Miracle-dz/UniFAR-FTUs huggingface dataset:
Current and Common Definitions of Treatment-Resistant Depression: Findings from a Systematic Review and Qualitative Interviews

Objective: No universal definition for treatment-resistant depression (TRD) exists. This lack of consensus reduces the generalizability of study findings and limits the ability to study TRD. In addition, anecdotally, there may be a difference between the definitions of TRD within research and those applied in practice. Thus, the objective of this work was to identify current common definitions of TRD used in both research and clinical practice. Method: A systematic review of published literature was conducted to document TRD definitions. Extracted data were grouped based on patient cohort and method of defining TRD. Validation studies were narratively summarized. Interviews with 6 key informants were conducted to understand how definitions are applied in practice. Results: In total, 155 definitions for TRD were identified in the published literature, and 48.4% of all definitions specified requirement of at least 2 treatment failures. Key informant interviews indicated the concept of TRD is rarely employed in clinical practice. Instead, concepts like “complex needs,” “struggling with their disease,” and “chronic” are used. When asked directly about how they would define TRD, interview participants said an adequate trial of psychotherapy as well as an adequate trial of at least 2 to 3 antidepressant medications. Conclusions: There is no universally accepted definition of TRD, and substantial heterogeneity exists. This study indicates discordance between the use of the term in research and clinical practice, with several key informants emphasizing that the terminology is rarely used in their clinical experience. Development of a shared, common definition across practice and research is required.
Mild Cognitive Impairment in Patients with Moderate to Severe Chronic Plaque Psoriasis

Background: Psoriasis is frequently associated with cardiometabolic comorbidities and depression that are risk factors for cognitive impairment. Objective: To investigate cognitive performance in psoriatic patients. Method: Cognitive performances were assessed by neuropsychological tests in 41 patients with psoriasis and 37 controls. Diagnostic criteria for mild cognitive impairment (MCI) were (1) subjective complaint of a memory deficit, confirmed by a relative or caregiver, (2) pathological performance on neuropsychological tests investigating cognitive domains, (3) normal performance of daily living activities and (4) no dementia. Neuroimaging was studied by high-field magnetic resonance imaging and cortical thickness analysis. Results: MCI was found in 18 out of 41 (44%) patients with psoriasis compared to 4 out of 37 (11%) controls (p = 0.002). In particular, patients with psoriasis had lower scores in the delayed recall of the Rey Auditory Verbal Learning Test (p = 0.04), Backwards Digit Span Test (p = 0.002), Weigl's Sorting Test (p = 0.01) and Trail Making Test B (p = 0.008). In the 7 patients submitted to cortical thickness analysis, a reduction in brain thickness in parahippocampal, superior temporal and frontal gyri of the left hemisphere was observed. Conclusions: Patients with psoriasis may have a precocious impairment of long-term verbal memory, executive functions and attention.
Malignant hepatic tumors: short-term reproducibility of apparent diffusion coefficients with breath-hold and respiratory-triggered diffusion-weighted MR imaging.

PURPOSE To prospectively evaluate the reproducibility of apparent diffusion coefficient (ADC) measurement in malignant hepatic tumors and to examine the influence of imaging methods, lesion location, and lesion size on the reproducibility of ADC measurement. MATERIALS AND METHODS The institutional review board approved the study protocol, and informed consent was obtained. Forty-nine patients underwent both breath-hold and respiratory-triggered diffusion-weighted (DW) magnetic resonance imaging on a 1.5-T system twice. Two independent readers measured the ADC of the largest malignant hepatic tumor for each patient on each image sets. Mean ADCs were compared between repeated acquisitions and imaging techniques by using the paired t test. Reproducibility of the ADC measurement and interobsever agreement were determined by using 95% Bland-Altman limits of agreement and intraclass correlation coefficients (ICCs). The effects of the imaging technique, lesion location, and lesion size on the reproducibility of the ADC measurements were assessed by comparing ICCs by using the z test. RESULTS There were no significant differences in the mean ADC between repeated acquisitions for breath-hold ([1.266-1.275] x 10(-3) mm(2)/sec vs [1.285-1.290] x 10(-3) mm(2)/sec; P = . 572-. 634) or respiratory-triggered ([1.487-1.502] x 10(-3) mm(2)/sec vs [1.421-1.441] x 10(-3) mm(2)/sec; P = . 073-. 091) DW MR imaging. The mean ADCs measured by using the respiratory-triggered method ([1.421-1.502] x 10(-3) mm(2)/sec) were significantly higher than those measured by using the breath-hold method ([1.266-1.290] x 10(-3) mm(2)/sec) (P < or = .001). The 95% limits of agreement between ADCs measured on repeated DW images were 28.7%-31.3% of the mean, and those between ADCs measured by two readers were 14.6%-22.5% of the mean. ADC measurement of malignant hepatic tumors tended to be more reproducible for right-lobe than for left-lobe lesions and for larger rather than smaller lesions. CONCLUSION Changes in ADCs of less than approximately 30% fall into the range of measurement error. Imaging technique significantly affected ADCs of malignant hepatic tumors. Lesion location and size are potentially influential on the reproducibility of ADC measurement.
Prognostic value and staging categories of anatomic masticator space involvement in nasopharyngeal carcinoma: a study of 924 cases with MR imaging.

