Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of deep medullary veins in pathogenesis of lacunes: Longitudinal observations from the CIRCLE study

Our purpose is to assess the role of deep medullary veins in pathogenesis of lacunes in patients with cerebral small vessel disease (cSVD). We included patients with baseline and 2.5-year follow-up MRI in CIRCLE study. Susceptibility Weighted Imaging-Phase images were used to evaluate deep medullary veins based on a brain region-based visual score, and T2-Fluid-Attenuated-Inversion-Recovery images were used to evaluate lacunes. Cerebral blood flow and microstructural parameters in white matter hyperintensities and normal appearing white matter were also analyzed. A total of 203 cSVD patients were analyzed and 101 (49.8%) patients had baseline lacunes. Among them, 64 patients had follow-up MRI, including 16 (25.0%) with new lacunes. The patients’ deep medullary veins median score was 9 (7–12). At baseline, high deep medullary veins score was independently associated with the presence of lacunes after adjusting for age, diabetes mellitus, white matter hyperintensities volume and cerebral blood flow or white matter microstructural parameters (all p < 0.001). Longitudinally, high deep medullary veins score was independently associated with new lacunes after adjusting for gender (p < 0.001). The association was also independent of white matter hyperintensities volumes, cerebral blood flow or white matter microstructural parameters (all p < 0.05). Our results suggest that deep medullary veins disruption might be involved in pathogenesis of lacunes.
Synaptic Plasticity at Inhibitory Synapses in the Ventral Tegmental Area Depends upon Stimulation Site

Abstract Drug exposure induces cell and synaptic plasticity within the brain reward pathway that could be a catalyst for progression to addiction. Several cellular adaptations have been described in the ventral tegmental area (VTA), a central component of the reward pathway that is the major source of dopamine release. For example, administration of morphine induces long-term potentiation (LTP) of excitatory synapses on VTA dopamine cells and blocks LTP at inhibitory synapses. Drug-induced synaptic changes have a common endpoint of increasing dopamine cell firing and dopamine release. However, gaining a complete picture of synaptic plasticity in the VTA is hindered by its complex circuitry of efferents and afferents. Most studies of synaptic plasticity in the VTA activated a mixed population of afferents, potentially yielding an incomplete and perhaps misleading view of how drugs of abuse modify VTA synapses. Here, we use midbrain slices from mice and find that electrical stimulation in two different regions induces different forms of plasticity, including two new forms of LTP at inhibitory synapses. High-frequency stimulation (HFS) induces LTP independently of NMDA receptor (NMDAR) activation, and surprisingly, some inhibitory inputs to the VTA also undergo NMDAR-independent LTP after a low-frequency stimulation (LFS) pairing protocol.
Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease

Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017). Based on hepatic expression quantitative trait loci analysis, it has been suggested that MBOAT7 loss of function promotes liver disease progression (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017), but this has never been formally tested. Here we show that Mboat7 loss, but not Tmc4, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. Mboat7 loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.
Can therapeutic strategies prevent and manage dyskinesia in Parkinson’s disease? An update

ABSTRACT Introduction: Dyskinesia is a motor complication of Parkinson’s disease (PD) characterized by clinical heterogeneity and complex pathogenesis and associated with long-term levodopa therapy. Recent and controversial views on the management of PD patients have suggested that overall dyskinesia rates, and particularly troublesome dyskinesia, may be declining due to more conservative levodopa dosing regimens, widespread availability and early introduction of deep brain stimulation, and use of continuous drug delivery strategies. Nevertheless, anti-dyskinetic agents continue to be evaluated in clinical trials and recent efforts have focused on non-dopaminergic drugs. Areas covered: In this review, the authors discuss the clinical phenomenology and current understanding of dyskinesia in PD with a focus on up-to-date therapeutic strategies to prevent and manage these drug-related involuntary movements. Expert opinion: The way dyskinesia in PD is currently managed should be changed and attention should be focused toward a more personalized medicine rather than a one-fits-all-approach. The correct identification of dyskinesia types and tailored treatments are crucial for a better management of these involuntary movements together with a holistic approach which considers additional influencing factors. The future for dyskinesia treatment is likely to be found in non-dopaminergic approaches, first set into motion by the introduction of amantadine.
An independently validated survival nomogram for lower grade glioma.

