Miracle-dz/UniFAR-FTUs huggingface dataset:
Rare Manifestation of Gout: Gouty Tophi in the Nose

Abstract Gout is a disease characterized by abnormal metabolism of the uric acid, leading to undesired buildup of monosodium urate crystals affecting mainly the first metatarsal-phalangeal joint of the foot and less commonly other joints or the soft tissues of the body. The prevalence of the disease increases with age, and it is statistically more observed in men than in women. We present the case of a 62-year-old male patient diagnosed as having gout 20 years ago. He came to the clinic with a nasal hump and a mass growing in his nose for the last 3 years, presenting as a nasal obstruction and facial deformity. Although the patient was treated with allopurinol and nonsteroidal anti-inflammatory drugs, surgical treatment was deemed necessary, and the patient was taken to receive a surgical resection of the nasal mass. The follow-up histopathology observation revealed deposits of urate crystals surrounded by a granulomatous inflammation. This confirmed the diagnosis—gouty tophi in the nose. In the follow-up period after the surgery, the patient reported overall improved breathing and aesthetic results. Tophi can be found in atypical locations, which increases morbidities and deformities caused by the disease. We report on this peculiar case of tophaceus gout as it is—a rare manifestation of the disease with tophi located in the nasal region.
Artificial intelligence outperforms pulmonologists in the interpretation of pulmonary function tests

The interpretation of pulmonary function tests (PFTs) to diagnose respiratory diseases is built on expert opinion that relies on the recognition of patterns and the clinical context for detection of specific diseases. In this study, we aimed to explore the accuracy and interrater variability of pulmonologists when interpreting PFTs compared with artificial intelligence (AI)-based software that was developed and validated in more than 1500 historical patient cases. 120 pulmonologists from 16 European hospitals evaluated 50 cases with PFT and clinical information, resulting in 6000 independent interpretations. The AI software examined the same data. American Thoracic Society/European Respiratory Society guidelines were used as the gold standard for PFT pattern interpretation. The gold standard for diagnosis was derived from clinical history, PFT and all additional tests. The pattern recognition of PFTs by pulmonologists (senior 73%, junior 27%) matched the guidelines in 74.4±5.9% of the cases (range 56–88%). The interrater variability of κ=0.67 pointed to a common agreement. Pulmonologists made correct diagnoses in 44.6±8.7% of the cases (range 24–62%) with a large interrater variability (κ=0.35). The AI-based software perfectly matched the PFT pattern interpretations (100%) and assigned a correct diagnosis in 82% of all cases (p<0.0001 for both measures). The interpretation of PFTs by pulmonologists leads to marked variations and errors. AI-based software provides more accurate interpretations and may serve as a powerful decision support tool to improve clinical practice. There is poor accuracy and substantial disagreement between pulmonologists when interpreting complex pulmonary function data. Automating interpretation with artificial intelligence provides a powerful decision support tool in clinical practice. http://ow.ly/Tj9h30nxw4U
Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models

Purpose: To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Experimental Design: Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a “hypoxia index” compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo. In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. Clin Cancer Res; 22(7); 1687–98. ©2015 AACR.
Potential Mutations in Chinese Pathologic Myopic Patients and Contributions to Phenotype

Purpose Pathologic myopia is a leading cause of visual impairment in East Asia. The aim of this study was to investigate the potential mutations in Chinese pathologic myopic patients and to analyze the correlations between genotype and clinical phenotype. Method One hundred and three patients with pathologic myopia and one hundred and nine unrelated healthy controls were recruited from Zhongshan Ophthalmic Center. Detailed clinical data, including ultra-widefield retinal images, measurements of best-corrected visual acuity, axial length, refractive error and ophthalmic examination results, were obtained. Blood samples were collected for high-throughput DNA targeted sequencing. Based on the screening results, phenotype-genotype correlations were analyzed. Results The study included 196 eyes of 103 patients (36 men and 67 women) with an average age of 52.19 (38.92 – 65.46) years, an average refractive error of -11.80 D (-16.38 – -7.22) and a mean axial length of 28.26 mm (25.79 – 30.73). The patients were subdivided into three groups: myopic chorioretinal atrophy (190 eyes of 101 patients), myopic choroidal neovascularization (17 eyes of 15 patients), and myopic traction retinopathy (71 eyes of 61 patients). Systematic analysis of variants in the 255 genes revealed six potential pathogenic mutations: PEX7, OCA2, LRP5 (rs545382, c.1647T>C), TSPAN12 (rs41623, c.765G>T), RDH5 (rs3138142, c.423C>T) and TTC21B (rs80225158, c.2385G>C). OCA2 mutations were primarily observed in patients with myopic traction maculopathy. Conclusion Genetic alterations contribute to various clinical characteristics in Chinese pathologic myopic patients. The study may provide new insights into the etiology of pathologic myopia and potential targets for therapeutic interventions.
First in human transapical implantation of an inverted transcatheter aortic valve prosthesis to treat native mitral valve stenosis.

