Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma

Resistance to standard cisplatin‐based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin‐4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways. Initially, immunohistochemistry analysis was conducted in specimens from patients with ESCC (n = 120). In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5‐fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively). Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45–18.03; P = 0.02, HR = 3.74, 95% CI, 1.19–11.76, respectively]. Suppression of MRE11A expression was associated with cisplatin resistance in ESCC cell lines. Additionally, MRE11A was found to be ubiquitinated after cisplatin treatment. We observed an amplification of UBQLN4 gene copy numbers and an increase in UBQLN4 protein levels in ESCC tissues. Binding of UBQLN4 to ubiquitinated‐MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels following DNA damage and promoting cisplatin resistance. In summary, MRE11A and UBQLN4 protein levels can serve as predictors for NAC response and as prognostic markers in ESCC patients.
Nursing professionals' mental well‐being and workplace impairment during the COVID‐19 crisis: A Network analysis

Abstract Aim To investigate the effects of years of nursing experience and mental health on work impairment among nurses during the COVID‐19 crisis. Background During the COVID‐19 crisis, nurses experience a greater psychological burden than other health care workers. Studies have not yet investigated the effects of years in nursing and mental health on potential work impairment during the COVID‐19 crisis in nurses. Methods A survey was administered to 83 nurses on active duty during the COVID‐19 crisis. The graphical LASSO and the DAG helped estimate the associations between years of nursing experience, mental health and work impairment. Results A moderate negative correlation emerged between years of nursing experience, avoidance and work impairment. A direct effect was observed between anxiety and work impairment. A moderate positive correlation emerged between anxiety, depression and work impairment. An indirect effect was observed between depression, burnout, insomnia, years of nursing experience and work impairment. Conclusions In the present sample, nurses' work impairment decreased with greater years of nursing experience and increased with higher anxiety, depression, burnout and avoidance levels. Implications for Nursing Management These findings can help design effective infectious disease management programmes for students and professionals in nursing to prevent breakdowns and avoid work impairment.
Nebulized antibiotics for ventilator-associated pneumonia: methodological framework for future multicenter randomized controlled trials

Purpose of review Although experimental evidence supports the use of nebulized antibiotics in ventilator-associated pneumonia (VAP), two recent multicenter randomized controlled trials (RCTs) have failed to demonstrate any benefit in VAP caused by Gram-negative bacteria (GNB). This review examines the methodological requirements concerning future RCTs. Recent findings High doses of nebulized antibiotics are required to reach the infected lung parenchyma. Breath-synchronized nebulizers do not allow delivery of high doses. Mesh nebulizers perform better than jet nebulizers. Epithelial lining fluid concentrations do not reflect interstitial lung concentrations in patients receiving nebulized antibiotics. Specific ventilator settings for optimizing lung deposition require sedation to avoid patient's asynchrony with the ventilator. Summary Future RCTs should compare a 3–5 day nebulization of amikacin or colistimethate sodium (CMS) to a 7-day intravenous administration of a new cephalosporine/ß-lactamase inhibitor. Inclusion criteria should be a VAP or ventilator-associated tracheobronchitis caused by documented extensive-drug or pandrug resistant GNB. If the GNB remains susceptible to aminoglycosides, nebulized amikacin should be administered at a dose of 40 mg/kg/day. If resistant to aminoglycosides, nebulized CMS should be administered at a dose of 15 millions international units (IU)/day. In VAP caused by pandrug-resistant GNB, 15 millions IU/day nebulized CMS (substitution therapy) should be compared with a 9 millions IU/day intravenous CMS.
Lung Transplantation for Severe Post–coronavirus Disease 2019 Respiratory Failure

Background. The coronavirus disease 2019 (COVID-19) pandemic has resulted in >72 million cases and 1.6 million deaths. End-stage lung disease from COVID-19 is a new and growing entity that may benefit from lung transplant; however, there are limited data on the patient selection, perioperative management, and expected outcomes of transplantation for this indication. Methods. A systematic review of the literature was performed with searches of MEDLINE and Web of Science databases as well as the gray literature. All manuscripts, editorials, commentaries, and gray literature reports of lung transplantation for COVID-related respiratory failure were included. A case from the University of Virginia is described and included in the review. Results. A total of 27 studies were included: 11 manuscripts, 5 commentaries, and 11 gray literature reports. The total number of transplantations for COVID-related lung disease was 21. The mean age was 55±12 years, 16 (76%) were male individuals, and the acuity was high, with 85% on extracorporeal membrane oxygenation preoperatively. There was a 95% early survival rate, with 1 additional late death. There is growing histopathologic evidence for permanent structural damage with no replicating virus at the time of transplantation. Conclusions. Bilateral lung transplantation is an effective treatment option with reasonable short-term outcomes for patients with end-stage lung failure secondary to COVID-19. However, specific considerations in this new population require a multidisciplinary approach. As we move into the second wave of the COVID-19 global pandemic, lung transplantation will likely have a growing role in management of these complex patients.
Effect of Sigmoid Sinus Position on the Difficulty and Approaches to Cochlear Implantation Surgery.