BACKGROUND Gliomas are the most common primary malignant brain tumor. Diffuse low-grade and intermediate-grade gliomas, which together comprise the lower-grade gliomas [LGG] (WHO grades II and III), present a therapeutic challenge to physicians due to the heterogeneity of their clinical behavior. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a survival nomogram for patients with newly diagnosed LGG. METHODS Data were obtained for newly diagnosed LGG patients from The Cancer Genome Atlas (TCGA) and the Ohio Brain Tumor Study (OBTS) with the following variables: tumor grade (II or III), age at diagnosis, sex, Karnofsky Performance Status (KPS), and molecular subtype (IDH mutant with 1p/19q codeletion [IDHmut-codel], IDH mutant without 1p/19q codeletion [IDHmut-non-codel], IDH wild-type [IDHwt]). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using TCGA data and independently validated using the OBTS data. Models were internally validated using 10-fold cross-validation and externally validated with calibration curves. RESULTS A final nomogram was validated for newly diagnosed LGG. Factors that increased the probability of survival included grade II tumor, younger age at diagnosis, having a high KPS, and the IDHmut-codel molecular subtype. CONCLUSIONS A nomogram that calculates individualized survival probabilities for patients with newly diagnosed LGG could be useful to healthcare providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software for implementing this nomogram is provided: https://hgittleman.shinyapps. io/LGG_Nomogram_H_Gittleman/.
Factors associated with oral health service utilization among adults and older adults in China, 2015-2016.

OBJECTIVES To explore the factors associated with utilization of oral health services among Chinese adults and older adults according to the Andersen Behavior Model. METHODS Data from the 4th National Oral Health Survey (2015-2016) in China were used. A total of 7206 people (3669 adults aged 35-44 years and 3537 older adults aged 65-74 years) were included in our analysis. Oral health service utilization in the past 12 months was the outcome variable. Explanatory variables were selected according to the Andersen Behavior Model. Descriptive statistics and bivariate associations (chi-square tests) were analysed, followed by hierarchical Poisson regression models, which were conducted to determine the factors associated with oral health service utilization. RESULTS In total, 21.4% (95% CI: 19.4%-23.7%) of adults (35-44 years old) and 20.7% (95% CI: 18.6%-22.9%) of older adults (65-74 years old) utilized oral health services in the past 12 months. Nearly 80% of adults (78.7%, 95% CI: 74.0%-82.7%) and more than 90% of older adults (93.7%, 95% CI: 91.0%-95.6%) visited a dentist for treatment. Adults aged 35-44 years old who were female (IRR: 1.15, 95% CI: 1.00-1.33, P = .047), had good oral health knowledge and attitudes (IRR: 1.30, 95% CI: 1.06-1.59, P = .011), perceived their oral health status as fair (IRR:1.51, 95% CI:1.24-1.85, P < .001) or poor/very poor (IRR:2.52, 95% CI:2.01-3.18, P < .001) and had a decayed, missing and filled teeth (DMFT) index >0 (IRR: 1.52, 95% CI: 1.11-2.09, P = .009) were more likely to report dental visits in the past 12 months. Older adults who utilized oral health services tended to be female (IRR: 1.32, 95% CI: 1.09-1.59, P = .004); to be covered by Urban Resident Basic Medical Insurance (URBMI) (IRR: 1.56, 95% CI: 1.18-2.05, P = .002), Urban Employee Basic Medical Insurance (UEBMI) (IRR: 1.69, 95% CI: 1.32-2.16, P < .001) or government medical insurance (GMI) (IRR: 1.03, 95% CI:1.01-2.16, P = .044); to have a high education level (IRR: 1.37, 95% CI: 1.08-1.74, P = .010); to have an income level in the 2nd tertile (IRR: 1.44, 95% CI: 1.13-1.84, P = .003) or 3rd tertile (IRR:1.52, 95% CI:1.18-1.95, P = .001); and to perceive their oral health status as poor or very poor (IRR: 1.53, 95% CI: 1.21-1.95, P = .001). CONCLUSIONS Sex and self-perceived oral health status were associated with oral health utilization among Chinese population. Additionally, for older adults, education level, household income and insurance coverage were determinants of dental service use. These findings can aid in creating more targeted policies to increase the use of dental services by Chinese adults.
Measurement of organ-specific and acute-phase blood protein levels in early Lyme disease

