Miracle-dz/UniFAR-FTUs huggingface dataset:
Autophagic- and Lysosomal-Related Biomarkers for Parkinson’s Disease: Lights and Shadows

Parkinson’s disease (PD) is a neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, for which no disease-modifying treatments exist. This lack of effective treatments is related to the advanced stage of neurodegeneration existing at the time of diagnosis. Thus, the identification of early stage biomarkers is crucial. Biomarker discovery is often guided by the underlying molecular mechanisms leading to the pathology. One of the central pathways deregulated during PD, supported both by genetic and functional studies, is the autophagy-lysosomal pathway. Hence, this review presents different studies on the expression and activity of autophagic and lysosomal proteins, and their functional consequences, performed in peripheral human biospecimens. Although most biomarkers are inconsistent between studies, some of them, namely HSC70 levels in sporadic PD patients, and cathepsin D levels and glucocerebrosidase activity in PD patients carrying GBA mutations, seem to be consistent. Hence, evidence exists that the impairment of the autophagy-lysosomal pathway underlying PD pathophysiology can be detected in peripheral biosamples and further tested as potential biomarkers. However, longitudinal, stratified, and standardized analyses are needed to confirm their clinical validity and utility.
Effects of Weekly Supplementation of Cholecalciferol and Calcifediol Among the Oldest-Old People: Findings From a Randomized Pragmatic Clinical Trial

Vitamin D inadequacy is pervasive in the oldest-old. Many vitamin D metabolites are available for supplementation, their effects on the recovery of adequate serum levels remain unknown. We investigate the effects of supplementation with cholecalciferol (D3) and calcifediol (25D3) on serum levels of 25(OH)D, 1-25(OH)D, bone and inflammatory markers, ultimately identifying clinical predictors of successful treatment. Sixty-seven oldest-old individuals were randomized to weekly administration of 150 mcg of 25D3 or D3, from hospital admission to 7 months after discharge. Supplementation of 25D3 and D3 were associated with increasing serum levels of 25(OH)D (p < 0.001) and 1-25(OH)D (p = 0.01). Participants on 25D3 experienced a steeper rise than those on D3 (group*time interaction p = 0.01), after adjustment for intact parathyroid hormone (iPTH) levels the differences disappeared (intervention*iPTH interaction p = 0.04). Vitamin D supplementation was associated with a decreasing trend of iPTH and C-reactive protein (CRP) (p < 0.001). Polypharmacy and low handgrip strength were predictors of failure of intervention, independent of vitamin D metabolites. In conclusion, D3 and 25D3 supplementation significantly increase vitamin D serum levels in the oldest-old individuals, with a tendency of 25D3 to show a faster recovery of acceptable iPTH levels than D3. Polypharmacy and low muscle strength weaken the recovery of adequate vitamin D serum levels.
Utility of Routine Frozen Section of Thyroid Nodules Classified as Follicular Neoplasm.

OBJECTIVES To evaluate the diagnostic performance of frozen section in thyroid nodules classified as follicular neoplasm. METHODS A diagnostic test meta-analysis was designed. Studies that assessed frozen section in patients with thyroid nodules and a fine-needle aspiration biopsy result of Bethesda IV were selected. The outcomes measured were the number of false- and true-positive and -negative results. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) instrument for methodological quality assessment and a bivariate mixed-effects regression framework and a likelihood-based estimation of the exact binomial approach. RESULTS Forty-six studies from 1991 to 2018 were included. Most studies had moderate methodological quality. The overall sensitivity and specificity were 43% (95% confidence internal [CI], 0.34-0.53) and 100% (95% CI, 0.99-1.00), respectively. The hierarchic summary receiver operating characteristic curve showed an area under the curve of 0.91 (95% CI, 0.80-0.97). CONCLUSIONS Frozen section demonstrates moderate diagnostic performance in patients with follicular neoplasm, and its utility for making intraoperative decisions is limited. Its routine use should be discouraged.
Timely Use of Conventional Vitrectomy and Endoscope-Assisted Vitrectomy for Endophthalmitis Following Open Ocular Trauma: A Retrospective Study of 18 Patients