Transcatheter aortic valve implantation has become well established in the past decade. Its superiority in comparison with conventional surgical aortic valve replacements in high-risk patients has been demonstrated in the Partner Cohort B trial.1 We report the first case of using an inverted transcatheter Edwards Sapien valve (Edwards Lifesciences, CA) in the native mitral valve position, to treat severe calcific mitral stenosis. A 70-year-old woman was admitted to the intensive care unit after having had a cardiorespiratory collapse requiring ventilatory support. She was initially referred for assessment of worsening breathlessness, 7 years after coronary artery bypass grafting and aortic valve replacement with a 21-mm Top Hat (Sulzer, Carbomedics, Austin, TX) valve. Investigations in another center revealed patent grafts, severe calcific mitral stenosis with a valve area of 0.9 cm2 and a mean gradient …
The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation

The drug‐induced liver injury (DILI)‐sim Initiative is a public‐private partnership involving scientists from industry, academia, and the US Food and Drug Administration (FDA). The Initiative uses quantitative systems toxicology (QST) to build and refine a model (DILIsym) capable of understanding and predicting liver safety liabilities in new drug candidates and to optimize interpretation of liver safety biomarkers used in clinical studies. Insights gained to date include the observation that most dose‐dependent hepatotoxicity can be accounted for by combinations of just three mechanisms (oxidative stress, interference with mitochondrial respiration, and alterations in bile acid homeostasis) and the importance of noncompetitive inhibition of bile acid transporters. The effort has also provided novel insight into species and interpatient differences in susceptibility, structure‐activity relationships, and the role of nonimmune mechanisms in delayed idiosyncratic hepatotoxicity. The model is increasingly used to evaluate new drug candidates and several clinical trials are underway that will test the model's ability to prospectively predict liver safety. With more refinement, in the future, it may be possible to use the DILIsym predictions to justify reduction in the size of some clinical trials. The mature model could also potentially assist physicians in managing the liver safety of their patients as well as aid in the diagnosis of DILI.
Placental Neuropeptide Y (NPY) and NPY receptors expressions and serum NPY levels in preeclampsia

Neuropeptide Y (NPY) has been reported as a vasoconstrictive substance that might be associated with preeclampsia. NPY mediates different effects via its specific NPY receptors. NPY action via Y1 receptor (Y1R) and/or Y5 receptor (Y5R) induces vascular smooth muscle cells proliferation while it is implicated in angiogenesis via Y2 receptor (Y2R) and/or Y5R. The objectives of this study were to (1) compare placental NPY, Y1 receptor (Y1R), Y2 receptor (Y2R), and Y5 receptor (Y5R) expressions between normal (NP) and preeclamptic (PE) pregnancies to determine whether gene expression of different NPY receptors are altered in the PE condition; (2) compare maternal serum NPY levels between NP and PE subjects; and (3) determine correlations between placental gene expressions as well as serum NPY levels with maternal and neonatal clinical parameters. There were 22 subjects each in the NP (gestational age 37–42 weeks) and PE (gestational age ≥34 weeks) groups. Clinical parameters and serum NPY levels were measured before delivery. NPY expression and serum NPY levels were comparable between NP and PE subjects. Y1R, Y2R, and Y5R expressions were significantly lower in PE than NP subjects. In all and NP subjects, placental Y2R showed the highest expression, tended to be higher than Y5R, and was significantly higher than Y1R. In PE subjects, placental Y2R was comparable to Y5R and both Y2R and Y5R were significantly higher than Y1R. The NPY receptor expression ratio between the PE/NP groups showed that it was lowest for Y2R (0.27) compared to Y1R (0.42) and Y5R (0.40) suggestive of decreased Y2R expression in PE subjects. In summary, a decrease in placental Y2R mRNA might be associated with abnormalities of placental angiogenesis which probably contributes to the pathophysiology of preeclampsia. The roles of NPY receptors mediating placental vascularization need to be further investigated. Impact statement Neuropeptide Y (NPY) has been reported as a vasoconstrictive substance which might be associated with preeclampsia. The novel findings of this study were that Y1R, Y2R, and Y5R expressions were significantly lower in the PE than the NP group. Moreover, the NPY receptor expression ratio between the PE/NP groups was lowest for Y2R (0.27) compared to Y1R (0.42) and Y5R (0.40) suggestive of a reduction of this receptor in the preeclampsia group. Our results suggested that decreased Y2R mRNA in the PE group might be associated with abnormalities of placental angiogenesis which probably contributes to the pathophysiology of preeclampsia.
Analysis between phenotypes and genotypes of inner ear malformation

