Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2+ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression

HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models. HER2+ breast leptomeningeal carcinomatosis (HER2+ LC) occurs when tumor cells spread to cerebrospinal fluid–containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2+ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2+ LC tumors might efficiently target HER2+ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2+ LC (Lepto) cell lines from nodular HER2+ LC tissues. These lines are phenotypically CD326+CD49f−, confirming that they are derived from HER2+ LC tumors, and express surface CD44+CD24−, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2+ breast cancer lines in vitro and in vivo. Interestingly, the three Lepto lines overexpressed Jumonji domain–containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion in vitro. JIB04 treatment of patient-derived xenograft mouse models in vivo reduced HER2+ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2+ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. Significance: HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models.
AutoImplant 2020-First MICCAI Challenge on Automatic Cranial Implant Design

The aim of this paper is to provide a comprehensive overview of the MICCAI 2020 AutoImplant Challenge. The approaches and publications submitted and accepted within the challenge will be summarized and reported, highlighting common algorithmic trends and algorithmic diversity. Furthermore, the evaluation results will be presented, compared and discussed in regard to the challenge aim: seeking for low cost, fast and fully automated solutions for cranial implant design. Based on feedback from collaborating neurosurgeons, this paper concludes by stating open issues and post-challenge requirements for intra-operative use. The codes can be found at https://github.com/Jianningli/tmi.
Functional brain plasticity during L1 training on complex sentences: Changes in gamma‐band oscillatory activity

The adult human brain remains plastic even after puberty. However, whether first language (L1) training in adults can alter the language network is yet largely unknown. Thus, we conducted a longitudinal training experiment on syntactically complex German sentence comprehension. Sentence complexity was varied by the depth of the center embedded relative clauses (i.e., single or double embedded). Comprehension was tested after each sentence with a question on the thematic role assignment. Thirty adult, native German speakers were recruited for 4 days of training. Magnetoencephalography (MEG) data were recorded and subjected to spectral power analysis covering the classical frequency bands (i.e., theta, alpha, beta, low gamma, and gamma). Normalized spectral power, time‐locked to the final closure of the relative clause, was subjected to a two‐factor analysis (“sentence complexity” and “training days”). Results showed that for the more complex sentences, the interaction of sentence complexity and training days was observed in Brodmann area 44 (BA 44) as a decrease of gamma power with training. Moreover, in the gamma band (55–95 Hz) functional connectivity between BA 44 and other brain regions such as the inferior frontal sulcus and the inferior parietal cortex were correlated with behavioral performance increase due to training. These results show that even for native speakers, complex L1 sentence training improves language performance and alters neural activities of the left hemispheric language network. Training strengthens the use of the dorsal processing stream with working‐memory‐related brain regions for syntactically complex sentences, thereby demonstrating the brain's functional plasticity for L1 training.
Anatomical effects of intravitreal anti-vascular endothelial growth factor injections on inner layers of the lesion-free retina

Abstract Purpose The primary aim of the study was to investigate the effects of anti-vascular endothelial growth factor (VEGF) injections on the inner retinal layer anatomy of the lesion-free retina in eyes treated for neovascular age-related macular degeneration (nAMD). The secondary aim was to compare the changes of inner retinal layers in the lesion-free region of treated eyes with the same region of the untreated, fellow eyes and, thus, to elucidate any adverse effect of anti-VEGF treatments independently of 1-year aging changes. Methods This was a retrospective, longitudinal, case–control study of 50 eyes of 25 patients. Twenty-five eyes with nAMD comprised the study group (16 eyes treated with aflibercept and 9 eyes treated with ranibizumab) and 25 fellow eyes with dry AMD (16 eyes in AREDS 2 and 9 eyes in AREDS 3) comprised the fellow eye group. Spectral-domain optical coherence tomography (SD-OCT) measurements were done at pre-treatment, 1 month after three loading anti-VEGF injections and at the end of 1 year. The retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL) thicknesses and total retinal thickness in the macula were measured. Thicknesses of inner retinal layers which were lesion-free in the outer nasal subfield of ETDRS grid were analysed and the changes in thicknesses during the follow-up period were compared between study and fellow eye groups. Paired t-test for normally distributed variables was applied for analyses of differences for the comparison of the results across the pre-and the post-. A p value of less than 0.05 was considered statistically significant. Results The mean number of injections was 5.76 ± 1.26 in the study group in 1 year. The mean decrease in total retinal thickness was significant with 6.08 ± 9.05 µm (p= 0.003) in nAMD group and was insignificant with 0.32 ± 1.03 µm (p> 0.05) in fellow eye group with dry AMD. Most of the retinal thickness decrease was during first three injections in nAMD group. Total retinal thickness and GCL thickness were thinner in the study group at every follow-up examination, but the difference between groups was not statistically significant (p> 0.05). RNFL, GCL, IPL, and INL thicknesses did not demonstrate a statistically significant change in both study and fellow eye groups during 1 year follow-up period (p> 0.05). Conclusions Repeated anti-VEGF injections in nAMD appear to have no significant effect on the RNFL, GCL, IPL, and INL thicknesses of the lesion-free retina. Additionally, there was no significant difference in inner retinal layer changes between in eyes treated with anti-VEGF injections for nAMD and fellow eye group during 1-year follow-up.
Irreducible Traumatic Radial Head Dislocation Due to Annular Ligament Interposition in a Child with Ulnar Plastic Deformation: A Case Report