Background Endophthalmitis, or inflammation of the internal tissues of the eye, may follow trauma and results in loss of vision if not treated promptly. Vitrectomy is used to debride the inflamed vitreous. This retrospective study aimed to compare the outcome from conventional vitrectomy (CV) and endoscope-assisted vitrectomy (EAV) performed for endophthalmitis within five days and 10 days after open ocular trauma. Material/Methods The clinical data from 18 patients (18 eyes) with endophthalmitis caused by open ocular trauma were analyzed at a single center. CV or EAV was performed based on the degree of vision and the involvement of the vitreous cavity. Results Of the 18 patients with endophthalmitis, seven patients underwent EAV, and 11 patients underwent CV. The number of cases with preoperative corneal laceration, edema, bleeding, and formation of corneal nebular opacity was higher in the EAV group compared to the CV group. Four patients had retinal detachment, of which three patients were treated with EAV. Seventeen patients had their sight restored by a single vitrectomy procedure. In 10 cases, the culture of the vitreous fluid was positive for infection, and eight patients had Gram-positive Staphylococcus epidermidis infection. Follow-up showed that vitrectomy performed within five days (P=0.001) and 10 days (P=0.047) of open ocular trauma resulted in significant improvement of visual acuity. Conclusions Vitrectomy for endophthalmitis due to open ocular trauma performed within five days of injury restored visual acuity. EAV was shown to be an effective alternative to CV.
Robot Helps When Robot Fits: Examining the Role of Baby Robots in Fertility Promotion

Considering China is facing a precipitous decline in its population, there is an emerging trend of developing baby robots to encourage people’s willingness to become “parents”. Based on the decomposed theory of planned behavior and the theory of uncanny valley, this study empirically investigated whether a baby robot could perform as a prominent antecedent of fertility intention in China, and how this relates to its visual appearance. Consistent with prior research, the current study used a between-subjects design to show (1) a baby robot could significantly improve people’s fertility attitude through temporal visual stimulation; (2) fertility attitude, subjective norms from peers, and perceived behavioral control of finance could significantly contribute to fertility intention. Theoretical contributions and implications are discussed in this study.
Trends in Hospital Admissions for Pertussis Infection: A Nationwide Retrospective Observational Study in Italy, 2002–2016

Background: Pertussis is a highly contagious infectious disease which continues to be an important public-health issue despite the high immunization coverage rates achieved. However, evidence of increased circulation of pertussis among adolescents and adults due to waning immunity and atypical clinical manifestations seem to be the main reasons for its resurgence. The aim of this study was the analysis of the epidemiological trend for pertussis-related hospitalizations in Italy, in relation with vaccination coverage and information from laboratory confirmed cases of pertussis. Methods: A retrospective observational study investigating hospitalizations for pertussis from 2002 to 2016 in Italy was conducted. Frequencies and rates of hospitalization were analyzed and hospitalization data were compared with a series of already published laboratory confirmed data. Results: This study highlighted a rising trend for pertussis hospitalizations in Italy since 2008. Infants aged <1 year showed the highest frequencies (63.39%) and average rates (74.60 × 100000 infants) of hospitalization despite an extremely high vaccination coverage (95.89%). An increasing trend of hospitalization frequency emerged for the age group with levels of IgG antibodies to pertussis toxin compatible with pertussis infection within the last year (20–29 years old age group). Conclusions: The rising trend for pertussis hospitalizations and the greater involvement of infants aged <1 year require an integrated approach, including the implementation of booster doses administration in adolescence and adulthood, the vaccination of pregnant women and the cocoon strategy.
Regulation of Mitochondria-Associated Membranes (MAMs) by NO/sGC/PKG Participates in the Control of Hepatic Insulin Response

Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets of NO, we explored whether NO regulates hepatic insulin sensitivity by targeting MAMs. In Huh7 cells, primary rat hepatocytes and mouse livers, enhancing NO concentration increased MAMs, whereas inhibiting eNOS decreased them. In vitro, those effects were prevented by inhibiting protein kinase G (PKG) and mimicked by activating soluble guanylate cyclase (sGC) and PKG. In agreement with the regulation of MAMs, increasing NO concentration improved insulin signaling, both in vitro and in vivo, while eNOS inhibition disrupted this response. Finally, inhibition of insulin signaling by wortmannin did not affect the impact of NO on MAMs, while experimental MAM disruption, using either targeted silencing of cyclophilin D or the overexpression of the organelle spacer fetal and adult testis-expressed 1 (FATE-1), significantly blunted the effects of NO on both MAMs and insulin response. Therefore, under physiological conditions, NO participates to the regulation of MAM integrity through the sGC/PKG pathway and concomitantly improves hepatic insulin sensitivity. Altogether, our data suggest that the induction of MAMs participate in the impact of NO on hepatocyte insulin response.
Prevalence of Child-Directed Marketing on Breakfast Cereal Packages before and after Chile’s Food Marketing Law: A Pre- and Post-Quantitative Content Analysis