OBJECTIVES To assess the effect of the position of the SS on CI regarding the ability to perform posterior tympanotomy, round window visibility, and mastoid pneumatization. MATERIALS AND METHODS This is a prospective study, including 65 adult patients with CI performed at our center during 2017. We used 3 methods to assess SS position using a computed tomography (CT) scan. Lee's line passing through the tympanic segment of the facial nerve. Park's line passing through the facial nerve and round window membrane. Our proposed method using a parallel line from the external auditory canal and passing through the facial nerve. Relation to mastoid pneumatization on CT and to intraoperative round window visibility were assessed in relation to intraoperative position of the SS. RESULTS The method by Park et al. was statistically significant (p<0.001); however, a cutoff point could not be set. Lee's method was statistically insignificant (p=0.091). Our proposed method was statistically significant with a cutoff point at ≤2.46 mm (p=0.001). SS position did not affect pneumatization nor round window visibility. CONCLUSION The position of SS preoperatively using a CT might suggest the inability to perform posterior tympanotomy and the need to change side or approach. However, it does not affect neither mastoid pneumatization nor visibility of the round window niche through the facial recess.
Influence of Precursor Compounds on the Structural and Catalytic Properties of Cobalt-Based Catalysts

The effects of different cobalt precursor compounds on the structural and catalytic properties of cobalt metal and Co3O4 catalysts have been investigated. The techniques employed for characterizing the different solids were XRD, ESR and TEM methods, together with their effectiveness as catalysts in the decomposition of H2O2 at 30–50 °C. The results obtained indicate that the investigated catalysts contained clusters or very small particles of cobalt metal or Co3O4 phases. Cobalt metal and Co3O4 catalysts based on cobalt chloride exhibited higher catalytic activities than other catalysts derived from cobalt nitrate and sulphate salts, respectively, due to their decreased particle sizes. The activation energies of the catalytic reaction over the as-prepared catalysts revealed that the different precursor compounds did not modify the energetic nature of the active sites involved in the catalyzed reaction but changed their concentrations.
Awareness of fentanyl exposure and the associated overdose risks among people who inject drugs in a Canadian setting.

INTRODUCTION Illicitly manufactured fentanyl continues to fuel the opioid overdose crisis throughout the USA and Canada. However, little is known about factors associated with knowingly or unknowingly using fentanyl. Therefore, we sought to identify the prevalence and correlates of suspected/known and unknown exposure to fentanyl (excluding the prescribed one) among people who inject drugs (PWID), including associated overdose risks. METHODS Data were derived from three prospective cohort studies of community-recruited people who use drugs in Vancouver, Canada in 2016-2017. Multivariable logistic regression was used to identify correlates of suspected/known exposure (i.e. urine drug screen positive and self-reporting past 3-day exposure) and unknown exposure to fentanyl (i.e. urine drug screen positive and self-reporting no past three-day exposure), respectively. RESULTS Among 590 PWID, 296 (50.2%) tested positive for fentanyl. Of those, 143 (48.3%) had suspected/known and 153 (51.7%) had unknown exposure to fentanyl. In multivariable analyses, using supervised injection sites and possessing naloxone were associated with both suspected/known and unknown exposure (all P < 0.05). Injecting drugs alone (adjusted odds ratio 3.26; 95% confidence interval: 1.72-6.16) was associated with known exposure, but not with unknown exposure. DISCUSSION AND CONCLUSIONS We found a high prevalence of fentanyl exposure in our sample of PWID, with one half of those exposed consuming fentanyl unknowingly. While those exposed to fentanyl appeared more likely to utilise some overdose prevention services, PWID with suspected/known fentanyl exposure were more likely to inject alone, indicating a need for additional overdose prevention efforts for this group.
GAS7 Deficiency Promotes Metastasis in MYCN-Driven Neuroblastoma

Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma. One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell–cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression. Significance: Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma. See related commentary by Menard, p. 2815
Candidates undertaking (invigilated) assessment online show no differences in performance compared to those undertaking assessment offline

Abstract Background Medical education has historically relied on high stakes knowledge tests sat in examination centres with invigilators monitoring academic malpractice. The COVID-19 pandemic has made such examination formats impossible, and medical educators have explored the use of online assessments as a potential replacement. This shift has in turn led to fears that the change in format or academic malpractice might lead to considerably higher attainment scores on online assessment with no underlying improvement in student competence. Method Here, we present an analysis of 8092 sittings of the Prescribing Safety Assessment (PSA), an assessment designed to test the prescribing skills of final year medical students in the UK. In-person assessments for the PSA were cancelled partway through the academic year 2020, with 6048 sittings delivered in an offline, traditionally invigilated format, and then 2044 sittings delivered in an online, webcam invigilated format. Results A comparison (able to detect very small effects) showed no attainment gap between online (M = 0.762, SD = 0.34) and offline (M = 0.761, SD = 0.34) performance. Conclusions The finding suggests that the transition to online assessment does not affect student performance. The findings should increase confidence in the use of online testing in high-stakes assessment.
Transcriptional control of the oxidative stress response and implications of using plant derived molecules for therapeutic interventions in cancer.

Oxidative stress response is critical for the malignant cells. It plays dual role by helping cancer cells survive and proliferate but also causing apoptosis and apoptosis like cell death. The oxidative stress response is characterized by a tight regulation of gene expression by a series of transcription factors (OSRts; oxidative stress response transcription factors). In this communication, we review the role of OSRts, notably NRF2 and p53 as well as other transcription factors, that modulate the response. We discuss how the oxidative stress response is hierarchal and controls 'live or die' signals. This is followed by a discussion on how plant derived molecules, including polyphenols, which are described both as prooxidants and antioxidants within the cancer cells, have been reported to affect the activities of OSRts. Deriving an example from preliminary data from our group, we discuss how plant derived molecules might modulate the oxidative stress response by causing structural perturbations in the proteinacious transcription factors, notably Nrf2 and p53. We look at this information in the light of understanding how plant derived molecules maybe used as lead compounds to develop modulators of the oxidative stress response.
Nonuniversality of the single‐chain rod‐to‐coil transition scaling functions: Exact results for directed walks

We report exact calculations of several thermodynamic and correlation quantities for the turn‐weighted self‐avoiding walk models on the directed square, partially directed square, and partially directed triangular lattices. The conformational transition from the coil‐to‐rod‐like chains, obtained as the statistical weight per turn goes to zero, obeys scaling laws. The scaling functions, however, are not universal for the different models considered.
Temperature dependence of intrinsic carrier generation in anthracene single crystals

The pulse technique is used to measure free carrier yields in anthracene single crystals as a function of temperature, photon energy, and applied field. Field dependence plots, measured over the temperature range 200–300 K, exhibit slope‐to‐intercept ratios described by S/I=3.2×10−5 (298/T)2 cm/V. This result is in quantitative agreement with that predicted by Onsager’s theory of geminate recombination. Activation energy (Ea) results are reported over a wide range of photon energies. We find that Ea is essentially constant (Ea=0.090 eV) over the photon energy range 4.4–5.2 eV and again constant (Ea=0.068 eV) over the range 5.4–6.2 eV. This observation is consistent with autoionization from two spectroscopically observed states: system II (1B2u) in the lower energy range, and system III (1B1u) in the higher energy range. The average thermalization lengths that would be associated with these Ea values are in the range 10–70 A depending on the form chosen for the distribution of charge pair configurations.
Xylan sorption kinetics at industrial conditions Part 2. Modeling

Abstract A model describing the sorption kinetics for black liquor birch xylan onto unbleached softwood kraft fibers at industrially relevant process conditions has been developed. The experimental results support the suggestion that xylan sorption is a physical process. Our model is based on the assumption that the mass transfer between bulk liquor and fiber surfaces is the rate determining step. The effects of changes in process conditions like temperature, NaOH concentration and ion strength are included in the model. The model fits the experimental data quite well for sorption temperatures between 87 and 127°C. Other mechanisms affect the observed sorption at higher sorption temperatures. Consequently, more data is needed to produce a model for sorption at elevated temperatures. Deviations from the experimental data at temperatures up to 127°C are proposed to be a result of competing mechanisms not accounted for in our model. These can, for instance, be the transportation of xylan from the surface into the cell wall, the degradation of xylan in solution, the removal of substituents from the xylan backbone, or a decrease in NaOH concentration in the solution.
Behavioral and myelin-related abnormalities following blast-induced mild traumatic brain injury in mice.

