Miracle-dz/UniFAR-FTUs huggingface dataset:
Atypical Activations of Fronto-Cerebellar Regions During Forethought in Parents of Children With ADHD

Objective: Although several studies suggest heritability of ADHD, only a few investigations of possible associations between people at risk and neural abnormalities in ADHD exist. In this study, we tested whether parents of children with ADHD would show atypical patterns of cerebral activations during forethought, a feature of working memory. Method: Using Functional Magnetic Resonance Imaging (fMRI), we compared 12 parents of children with ADHD and 9 parents of control children during a forethought task. Results: Parents of children with ADHD exhibited significantly increased neural activations in the posterior lobes of the cerebellum and in the left inferior frontal gyrus, relative to parents of control children. Conclusion: These findings are consistent with previous reports in children and suggest the fronto-cerebellar circuit’s abnormalities during forethought in parents of children with ADHD. Future studies of people at risk of ADHD are needed to fully understand the extent of the fronto-cerebellar heritability.
SP174 Antibody Lacks Specificity for NRAS Q61R and Cross-Reacts With HRAS and KRAS Q61R Mutant Proteins in Malignant Melanoma

HRAS, KRAS, and NRAS, highly homologous proteins, are often mutationally activated in cancer. Usually, mutations cluster in codons 12, 13, and 61 and are detected by molecular genetic testing of tumor DNA. Recently, immunohistochemistry with SP174 antibody has been introduced to detect NRAS Q61R-mutant protein. Studies on malignant melanomas showed that such an approach could be a viable alternative to molecular genetic testing. This investigation was undertaken to evaluate the value of SP174 immunohistochemistry for detection of NRAS Q61R-mutant isoform. Two hundred ninety-two malignant melanomas were evaluated using Leica Bond-Max automated immunostainer. Twenty-nine tumors (10%) showed positive immunoreactivity. NRAS codon 61 was polymerase chain reaction amplified and sequenced in 24 positive and 92 negative cases using Sanger sequencing, quantitative polymerase chain reaction, and next-generation sequencing approaches. A c.182A>G substitution leading to NRAS Q61R mutation was identified in 22 tumors. Two NRAS wild-type tumors revealed c.182A>G substitutions in HRAS and KRAS codon 61, respectively. Both mutations were detected by next-generation sequencing and independently confirmed by Sanger sequencing. None of 85 NRAS codon 61 wild-type tumors and 7 NRAS mutants other than Q61R showed immunoreactivity with SP174 antibody. Thus, SP174 antibody was 100% sensitive in detecting NRAS Q61R-mutant isoform in malignant melanoma, but not fully specific as it cross-reacted with HRAS and KRAS Q61R-mutant proteins. Therefore, molecular testing is needed to determine which RAS gene is mutated. The rarity of HRAS and KRAS Q61R mutants in malignant melanoma let previous investigations erroneously conclude that SP174 is specific for NRAS Q61R-mutant protein.
Ethanolamine and Phosphatidylethanolamine: Partners in Health and Disease

Phosphatidylethanolamine (PE) is the second most abundant phospholipid in mammalian cells. PE comprises about 15–25% of the total lipid in mammalian cells; it is enriched in the inner leaflet of membranes, and it is especially abundant in the inner mitochondrial membrane. PE has quite remarkable activities: it is a lipid chaperone that assists in the folding of certain membrane proteins, it is required for the activity of several of the respiratory complexes, and it plays a key role in the initiation of autophagy. In this review, we focus on PE's roles in lipid-induced stress in the endoplasmic reticulum (ER), Parkinson's disease (PD), ferroptosis, and cancer.
Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells

Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously shown that S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A can modulate histone methylation and disrupt EZH2 complex. Here, we used 3-deazaneplanocin A, together with other chromatin remodeling agents, as well as RNA interference–mediated EZH2 depletion, to probe the role of EZH2 in coordination with other epigenetic components in gene regulation in breast cancer cells. Through genome-wide gene expression analysis, coupled with extensive chromatin immunoprecipitation analysis of histone modifications, we have identified a variety of gene sets that are regulated either by EZH2 alone or through the coordinated action of EZH2 with HDAC and/or DNA methylation. We further found that tumor antigen GAGEs were regulated by distinct epigenetic mechanisms in a cell context–dependent manner, possibly reflecting mechanistic heterogeneity in breast cancer. Intriguingly, we found that EZH2 regulates a remarkable cohort of genes whose functions are highly enriched in immunoresponse and autocrine inflammation network, and that their transcriptional activation upon EZH2 perturbation is cancer specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings show the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation. [Mol Cancer Ther 2009;8(12):3191–202]
Prevalence of posttraumatic stress disorder and major depressive disorder in Tibetan refugee children.