Food marketing has been identified as a contributing factor in childhood obesity, prompting global health organizations to recommend restrictions on unhealthy food marketing to children. Chile has responded to this recommendation with a restriction on child-directed marketing for products that exceed certain regulation-defined thresholds in sugars, saturated fats, sodium, or calories. Child-directed strategies are allowed for products that do not exceed these thresholds. To evaluate changes in marketing due to this restriction, we examined differences in the use of child-directed strategies on breakfast cereal packages that exceeded the defined thresholds vs. those that did not exceed the thresholds before (n = 168) and after (n = 153) the restriction was implemented. Photographs of cereal packages were taken from top supermarket chains in Santiago. Photographed cereals were classified as “high-in” if they exceeded any nutrient threshold described in the regulation. We found that the percentage of all cereal packages using child-directed strategies before implementation (36%) was significantly lower after implementation (21%), p < 0.05. This overall decrease is due to the decrease we found in the percentage of “high-in” cereals using child-directed strategies after implementation (43% before implementation, 15% after implementation), p < 0.05. In contrast, a greater percentage of packages that did not qualify as “high-in” used child-directed strategies after implementation (30%) compared with before implementation (8%), p < 0.05. The results suggest that the Chilean food marketing regulation can be effective at reducing the use of child-directed marketing for unhealthy food products.
Exome-chip association analysis of intracranial aneurysms

Objective To investigate to what extent low-frequency genetic variants (with minor allele frequencies <5%) affect the risk of intracranial aneurysms (IAs). Methods One thousand fifty-six patients with IA and 2,097 population-based controls from the Netherlands were genotyped with the Illumina HumanExome BeadChip. After quality control (QC) of samples and single nucleotide variants (SNVs), we conducted a single variant analysis using the Fisher exact test. We also performed the variable threshold (VT) test and the sequence kernel association test (SKAT) at different minor allele count (MAC) thresholds of >5 and >0 to test the hypothesis that multiple variants within the same gene are associated with IA risk. Significant results were tested in a replication cohort of 425 patients with IA and 311 controls, and results of the 2 cohorts were combined in a meta-analysis. Results After QC, 995 patients with IA and 2,080 controls remained for further analysis. The single variant analysis comprising 46,534 SNVs did not identify significant loci at the genome-wide level. The gene-based tests showed a statistically significant association for fibulin 2 (FBLN2) (best p = 1 × 10−6 for the VT test, MAC >5). Associations were not statistically significant in the independent but smaller replication cohort (p > 0.57) but became slightly stronger in a meta-analysis of the 2 cohorts (best p = 4.8 × 10−7 for the SKAT, MAC ≥1). Conclusion Gene-based tests indicated an association for FBLN2, a gene encoding an extracellular matrix protein implicated in vascular wall remodeling, but independent validation in larger cohorts is warranted. We did not identify any significant associations for single low-frequency genetic variants.
Clinical Evolution of Epithelial-Mesenchymal Transition in Human Carcinomas.

The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial-mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and co-localized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution ("EMT IFA"). We report the discovery of β-catenin+ cancer cells that co-express E-cadherin and vimentin in core needle biopsies from patients with various advanced metastatic carcinomas wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes. Treatment of carcinoma models with anticancer drugs that differ in their mechanism of action (the tyrosine kinase inhibitor pazopanib in MKN45 gastric carcinoma xenografts, and the combination of tubulin-targeting agent paclitaxel with the BCR-ABL inhibitor nilotinib in MDA-MB-468 breast cancer xenografts) caused changes in the tumor epithelial-mesenchymal character. Moreover, the appearance of partial-EMT or mesenchymal-like carcinoma cells in MDA-MB-468 tumors treated with the paclitaxel-nilotinib combination resulted in upregulation of cancer stem cell (CSC) markers and susceptibility to FAK inhibitor. A metastatic prostate cancer patient treated with the PARP inhibitor talazoparib exhibited similar CSC marker upregulation. Therefore, the phenotypic plasticity conferred on carcinoma cells by EMT allows for rapid adaptation to cytotoxic or molecularly-targeted therapy and could create a form of acquired drug resistance that is transient in nature.
Aqueous Humor Biomarkers Identify Three Prognostic Groups in Uveal Melanoma.

