2 and DNA Binding Domains

The breast cancer suppressor BRCA2 is essential for the maintenance of genomic integrity in mammalian cells through its role in DNA repair by homologous recombination (HR). Human BRCA2 is 3,418 amino acids and is comprised of multiple domains that interact with the RAD51 recombinase and other proteins as well as with DNA. To gain insight into the cellular function of BRCA2 in HR, we created fusions consisting of various BRCA2 domains and also introduced mutations into these domains to disrupt specific protein and DNA interactions. We find that a BRCA2 fusion peptide deleted for the DNA binding domain and active in HR is completely dependent on interaction with the PALB2 tumor suppressor for activity. Conversely, a BRCA2 fusion peptide deleted for the PALB2 binding domain is dependent on an intact DNA binding domain, providing a role for this conserved domain in vivo; mutagenesis suggests that both single-stranded and double-stranded DNA binding activities in the DNA binding domain are required for its activity. Given that PALB2 itself binds DNA, these results suggest alternative mechanisms to deliver RAD51 to DNA. In addition, the BRCA2 C terminus contains both RAD51-dependent and -independent activities which are essential to HR in some contexts. Finally, binding the small peptide DSS1 is essential for activity when its binding domain is present, but not when it is absent. Our results reveal functional redundancy within the BRCA2 protein and emphasize the plasticity of this large protein built for optimal HR function in mammalian cells. The occurrence of disease-causing mutations throughout BRCA2 suggests sub-optimal HR from a variety of domain modulations