Abstract Background: The clinical characteristics of LVAS have attracted more and more attention, its audiology and imaging features have also been deeply studied. Objective: To analyze phenotypes, genotypes of EVA, and find out the relationship between them. Methods: Sixty EVA patients were tested by audiometry, temporal bone high-resolution CT and inner ear MRI. SNPscan technology were carried out after the patients signed informed consent. SPSS19.0 software was used. Result: 1. Three types malformations include EVA, EVA with Mondini and Mondini were found. They accounted for 48.20%, 40.10%, and 11.70%. 2. The SLC26A4 gene mutation frequency was (47/53) 88.68% in EVA patients. The most common genotype was c.919-2A > G/c.919-2A > G, accounting for 28.30%. The most common mutation type was c.9I9-2A > G. 3. GJB2 and SLC26A4 gene mutation frequencies were significantly different (χ2＝65.185, p<.001). Conclusions: 1. EVA patients with severe sensorineural hearing loss were always diagnosed in childhood and Cochlear implantation was feasible for these patients with the bilateral hearing loss. 2. SLC26A4 gene was closely related to EVA. 3. GJB2 and mtDNA genes were not responsible for EVA. Significance: The relationship between genotype and clinical phenotype provides a theoretical basis for future gene diagnosis and prevention and treatment of LVAS.
Protective factors that buffer against the intergenerational transmission of trauma from mothers to young children: A replication study of angels in the nursery

Abstract This replication study examined protective effects of positive childhood memories with caregivers (“angels in the nursery”) against lifespan and intergenerational transmission of trauma. More positive, elaborated angel memories were hypothesized to buffer associations between mothers’ childhood maltreatment and their adulthood posttraumatic stress disorder (PTSD) and depression symptoms, comorbid psychopathology, and children's trauma exposure. Participants were 185 mothers (M age = 30.67 years, SD = 6.44, range = 17–46 years, 54.6% Latina, 17.8% White, 10.3% African American, 17.3% other; 24% Spanish speaking) and children (M age = 42.51 months; SD = 15.95, range = 3–72 months; 51.4% male). Mothers completed the Angels in the Nursery Interview (Van Horn, Lieberman, & Harris, 2008), and assessments of childhood maltreatment, adulthood psychopathology, children's trauma exposure, and demographics. Angel memories significantly moderated associations between maltreatment and PTSD (but not depression) symptoms, comorbid psychopathology, and children's trauma exposure. For mothers with less positive, elaborated angel memories, higher levels of maltreatment predicted higher levels of psychopathology and children's trauma exposure. For mothers with more positive, elaborated memories, however, predictive associations were not significant, reflecting protective effects. Furthermore, protective effects against children's trauma exposure were significant only for female children, suggesting that angel memories may specifically buffer against intergenerational trauma from mothers to daughters.
Genetic risk factors and gene–environment interactions in adult and childhood attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the ‘missing heritability’ of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene–environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene–environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.
Protection from EAE in DOCK8 mutant mice occurs despite increased Th17 cell frequencies in the periphery

Mutation of Dedicator of cytokinesis 8 (DOCK8) has previously been reported to provide resistance to the Th17 cell dependent EAE in mice. Contrary to expectation, we observed an elevation of Th17 cells in two different DOCK8 mutant mouse strains in the steady state. This was specific for Th17 cells with no change in Th1 or Th2 cell populations. In vitro Th cell differentiation assays revealed that the elevated Th17 cell population was not due to a T cell intrinsic differentiation bias. Challenging these mutant mice in the EAE model, we confirmed a resistance to this autoimmune disease with Th17 cells remaining elevated systemically while cellular infiltration in the CNS was reduced. Infiltrating T cells lost the bias toward Th17 cells indicating a relative reduction of Th17 cells in the CNS and a Th17 cell specific migration disadvantage. Adoptive transfers of Th1 and Th17 cells in EAE‐affected mice further supported the Th17 cell‐specific migration defect, however, DOCK8‐deficient Th17 cells expressed normal Th17 cell‐specific CCR6 levels and migrated toward chemokine gradients in transwell assays. This study shows that resistance to EAE in DOCK8 mutant mice is achieved despite a systemic Th17 bias.
Stratifin Inhibits SCFFBW7 Formation and Blocks Ubiquitination of Oncoproteins during the Course of Lung Adenocarcinogenesis