The traumatic dislocation of the radial head in children is commonly treated by closed reduction. Sometimes, however, this strategy of treatment may not be effective due to the location of soft tissues in the radio‐shoulder joint. The literature presents a few cases of the irreducible radial head dislocation with ulnar plastic deformation. Because it is a relatively rare condition, such a traumatic dislocation can be easily missed. Neglected injuries can lead to unwanted complications and unpredictable surgical outcomes.
Ume6 Acts as a Stable Platform To Coordinate Repression and Activation of Early Meiosis-Specific Genes in Saccharomyces cerevisiae

In response to nutrient starvation, the budding yeast Saccharomyces cerevisiae abandons mitotic proliferation and embarks on a differentiation process that leads through meiosis to the formation of haploid spores. This process is driven by cascading waves of meiosis-specific-gene expression. ABSTRACT In response to nutrient starvation, the budding yeast Saccharomyces cerevisiae abandons mitotic proliferation and embarks on a differentiation process that leads through meiosis to the formation of haploid spores. This process is driven by cascading waves of meiosis-specific-gene expression. The early meiosis-specific genes are repressed during mitotic proliferation by the DNA-binding protein Ume6 in combination with repressors Rpd3 and Sin3. The expression of meiosis-specific transcription factor Ime1 leads to activation of the early meiosis-specific genes. We investigated the stability and promoter occupancy of Ume6 in sporulating cells and determined that it remains bound to early meiosis-specific gene promoters when those genes are activated. Furthermore, we find that the repressor Rpd3 remains associated with Ume6 after the transactivator Ime1 has joined the complex and that the Gcn5 and Tra1 components of the SAGA complex bind to the promoter of IME2 in an Ime1-dependent fashion to induce transcription of the early meiosis-specific genes. Our investigation supports a model whereby Ume6 provides a platform allowing recruitment of both activating and repressing factors to coordinate the expression of the early meiosis-specific genes in Saccharomyces cerevisiae.
Association between serum indoxyl sulfate levels with carotid-femoral pulse wave velocity in patients with chronic kidney disease

Abstract Background The role of indoxyl sulfate (IS), an important protein-bound uremic toxin, in arterial stiffness (AS) in patients with chronic kidney disease (CKD) is unclear. Materials and methods We investigated the association between serum IS levels and AS in a cross-sectional study of 155 patients with CKD. Patients in the AS group was defined as carotid-femoral pulse wave velocity (cfPWV) value >10 m/s measured by a validated tonometry system (SphygmoCor), while values ≤10 m/s were regarded as without AS group Serum IS was measured by liquid chromatography–mass spectrometry analysis. Results Of these CKD patients, AS was present in 51 (32.9%) patients, who were older, had a higher rate of diabetes, higher systolic blood pressure (SBP), and higher IS levels compared to those without AS. By multivariable logistic regression analysis, IS (adjusted odds ratio [aOR] 1.436, 95% confidence interval [CI] 1.085–1.901, p = 0.011), age (aOR 1.058, 95% CI 1.021–1.097, p = 0.002), and SBP (aOR 1.019, 95%CI 1.000–1.038, p = 0.049) were independent predictors of AS. By multivariable stepwise linear regression analysis, logarithmically transformed IS, age, DM, and SBP were significantly correlated with cfPWV. The area under the receiver-operating characteristic curve for serum log-IS was 0.677 (95%CI 0.598–0.750, p = 0.0001) to predict the development of AS in patients with CKD. Conclusion These finding demonstrate that in addition to older and higher SBP, a high serum IS level is a significant biomarker associated with AS in patients with CKD.
Trust in artificial intelligence within production management – an exploration of antecedents