PURPOSE To identify the prognostic value and staging categories of masticator space involvement in nasopharyngeal carcinoma (NPC) as determined with anatomic criteria ("anatomic masticator space involvement") to determine whether it is necessary for the masticator space described with criteria of the American Joint Committee on Cancer to exclude the medial and lateral pterygoid muscles. MATERIALS AND METHODS This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. NPC was diagnosed in 924 patients with magnetic resonance (MR) imaging, and medical records and imaging studies were retrospectively analyzed. The overall survival, local relapse-free survival, and distant metastasis-free survival of these patients were analyzed by using the Kaplan-Meier method; differences were compared by using the log-rank test. RESULTS The frequency of anatomic masticator space involvement was 19.7% (182 of 924 patients). With use of multivariate analysis, anatomic masticator space involvement was identified as an independent prognostic factor for overall survival (P = .02). In addition, anatomic masticator space involvement was associated with a marginally significant decrease in local relapse-free survival (P = .05); however, it had no effect on distant metastasis-free survival. There were no statistically significant differences between different degrees of anatomic masticator space involvement with regard to overall survival and local relapse-free survival in NPC (P = .34 and P = .54, respectively) or between T3 or T4 disease and anatomic masticator space involvement with regard to overall survival and local relapse-free survival (P = .63 and P = .44, respectively). CONCLUSION Anatomic masticator space involvement affects the overall survival and local relapse-free survival of patients with NPC. When masticator space involvement includes the medial and lateral pterygoid muscles, the disease should be classified as stage T4.
Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress–Gene Response

Background: The human genome folds in 3 dimensions to form thousands of chromatin loops inside the nucleus, encasing genes and cis-regulatory elements for accurate gene expression control. Physical tethers of loops are anchored by the DNA-binding protein CTCF and the cohesin ring complex. Because heart failure is characterized by hallmark gene expression changes, it was recently reported that substantial CTCF-related chromatin reorganization underpins the myocardial stress–gene response, paralleled by chromatin domain boundary changes observed in CTCF knockout. Methods: We undertook an independent and orthogonal analysis of chromatin organization with mouse pressure-overload model of myocardial stress (transverse aortic constriction) and cardiomyocyte-specific knockout of Ctcf. We also downloaded published data sets of similar cardiac mouse models and subjected them to independent reanalysis. Results: We found that the cardiomyocyte chromatin architecture remains broadly stable in transverse aortic constriction hearts, whereas Ctcf knockout resulted in ≈99% abolition of global chromatin loops. Disease gene expression changes correlated instead with differential histone H3K27-acetylation enrichment at their respective proximal and distal interacting genomic enhancers confined within these static chromatin structures. Moreover, coregulated genes were mapped out as interconnected gene sets on the basis of their multigene 3D interactions. Conclusions: This work reveals a more stable genome-wide chromatin framework than previously described. Myocardial stress–gene transcription responds instead through H3K27-acetylation enhancer enrichment dynamics and gene networks of coregulation. Robust and intact CTCF looping is required for the induction of a rapid and accurate stress response.
Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer

Purpose: To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC). Experimental Design: We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen. Results: We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro. We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro. Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo. Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA (P = 0.002) and validation (P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset. Conclusions: We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy.
Characterisation of K+ Currents in the C8-B4 Microglial Cell Line and their Regulation by Microglia Activating Stimuli