Purpose: Aberrant overexpression of SFN (stratifin) plays an oncogenic role in lung adenocarcinoma. We have shown previously that SKP1, an adapter component of E3 ubiquitin ligase forming an SCF complex, is a unique SFN-binding protein in lung adenocarcinoma cells. Experimental Design: In silico simulation and in vitro mutagenesis analysis were performed to identify the SFN-binding domain on SKP1. We examined expression, localization, and stability of SKP1 after knockdown of SFN using lung adenocarcinoma cells including A549. In silico library screening and experimental validation were used for drug screening. Daily oral administration of each candidate drugs to A549-injected tumor-bearing mice was performed to evaluate their in vivo antitumor efficacy. Results: Suppression of SFN upregulated the stability of SKP1 and accelerated its cytoplasm-to-nucleus translocation. Consistently, IHC analysis revealed that cytoplasmic expression of SKP1 was significantly associated with SFN positivity, tumor malignancy, and poorer patient outcome. After SFN suppression, ubiquitination of oncoproteins, including p-cyclin E1, p-c-Myc, p-c-Jun, and cleaved Notch 1, which are target proteins of SCFFBW7, was strongly induced. These results indicate that SFN–SKP1 binding results in SCFFBW7 dysfunction and allows several oncoproteins to evade ubiquitination and subsequent degradation. Because inhibition of SFN-SKP1 binding was expected to have antitumor efficacy, we next searched for candidate SFN inhibitors. Aprepitant and ticagrelor were finally selected as potential SFN inhibitors that dose dependently reduced SFN-SKP1 binding and tumor progression in vivo. Conclusions: As overexpression of SFN is detectable in most adenocarcinoma, we believe that SFN inhibitors would be novel and promising antitumor drugs for lung adenocarcinoma.
A Greedy Assist-as-Needed Controller for Upper Limb Rehabilitation

Previous studies on robotic rehabilitation have shown that subjects’ active participation and effort involved in rehabilitation training can promote the performance of therapies. In order to improve the voluntary effort of participants during the rehabilitation training, assist-as-needed (AAN) control strategies regulating the robotic assistance according to subjects’ performance and conditions have been developed. Unfortunately, the heterogeneity of patients’ motor function capability in task space is not taken into account during the implementation of these controllers. In this paper, a new scheme called greedy AAN (GAAN) controller is designed for the upper limb rehabilitation training of neurologically impaired subjects. The proposed GAAN control paradigm includes a baseline controller and a Gaussian RBF network that is utilized to model the functional capability of subjects and to provide corresponding a task challenge for them. In order to avoid subjects’ slacking and encourage their active engagement, the weight vectors of RBF networks evaluating subjects’ impairment level are updated based on a greedy strategy that makes the networks progressively learn the maximum forces over time provided by subjects. Simultaneously, a challenge level modification algorithm is employed to adjust the task challenge according to the task performance of subjects. Experiments on 12 subjects with neurological impairment are conducted to validate the performance and feasibility of the GAAN controller. The results show that the proposed GAAN controller has significant potential to promote the subjects’ voluntary engagement during training exercises.
Phospholipid regulation of innate immunity and respiratory viral infection

Toll-like receptors (TLRs) coupled to intracellular signaling cascades function as central elements of innate immunity that control transcription of numerous pro-inflammatory genes. Two minor anionic phospholipids present in the pulmonary surfactant complex, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), antagonize the cognate ligand activation of TLRs 2 and 4. The lipids block recognition of activating ligands by the TLRs, either directly or via the TLR4 coreceptors CD14 and MD2. Antagonism of TLR activation results in inhibition of the initiating step of the pro-inflammatory signaling pathways. Evidence for this mechanism of action comes from direct binding studies between CD14 and MD2 with POPG and PI. Additional evidence for this mechanism of antagonism also comes from monitoring the reduction of protein phosphorylation events that characterize the intracellular signaling by activated TLRs. The pathogenesis of respiratory syncytial virus (RSV) and influenza A virus (IAV) have been linked to TLR4 activation, and we examined the action of POPG and PI as potential antagonists of the pathology of these viruses. Surprisingly, POPG and PI dramatically curtail infection, in addition to inhibiting inflammatory sequelae associated with RSV and IAV infections. The mechanism of action by the lipids is disruption of virus particle binding to host cell plasma membrane receptors, required for viral uptake. The antagonism of activation of TLRs and virus binding to the alveolar epithelium by resident constituents of the pulmonary surfactant system suggests that POPG and PI function in homeostasis, to prevent inflammatory processes that result in reductions in gas exchange within the alveolar compartment.