In civilian and military settings, mild traumatic brain injury (mTBI) is a common consequence of impacts to the head, sudden blows to the body, and exposure to high-energy atmospheric shockwaves from the blast. In some cases, mTBI from blast exposure results in long-term emotional and cognitive deficits and an elevated risk for certain neuropsychiatric diseases. Here, we tested the effects of mTBI on various forms of auditory-cued fear learning and other measures of cognition in male C57BL/6J mice following single or repeated blast exposure (bTBI). bTBI produced an abnormality in the temporal organization of cue-induced freezing behavior in a conditioned trace fear test. Spatial working memory, evaluated by the Y-maze task performance, was also deleteriously affected by bTBI. RT-qPCR analysis for glial markers indicated an alteration in the expression of myelin-related genes in the hippocampus and corpus callosum one to eight weeks after bTBI. Immunohistochemical and ultrastructural analyses detected bTBI-related myelin and axonal damage in the hippocampus and corpus callosum. Together these data suggest a possible link between blast-induced mTBI, myelin/axonal injury, and cognitive dysfunction.
Genetic priming of sensory neurons in mice that overexpress PAR2 enhances allergen responsiveness

Significance Dermatitis is a major inflammatory skin condition that is associated with pruritus and affects millions of people worldwide. However, there is still little knowledge about the contribution of the cutaneous sensory neurons to the chronic disease. Here we show that chronic, but not acute, exposure to allergens/pruritogens induces robust itch in the dermatitis-prone Grhl3PAR2/+ transgenic mouse line, in part due to profound transcriptional changes that are induced in trigeminal ganglion neurons that innervate the allergen-treated skin. Most upregulated genes were concentrated in unmyelinated primary afferents that express TRPV1, a known pruritoceptor. As comparable transcriptional changes were recorded in a second dermatitis model, we conclude that a common genetic priming program in sensory neurons contributes to dermatitis. Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neurons that transmit pruritic signals are well-cataloged, little is known about the neuronal alterations that occur as a result of skin disruption in AD. To address this question, we examined the molecular and behavioral consequences of challenging Grhl3PAR2/+ mice, which overexpress PAR2 in suprabasal keratinocytes, with serial topical application of the environmental allergen house dust mite (HDM). We monitored behavior and used RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in trigeminal ganglia (TG), before and after HDM. We found that neither Grhl3PAR2/+ nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in Grhl3PAR2/+ mice. Despite the absence of scratching in untreated Grhl3PAR2/+ mice, several TG genes in these mice were up-regulated compared to WT. HDM treatment of the Grhl3PAR2/+ mice enhanced up-regulation of this set of genes and induced additional genes, many within the subset of TG neurons that express TRPV1. The same set of genes was up-regulated in HDM-treated Grhl3PAR2/+ mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a common genetic program is induced in two AD models. Taken together, we conclude that transcriptional changes that occur in primary sensory neurons in dermatitis-susceptible animals underlie a genetic priming that not only sensitizes the animal to chronic allergens but also contributes to pruritus in atopic skin disease.
Selective Asymmetry of Ocular Vestibular-Evoked Myogenic Potential in Patients with Acute Utricular Macula Loss.

OBJECTIVES We retrospectively evaluated a chart review of 3,525 patients evaluated for any acute disturbance. A total of 1,504 patients with acute vestibular syndrome (AVS) received an instrumental vestibular assessment within 72 h from the onset of the symptoms evaluated using simultaneously a combination of ocular vestibular-evoked myogenic potential (oVEMPs), cervical vestibular-evoked myogenic potential (cVEMPs), video head-impulse test (vHIT), and subjective visual vertical (SVV) were included in this study. MATERIALS AND METHODS A total of 41 patients with AVS that showed a normal horizontal canal function tested with vHIT, a normal cVEMP function, unilaterally reduced or absent oVEMP n10, and an altered SVV were enrolled. RESULTS We found that although these patients referred acute vertigo and presented spontaneous nystagmus, they showed physiological values of vHIT and a normal saccular function, as shown by symmetrical cVEMPs. CONCLUSION Our findings support the hypothesis that a percentage of patients evaluated during an AVS using an instrumental vestibular assessment could present selective utricular macula dysfunction.