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that 1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or 2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2 and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.
Molecular Detection of Filamentous Fungi in Formalin-Fixed Paraffin-Embedded Specimens in Invasive Fungal Wound Infections Is Feasible with High Specificity

Trauma-related invasive fungal wound infections (IFIs) are associated with significant morbidity and mortality. Early identification and treatment are critical. Traditional identification methods (e.g., fungal cultures and histopathology) can be delayed and insensitive. We assessed a PCR-based sequencing assay for rapid identification of filamentous fungi in formalin-fixed paraffin-embedded (FFPE) specimens obtained from combat casualties injured in Afghanistan. ABSTRACT Trauma-related invasive fungal wound infections (IFIs) are associated with significant morbidity and mortality. Early identification and treatment are critical. Traditional identification methods (e.g., fungal cultures and histopathology) can be delayed and insensitive. We assessed a PCR-based sequencing assay for rapid identification of filamentous fungi in formalin-fixed paraffin-embedded (FFPE) specimens obtained from combat casualties injured in Afghanistan. Blinded FFPE specimens from cases (specimens positive on histopathology) and controls (specimens negative on histopathology) were submitted for evaluation with a panfungal PCR. The internal transcribed spacer 2 (ITS2) region of the fungal ribosomal repeat was amplified and sequenced. The PCR results were compared with findings from histopathology and/or culture. If injury sites contributed multiple specimens, findings for the site were collapsed to the site level. We included 64 case subjects (contributing 95 sites) and 102 controls (contributing 118 sites). Compared to histopathology, panfungal PCR was specific (99%), but not as sensitive (63%); however, sensitivity improved to 83% in specimens from sites with angioinvasion. Panfungal PCR identified fungi of the order Mucorales in 33 of 44 sites with angioinvasion (75%), whereas fungal culture was positive in 20 of 44 sites (45%). Saksenaea spp. were the dominant fungi identified by PCR in specimens from angioinvasion sites (57%). Panfungal PCR is specific, albeit with lower sensitivity, and performs better at identifying fungi of the order Mucorales than culture. DNA sequencing offers significant promise for the rapid identification of fungal infection in trauma-related injuries, leading to more timely and accurate diagnoses.
Diffusion-Weighted Imaging of Breast Cancer: Correlation of the Apparent Diffusion Coefficient Value with Pathologic Prognostic Factors.

Objective The aim was to evaluate relationship between apparent diffusion coefficient (ADC) values with pathologic prognostic factors in breast carcinoma (BC). Materials and Methods 83 patients were enrolled in this study. Prognostic factors included age, tumor size, expression of estrogen receptor (ER) and progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), nuclear grade (NG), lymph node involvement and histologic type. The relationship between ADC and prognostic factors was determined using Independent sample t-test, ANOVA, Pearson correlation and relative operating characteristics (ROC) analysis. Results There was no significant difference between ADC and prognostic factors, including age, tumor size, ER, HER2 and histologic type. The PR-positive tumors (p=0.03) and axillary lymph node involvement (p=0.000) showed a significant association with lower ADC values. The ADC values were significantly lower in high-grade tumors than low-grade tumors (p=0.000). ROC analysis showed an optimal ADC threshold of 0.66 (×10-3 mm2/s) for differentiating low-grade tumors from high-grade tumors (sensitivity, 85.5%; specificity, 81%; area under curve, 0.90). Conclusion The lower ADC values of BC were significantly associated with positive expression of PR, LN positivity and high-grade tumor. Especially, ADC values were valuable in predicting NG subgroups.
PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer

The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; p = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials.
Experimental Modeling of Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases. Animal models (mainly mouse and zebrafish) have already significantly contributed to understanding the role of several acquired and germline mutations in MPN oncogenic signaling. Novel technologies such as induced pluripotent stem cells (iPSCs) and precise genome editing (using CRISPR/Cas9) contribute to the emerging understanding of MPN pathogenesis and clonal architecture, and form a convenient platform for evaluating drug efficacy. In this overview, the genetic landscape of MPN is briefly described, with an attempt to cover the main discoveries of the last 15 years. Mouse and zebrafish models of the driver mutations are discussed and followed by a review of recent progress in modeling MPN with patient-derived iPSCs and CRISPR/Cas9 gene editing.
Neuroprotective and Antioxidant Effect of Naringenin-Loaded Nanoparticles for Nose-to-Brain Delivery

Parkinson’s disease (PD) is a neurodegenerative disorder resulting in a decreased nigrostriatal availability of dopamine. Oxidative stress is one factor contributing to PD. Naringenin (NAR), a flavonoid, is a potent antioxidant shown to be beneficial in experimental PD. The clinical development of NAR has been hampered due to its low bioavailability resulting from gastrointestinal degradation, inefficient permeability, and low aqueous solubility. The objective of the present research was to formulate and characterize naringenin-loaded chitosan nanoparticles (NAR NPs) for nose-to-brain delivery. The cellular uptake, cytotoxicity, and neuroprotective effects of NAR NPs were determined using the SH-SY5Y cell line in vitro. NAR NPs were prepared using the ionic gelation method and characterized by zetasizer, transmission electron microscopy (TEM), and field emission microscopy (FESEM). The average particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, and 24 h in vitro release profile were 87.6 ± 8.47 nm, 0.31 ± 0.04, 15.36 ± 2.05 mV, 91.12 ± 2.99%, and 54.80 ± 4.22%, respectively. The percentage NAR permeation through nasal mucosa from NPs was found to be 67.90 ± 0.72%. Cellular uptake of prepared NPs was confirmed by fluorescence microscopy. Neuroprotective activity of NAR NPs was evaluated through viability assays and by estimating reactive oxygen species (ROS) levels. NAR NPs showed enhanced neuroprotective ability and antioxidant effect against 6-OHDA-induced neurotoxicity in SH-SY5Y cells. However, animal studies are necessary to establish the potential of NAR NPs to be an effective carrier for the treatment of PD for nose-to-brain delivery.
Oxidative stress differentially induces tau dissociation from neuronal microtubules in neurites of neurons cultured from different regions of the embryonic Gallus domesticus brain

Abnormal phosphorylation of microtubule‐associated proteins such as tau has been shown to play a role in neurodegenerative disorders. It is hypothesized that oxidative stress‐induced aggregates of hyperphosphorylated tau could lead to the microtubule network degradation commonly associated with neurodegeneration. We investigated whether oxidative stress induced tau hyperphosphorylation and focused on neurite degradation using cultured neurons isolated from the embryonic chick brain as a model system. Cells were isolated from the cerebrum, cerebellum, and tectum of 14‐day‐old chicks, grown separately in culture, and treated with tert‐Butyl hydroperoxide (to simulate oxidative stress) for 48 hr. Relative expression and localization of tau or phospho‐tau and β‐tubulin III in neurites were determined using quantitative immunocytochemistry and confocal microscopy. In untreated cells, tau was tightly colocalized with β‐tubulin III. Increasing levels of oxidative stress induced an increase in overall tau expression in neurites of cerebral and tectal but not the cerebellar neurons, coupled with a decrease in phospho‐tau expression in tectal but not the cerebral or cerebellar neurons. In addition, oxidative stress induced the degeneration of the distal ends of the neurites and redistribution of phospho‐tau toward the neuronal soma in the cerebral but not the tectal and cerebellar neurons. These results suggest that oxidative stress induces changes in tau protein that precede cytoskeletal degradation and neurite retraction. Additionally, there is a differential susceptibility of neuronal subpopulations to oxidative stress, which may offer potential avenues for investigation of the cellular mechanisms underlying the differential manifestations of neurodegenerative disorders in different regions of the brain.