Abstract Industry 4.0, big data, predictive analytics, and robotics are leading to a paradigm shift on the shop floor of industrial production. However, complex, cognitive tasks are also subject of change, due to the development of artificial intelligence (AI). Smart assistants are finding their way into the world of knowledge work and require cooperation with humans. Here, trust is an essential factor that determines the success of human-AI cooperation. Within this article, an analysis within production management identifies possible antecedent variables on trust in AI and evaluates these due to interaction scenarios with AI. The results of this research are five antecedents for human trust in AI within production management. From these results, preliminary design guidelines are derived for a socially sustainable human-AI interaction in future production management systems. Practitioner summary: In the future, artificial intelligence will assist cognitive tasks in production management. In order to make good decisions, humans trust in AI has to be well calibrated. For trustful human-AI interactions, it is beneficial that humans subjectively perceive AI as capable and comprehensible and that they themselves are digitally competent.
Application of Physiologically Based Pharmacokinetic‐Pharmacodynamic Modeling in Preterm Neonates to Guide Gentamicin Dosing Decisions and Predict Antibacterial Effect

Clinical studies in preterm neonates are rarely performed due to ethical concerns and difficulties associated with trials and recruitment. Consequently, dose selection in this population is primarily empirical. Scaling neonatal doses from adult doses does not account for developmental changes and may not accurately predict drug kinetics. This is especially important for gentamicin, a narrow therapeutic index aminoglycoside antibiotic. While gentamicin's bactericidal effect is associated with its peak plasma concentration, keeping trough concentrations below 1 µg/mL prevents toxicity and also helps to counteract adaptive resistance in bacteria such as Escherichia coli. In this study, physiologically based pharmacokinetic‐pharmacodynamic (PBPK‐PD) modeling was used to support and/or guide dosing decisions and to predict the antibacterial effect in preterm neonates. A gentamicin PBPK model was successfully verified in healthy adults and preterm neonates across all gestational ages. Clinical data from a neonatal intensive care unit at NYU Langone Hospital–Long Island was used to identify dosing regimens associated with increased incidence of elevated gentamicin trough concentrations in different preterm patient cohorts. Model predictions demonstrated that a higher dose with an extended‐dosing interval (every 36 hours) in neonates with a postmenstrual age of 30 to 34 weeks and ≥35 weeks, with postnatal age 8 to 28 days and 0 to 7 days, respectively, were more likely to have a trough <1 µg/mL when compared with once‐daily (every 24 hours) dosing. PBPK‐PD modeling suggested that a higher dose administered every 36 hours may provide effective antibacterial therapy.
“The Doctor Says You Cannot Have [Buprenorphine]” Autonomy and Use of Prescribed or Non-Prescribed Buprenorphine

Abstract Background People may overcome barriers to professional buprenorphine treatment by using non-prescribed buprenorphine (NPB) to manage opioid use disorder (OUD). Little is known about how people perceive NPB differently than formal treatment. This qualitative study investigated how and why people use NPB as an alternative to formal treatment. Methods In-depth, semi-structured interviews were conducted with participants of harm reduction agencies (N = 22) who had used buprenorphine. Investigators independently coded transcribed interviews, generating themes through iterative reading and analysis of transcripts. Results Three main factors drove decisions about prescribed and non-prescribed buprenorphine use: 1) autonomy; 2) treatment goals; and 3) negative early experiences with NPB. An overarching theme from our analysis was that participants valued autonomy in seeking to control their substance use. NPB was a valuable tool toward this goal and professional OUD treatment could impede autonomy. Participants mostly used NPB to “self-manage” OUD symptoms. Many participants had concerns about long-term buprenorphine treatment and instead used NPB over short periods of time. Several participants also reported negative experiences with NPB, including symptoms of withdrawal, which then deterred them from seeking out professional treatment. Conclusions These results support prior studies showing that people use NPB to self-manage withdrawal symptoms and to reduce use of illicit opioids. Despite these benefits, participants focused on short-term goals and negative consequences were common. Increasing buprenorphine treatment engagement may require attention to patients’ sense of autonomy, and also assurance that long-term treatment is safe, effective, and reliably accessible.
Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab.

Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from 2 locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in > 5% but < 50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the non-heterogenous subgroup and 0% in the heterogenous group (p<0.0001, adjusted for hormone receptor status). Single cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 non-amplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies.
Molecular dynamics reveals formation path of benzonitrile and other molecules in conditions relevant to the interstellar medium