OBJECTIVE In an exploratory survey the prevalence of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) was estimated in children who escaped from Tibet and found refuge in Tibetan settlements in India. METHOD As part of an exploratory mission of the international medical relief organization Doctors Without Borders (Medecins Sans Frontieres), 61 randomly selected children from four group homes of the Tibetan Children Village in Dharamsala, India, were interviewed for symptoms of PTSD and MDD. RESULTS 11.5% of the children met DSM-IV criteria for PTSD, and the same proportion met criteria for MDD. Children who had arrived from Tibet more recently (in the previous 18 months) showed a tendency for greater prevalence of PTSD than children who had been refugees longer. CONCLUSION Tibetan children who succeed in their journey into exile suffer levels of stress-related disorders comparable with those of children in war situations or those exposed to natural disasters. However, in this population, several protective factors may help reduce the level of distress over time.
Evaluative Responses to Five Kinds of Water Features

How do humans respond to different water features used by designers in urban plazas? Thirty participants viewed colour photographs of controlled views of five kinds of water features (Still, Flowing, Falling, Jet and Combination) and rated each scene on nine bi-polar adjective scales. The analyses focused on three composite scales, one for Preference, one for Calming and one for Excitement. Although the water features generally received favourable ratings, analysis of variance and tests of effect sizes revealed that participants had higher preferences for jets and combination; they rated still water as most calming; and they rated moving water as higher in excitement than still water. To test the generalization of the findings, replications in more realistic conditions are called for.
Audiovisual Resource Allocation for Bimodal Virtual Environments

Fidelity is of key importance if virtual environments are to be used as authentic representations of real environments. However, simulating the multitude of senses that comprise the human sensory system is computationally challenging. With limited computational resources, it is essential to distribute these carefully in order to simulate the most ideal perceptual experience. This paper investigates this balance of resources across multiple scenarios where combined audiovisual stimulation is delivered to the user. A subjective experiment was undertaken where participants (N=35) allocated five fixed resource budgets across graphics and acoustic stimuli. In the experiment, increasing the quality of one of the stimuli decreased the quality of the other. Findings demonstrate that participants allocate more resources to graphics; however, as the computational budget is increased, an approximately balanced distribution of resources is preferred between graphics and acoustics. Based on the results, an audiovisual quality prediction model is proposed and successfully validated against previously untested budgets and an untested scenario.
Patterns of care for women with cervical cancer in the United States

Recommendations for pretreatment evaluation and treatment of cervical cancer have significantly evolved over the last decade because of the results of multiple randomized studies comparing the addition of platin‐based chemoradiation as well as the widespread dissemination and use of imaging modalities. This analysis was initiated to determine any systemic changes in management of cervical cancers.
DINGO: differential network analysis in genomics

MOTIVATION Cancer progression and development are initiated by aberrations in various molecular networks through coordinated changes across multiple genes and pathways. It is important to understand how these networks change under different stress conditions and/or patient-specific groups to infer differential patterns of activation and inhibition. Existing methods are limited to correlation networks that are independently estimated from separate group-specific data and without due consideration of relationships that are conserved across multiple groups. METHOD We propose a pathway-based differential network analysis in genomics (DINGO) model for estimating group-specific networks and making inference on the differential networks. DINGO jointly estimates the group-specific conditional dependencies by decomposing them into global and group-specific components. The delineation of these components allows for a more refined picture of the major driver and passenger events in the elucidation of cancer progression and development. RESULTS Simulation studies demonstrate that DINGO provides more accurate group-specific conditional dependencies than achieved by using separate estimation approaches. We apply DINGO to key signaling pathways in glioblastoma to build differential networks for long-term survivors and short-term survivors in The Cancer Genome Atlas. The hub genes found by mRNA expression, DNA copy number, methylation and microRNA expression reveal several important roles in glioblastoma progression. AVAILABILITY AND IMPLEMENTATION R Package at: odin.mdacc. tmc.edu/∼vbaladan. CONTACT veera@mdanderson.org SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Combination therapy of BRAF inhibitors for advanced melanoma with BRAF V600 mutation: a systematic review and meta-analysis