Microglia are the intrinsic immune cells of the brain. As such, they are crucially involved in neuro-protection as well as neuro-degeneration. Their activation leads to the induction of cytokine and chemokine release, the production of reactive oxygen species and nitric oxide and an increased outward potassium conductance. In this study, we focus our interest on potassium currents and channels in the C8-B4 murine microglial cell line and compare them with those of primary cultured microglia from neo-natal mice. Using the whole cell patch-clamp technique, we have recorded prominent inward and outward rectifying voltage-dependent potassium currents but no calcium-activated potassium currents. Using pharmacological, biophysical and molecular approaches, we demonstrate that Kv1.3 and Kir2.1 channels underlie outward and inward rectifying potassium currents, respectively. In contrast to primary cultured microglia, we observe that an outward rectifying potassium current is already present in unstimulated C8-B4 cells. However, as seen in primary microglia, this current increases after treatment with LPS, IFN-γ, TGF-β and GM-CSF and is suppressed by treatment with protein kinase inhibitors. Our study indicates that the C8-B4 cell line shows similar though not identical potassium channel properties compared to primary cultured microglia. We demonstrate that despite some differences, they are a useful tool to study potassium currents in microglial activation mechanisms by means of electrophysiological methods without the need for preparation of cells as primary culture.
Determinants of early ponderal and statural growth in full-term infants in the EDEN mother-child cohort study.

BACKGROUND Growth velocity in the first months of postnatal life has been associated with later overweight and obesity. OBJECTIVE We analyzed prenatal and postnatal factors in association with weight, length, and growth velocities in the first 3 mo of life. DESIGN We estimated weight, length, and instantaneous weight- and length-growth velocities (in g/d and mm/d) in 1418 term infants at 1 and 3 mo of age and evaluated the following potential determinants: maternal prepregnancy body mass index (BMI), 1-h plasma glucose concentrations during pregnancy, smoking, socioeconomic status, parity, paternal BMI, parental heights, and infant feeding, gestational age, and sex. RESULTS Maternal obesity and plasma glucose concentrations were associated with the weights and lengths of offspring at birth but not at 1 and 3 mo after birth. In contrast, there was no association between paternal BMI and anthropometric measures of offspring at birth, but by 3 mo of age infants of obese fathers had significantly higher weights and weight-growth velocities than did infants of fathers with a normal BMI. Maternal weight gain was a significant predictor of weight at birth and 3 mo of age. Exclusively breastfed infants had a slower weight-growth velocity as early as 1 mo of age compared with exclusively formula-fed infants. CONCLUSIONS In the first 3 mo of life, the positive associations between maternal obesity, plasma glucose concentrations, and infant anthropometric measures at birth seem to progressively fade away, whereas the emerging association with paternal BMI may indicate an early postnatal influence of paternal genetics. Among the determinants we evaluated, some are potentially modifiable, such as maternal gestational weight gain and infant feeding. The identification of optimal patterns of growth remains crucial before providing any clinical recommendations.
Sarcopenia for predicting mortality among elderly nursing home residents

Abstract Little is known about the prognostic value of the strength, assistance walking, rise from a chair, climb stairs, and falls questionnaire (SARC-F) and SARC-F combined with calf circumference (SARC-CalF) among elderly nursing home residents. To compare the prognostic value of SARC-F and SARC-CalF for mortality in this population. We conducted a prospective study in four nursing homes in western China. Sarcopenia was estimated using SARC-F and SARC-CalF, respectively. Nutrition status, activities of daily living, and other covariates were evaluated. The survival status was collected via medical records and telephone interviews at the 12th month after the baseline investigation. We used multivariate Cox proportional-hazard models to calculate the hazard ratio (HR) and 95% confidence interval (CI) for 1-year all-cause mortality by SARC-F-defined sarcopenia and SARC-CalF-defined sarcopenia, separately. We included 329 participants (median age: 85 years). The prevalences of SARC-F-defined sarcopenia and SARC-CalF-defined sarcopenia were 39.8% and 46.8%, respectively. During the 1-year follow-up period, 73 participants (22.7%) died. The mortality was 29.0% and 18.3% in the participants with or without SARC-F-defined sarcopenia, respectively (P = .025). The mortality was 26.6% and 19.0% in the participants with or without SARC-CalF-defined sarcopenia, respectively (P = .105). After adjusted for the relevant confounders including malnutrition, SARC-F-defined sarcopenia was independently associated with an increased risk of 1-year mortality (adjusted HR: 2.08; 95% CI: 1.27–3.42). However, SARC-CalF-defined sarcopenia was not an independent predictor of 1-year mortality (adjusted HR: 1.54; 95% CI: 0.95–2.47). Sarcopenia is highly prevalent in Chinese elderly nursing home residents according to SARC-F or SARC-CalF. SARC-F-defined sarcopenia appears to be better for predicting the 1-year mortality of Chinese nursing home residents than SARC-CalF-defined sarcopenia.
Sports-Related Concussion: Neurometabolic Aspects