Significance Understanding how aromatic molecules are formed in the harsh environment of the interstellar medium has long presented a significant unsolved puzzle to scientists. This paper investigates how small aromatic molecules and aromatic nitrogen heterocycles (as well as nonaromatic molecules) are formed from van der Waals clusters upon ionization. Applying ab initio molecular dynamics, we demonstrate that when the clusters contain acetylene and cyanoacetylene—some of the building blocks found in Taurus Molecular Cloud-1—the formation of benzonitrile cation can be predicted. Our results also envisage the formation of other important compounds, including a bicyclic structure, and can help facilitate astronomy’s search for additional aromatic molecules in the interstellar medium. Polycyclic aromatic hydrocarbons and polycyclic aromatic nitrogen heterocycles are believed to be widespread in different areas of the interstellar medium. However, the astronomical detection of specific aromatic molecules is extremely challenging. As a result, only a few aromatic molecules have been identified, and very little is known about how they are formed in different areas of the interstellar medium. Recently, McGuire et al. [Science 359, 202–205 (2018)] detected the simple aromatic molecule benzonitrile in Taurus Molecular Cloud-1. Although benzonitrile has been observed, the molecular mechanism for its formation is still unknown. In this study, we use quantum chemistry and ab initio molecular dynamics to model ionization processes of van der Waals clusters containing cyanoacetylene and acetylene molecules. We demonstrate computationally that the clusters' ionization leads to molecular formation. For pure cyanoacetylene clusters, we observe bond formation among two and three monomer units, whereas in mixed clusters, bond formation can also occur in up to four units. We show that the large amount of energy available to the system after ionization can lead to barrier crossing and the formation of complex molecules. Our study reveals the rich chemistry that is observed upon ionization of the clusters, with a wide variety of molecules being formed. Benzonitrile is among the observed molecules, and we study the potential energy path for its formation. These results also offer insights that can guide astronomers in their search for aromatic molecules in the interstellar medium.
Spatial neglect treatment: The brain’s spatial-motor Aiming systems

ABSTRACT Animal and human literature supports spatial-motor “Aiming” bias, a frontal-subcortical syndrome, as a core deficit in spatial neglect. However, spatial neglect treatment studies rarely assess Aiming errors. Two knowledge gaps result: spatial neglect rehabilitation studies fail to capture the impact on motor-exploratory aspects of functional disability. Also, across spatial neglect treatment studies, discrepant treatment effects may also result from sampling different proportions of patients with Aiming bias. We review behavioural evidence for Aiming spatial neglect, and demonstrate the importance of measuring and targeting Aiming bias for treatment, by reviewing literature on Aiming spatial neglect and prism adaptation treatment, and presenting new preliminary data on bromocriptine treatment. Finally, we review neuroanatomical and network disruption that may give rise to Aiming spatial neglect. Because Aiming spatial neglect predicts prism adaptation treatment response, assessment may broaden the ability of rehabilitation research to capture functionally-relevant disability. Frontal brain lesions predict both the presence of Aiming spatial neglect, and a robust response to some spatial neglect interventions. Research is needed that co-stratifies spatial neglect patients by lesion location and Aiming spatial neglect, to personalize spatial neglect rehabilitation and perhaps even open a path to spatial retraining as a means of promoting better mobility after stroke.
Functional Disability Among Older Versus Younger Adults With Advanced Non–Small-Cell Lung Cancer

PURPOSE: To determine patient and disease characteristics associated with functional disability among adults with advanced non–small-cell lung cancer (NSCLC). METHODS: In a prospective cohort of participants newly diagnosed with advanced NSCLC and beginning systemic treatment, functional disability in usual activities, mobility, and self-care was measured using the EuroQol-5D-5L at baseline. Demographics, comorbidities, brain metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), and psychologic variables (depression [Patient Health Questionnaire-9] and anxiety [Generalized Anxiety Disorder 7-item scale]) were captured. Patients were classified into two disability groups (none-slight or moderate-severe) on the basis of total functional status scores. Differences between disability groups were determined (chi-square and t tests). Associations between patient characteristics and baseline disability were assessed using logistic regression. RESULTS: Among 173 participants, mean age was 63.3 years, 56% were male, 83% had ECOG PS 0-1, and 41% had brain metastases. Baseline disability was present in 39% of participants, with patients having moderate to severe disability in usual activities (37.6%), mobility (26.6%), and self-care (5.2%). Depressive and/or anxiety symptoms ranged from none to severe (Patient Health Questionnaire 9-item scale M = 6.5, SD = 5.3). Depressive symptoms were the only characteristic associated with a higher odds of baseline disability (adjusted odds ratio [aOR]: 1.26; 95% CI, 1.15 to 1.38; P < .001). Participants with poorer ECOG PS (aOR: 4.64; 95% CI, 1.84 to 11.68; P = .001) and depressive symptoms (aOR: 1.15; 95% CI, 1.07 to 1.24; P < .001) had higher odds of moderate-severe mobility disability compared with the none-slight disability group. CONCLUSION: More than one third of all adults with advanced NSCLC have moderate-severe functional disability at baseline. Psychologic symptoms were significantly associated with moderate-severe baseline disability.