Abstract Background: Although BRAF inhibitors have been used to treat advanced melanoma with BRAF mutation, combination strategies are suggested due to acquired resistance to BRAF inhibitors. Objective: To assess the efficacy of BRAF inhibitor-based combination therapy for the treatment of advanced melanoma with BRAF mutation. Methods: We conducted a systematic review and meta-analysis of studies that compared BRAF inhibitor-based combination therapy with BRAF inhibitor monotherapy. We searched MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. The random-effects inverse variance and Mantel–Haenszel methods were used to pool the results. Results: Four randomized controlled trials and one cohort study were identified. A combination therapy with BRAF inhibitors and MEK inhibitors was used in all studies. The combined hazard ratios of overall survival (OS) and progression-free survival (PFS) comparing combination therapy with monotherapy were 0.70 [95% confidence interval (CI) 0.62–0.78] and 0.59 (95% CI 0.55–0.63), respectively. The combined risk ratio of objective response rate (ORR) was 1.30 (95% CI 1.20–1.40), which meant more patients achieved complete/partial responses in combination therapy group than those in the monotherapy group. Conclusions: Combination therapy with BRAF inhibitors and MEK inhibitors significantly improved OS, PFS, and ORR in patients with advanced melanoma with BRAF mutation.
A long non-coding RNA is required for targeting centromeric protein A to the human centromere

The centromere is a specialized chromatin region marked by the histone H3 variant CENP-A. Although active centromeric transcription has been documented for over a decade, the role of centromeric transcription or transcripts has been elusive. Here, we report that centromeric α-satellite transcription is dependent on RNA Polymerase II and occurs at late mitosis into early G1, concurrent with the timing of new CENP-A assembly. Inhibition of RNA Polymerase II-dependent transcription abrogates the recruitment of CENP-A and its chaperone HJURP to native human centromeres. Biochemical characterization of CENP-A associated RNAs reveals a 1.3 kb molecule that originates from centromeres, which physically interacts with the soluble pre-assembly HJURP/CENP-A complex in vivo, and whose down-regulation leads to the loss of CENP-A and HJURP at centromeres. This study describes a novel function for human centromeric long non-coding RNAs in the recruitment of HJURP and CENP-A, implicating RNA-based chaperone targeting in histone variant assembly.
A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions

PTK7 is a tumor-initiating cell antigen, which can be targeted with an antibody-drug conjugate to confer sustained tumor regressions. Initiating an antitumor attack Cancer is notorious for relapsing after treatment, making it difficult to eradicate from a patient’s body. Such relapses are driven by tumor-initiating cells, a type of stem cells that give rise to tumors. Damelin et al. determined that a protein called PTK7 is frequently present on tumor-initiating cells and developed an antibody-drug conjugate for targeting it. The authors demonstrated the effectiveness of this therapy in mouse models of several tumor types and confirmed that it reduces tumor-initiating cells and outperforms standard chemotherapy. The antibody-drug conjugate also had some unexpected benefits, reducing tumor angiogenesis and promoting antitumor immunity, all of which may contribute to its effectiveness. Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non–small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient–derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline–based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients.
Differential Expression of Stress and Immune Response Pathway Transcripts and miRNAs in Normal Human Endothelial Cells Subjected to Fractionated or Single-Dose Radiation

Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2 Gy × 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed. Implications: Radiation-induced alterations in stress and immune response genes in endothelial cells contribute to changes in normal tissue and tumor microenvironment, and affect the outcome of radiotherapy. Mol Cancer Res; 12(7); 1002–15. ©2014 AACR.
Epigenetic Control of Ccr7 Expression in Distinct Lineages of Lung Dendritic Cells

Adaptive immune responses to inhaled allergens are induced following CCR7-dependent migration of precursor of dendritic cell (pre-DC)–derived conventional DCs (cDCs) from the lung to regional lymph nodes. However, monocyte-derived (moDCs) in the lung express very low levels of Ccr7 and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7-associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung.
Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

Background— The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. Methods and Results— Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1–13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E′, and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P<0.05). Conclusions— There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.
Breaking cycles of risk: The mitigating role of maternal working memory in associations among socioeconomic status, early caregiving, and children's working memory

Abstract Previous research has documented socioeconomic-related disparities in children's working memory; however, the putative proximal caregiving mechanisms that underlie these effects are less known. The present study sought to examine whether the effects of early family socioeconomic status on children's working memory were mediated through experiences of caregiving, specifically maternal harsh discipline and responsiveness. Utilizing a psychobiological framework of parenting, the present study also tested whether maternal working memory moderated the initial paths between the family socioeconomic context and maternal harsh discipline and responsiveness in the mediation model. The sample included 185 socioeconomically diverse mother–child dyads assessed when children were 3.5 and 5 years old. Results demonstrated that maternal harsh discipline was a unique mediator of the relation between early experiences of family socioeconomic adversity and lower working memory outcomes in children. Individual differences in maternal working memory emerged as a potent individual difference factor that specifically moderated the mediating influence of harsh discipline within low socioeconomic contexts. The findings have implications for early risk processes underlying deficits in child working memory outcomes and potential targets for parent–child interventions.