Abstract Concussion is a transitory brain injury resulting from a blow to the head. Concussion is considered a mild traumatic brain injury (mTBI), which is self-limited. Repetitive mTBI has been associated with chronic, progressive neurological damage. Extreme biochemical changes occur in neuron cells as a result of mTBI. These metabolic disturbances may reflect the symptoms observed in patients who had suffered concussions. However, it has been difficult to correlate clinical signs and symptoms. Currently, there are no laboratory tests to diagnose concussion, though several biomarkers are being investigated. Further studies are needed to elucidate the biochemical details of the metabolic cascade and the associated time frame, which will help determine when an athlete can safely return to the game.
Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of TP53 in HNSCC occurs in 60% to 80% of non–HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms. Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival. Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo. A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC. Clin Cancer Res; 23(21); 6541–54. ©2017 AACR.
Controlled Release of Alendronate from Polymeric Films

Bisphosphonate drugs alter the balance of bone resorption and formation, leading to a net increase in bone density. Therefore, these drugs are commonly used to treat osteoporosis or as an adjunct to cancer chemotherapy. Local delivery of bisphosphonates, such as alendronate, from polymeric films has the potential to improve efficacy and decrease side-effects common to oral bisphosphonate therapy. Alendronate was effectively encapsulated in film formulations composed of poly(lactic-co-glycolic acid) (PLGA) blended with poly(DL-lactic acid)-block-methoxy poly(ethylene glycol) (diblock co-polymer) and the films were characterized for elasticity, swelling, thermal and drug-release properties. Increasing the proportion of diblock co-polymer in the formulation decreased the glass transition temperature of PLGA, allowing for improved handling via increases in film elasticity. Immersion in aqueous media caused a rapid stiffening and swelling of the films. The inclusion of diblock co-polymer increased the rate of drug release from the films over a 3-week period. Drug-loaded polymeric films containing 0.25% alendronate increased osteoblast viability after 4 days compared to polymer alone. After 5 weeks, there was a significant increase in alkaline phosphatase activity and calcium nodule formation in osteoblasts grown on films containing 1.25% alendronate in 5% diblock co-polymer in PLGA.
REACTIVITY OF OH AND CH3OH BETWEEN 22 AND 64 K: MODELING THE GAS PHASE PRODUCTION OF CH3O IN BARNARD 1b

In recent years, ultra-low temperature chemical kinetic experiments have demonstrated that some gas-phase reactions are much faster than was previously thought. One example is the reaction between OH and CH3OH, which has recently been found to be accelerated at low temperatures yielding CH3O as its main product. This finding raised the question of whether or not the CH3O observed in the dense core Barnard 1b could be formed by the gas-phase reaction of CH3OH and OH. Several chemical models including this reaction and grain-surface processes have been developed to explain the observed abundance of CH3O, but they have met with little success. Here, we report for the first time the rate coefficients for the gas-phase reaction of OH and CH3OH down to a temperature of 22 K, which is very close to the temperature in cold interstellar clouds. Two independent experimental set-ups based on the supersonic gas expansion technique coupled to the pulsed laser photolysis laser-induced fluorescence technique were used to determine the rate coefficients in the temperature range 22–64 K. The temperature dependence obtained in this work can be expressed as k(22–64 K) = ( 3.6 ± 0.1 ) × 10 − 12 ( T / 300 K ) − ( 1.0 ± 0.2 ) cm3 molecule−1 s−1. Implementing this expression in a chemical model of a cold, dense cloud results in CH3O/CH3OH abundance ratios similar to or slightly lower than the value of ∼3 × 10−3 observed in Barnard 1b. This finding confirms that the gas-phase reaction between OH and CH3OH is an important contributor to the formation of interstellar CH3O. The role of grain-surface processes in the formation of CH3O, although it cannot be fully neglected, remains controversial.