Purpose To investigate whether we can identify different patterns of inflammation in the aqueous humor of a uveal melanoma (UM)-containing eye, and whether these are related to prognosis. Methods Ninety samples of aqueous humor from UM-containing eyes were analyzed using a high-throughput multiplex immunoassay that enables simultaneous analysis of 92 predefined protein biomarkers. Cytokine expression was compared to clinical and histopathological characteristics. Cluster analysis was performed, after which the clusters were compared with clinical and histopathological tumor characteristics. Results Cluster analysis revealed three distinct clusters, with one cluster showing hardly any inflammatory cytokines, one showing intermediate levels, and one showing a high expression of inflammation-related biomarkers. Significant differences between the clusters were seen with regard to patient age (P = 0.008), tumor prominence (P = 0.001), ciliary body involvement (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P < 0.001), monosomy of chromosome 3 (P = 0.03), and gain of chromosome 8q (P = 0.04), with the cluster with a highest cytokine expression having the worst prognostic markers. Especially apoptosis-related cytokines were differentially expressed. Conclusions Analysis of cytokines in the aqueous humor shows distinct differences between aqueous humor samples and allocates these samples into three different prognostic tumor clusters. Especially large tumors with ciliary body involvement and monosomy 3 were associated with many cytokines, especially apoptosis-related cytokines. The presence of these cytokines in the aqueous humor may play a role in the lack of effective antitumor immune responses.
Anthracycline-induced cardiotoxicity during and after treatment for childhood cancer : long-term risk, risk factors and prevention

Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva. nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
CD31 Acts as a Checkpoint Molecule and Is Modulated by FcγR-Mediated Signaling in Monocytes

Key Points FcγR activation in human monocytes regulates the localization and expression of CD31. FcγR-mediated CD31 downregulation is mediated mainly through FcγRIIa and PI3K. CD31 negatively regulates FcγR-mediated phagocytosis but not cytokine production. Monocytes and macrophages express FcγR that engage IgG immune complexes such as Ab-opsonized pathogens or cancer cells to destroy them by various mechanisms, including phagocytosis. FcγR-mediated phagocytosis is regulated by the concerted actions of activating FcγR and inhibitory receptors, such as FcγRIIb and SIRPα. In this study, we report that another ITIM-containing receptor, PECAM1/CD31, regulates FcγR function and is itself regulated by FcγR activation. First, quantitative RT-PCR and flow cytometry analyses revealed that human monocyte FcγR activation leads to a significant downregulation of CD31 expression, both at the message level and at surface expression, mainly mediated through FcγRIIa. Interestingly, the kinetics of downregulation between the two varied, with surface expression reducing earlier than the message. Experiments to analyze the mechanism behind this discrepancy revealed that the loss of surface expression was because of internalization, which depended predominantly on the PI3 kinase pathway and was independent of FcγR internalization. Finally, functional analyses showed that the downregulation of CD31 expression in monocytes by small interfering RNA enhanced FcγR-mediated phagocytic ability but have little effect on cytokine production. Together, these results suggest that CD31 acts as a checkpoint receptor that could be targeted to enhance FcγR functions in Ab-mediated therapies.
Clinical characteristics, treatment, and survival outcome in pediatric patients with atypical teratoid/rhabdoid tumors: a retrospective study by the Japan Children's Cancer Group.

OBJECTIVE The prognosis of atypical teratoid/rhabdoid tumors (ATRTs) has improved in recent years with the use of multimodal therapy, mainly in cases not involving metastatic disease. The authors wanted to obtain historical control data and evaluate the suitable treatments in Japanese children with ATRTs that were proven negative for INI-1 immunostaining. METHODS The authors retrospectively collected clinical information on 38 pediatric patients with ATRTs treated from 2005 to 2016 and analyzed the data for this series. RESULTS The median age of the patient population was 1.3 years, and the male/female ratio was approximately 2:1. Twenty-three patients (60.5%) had metastases. The effects of treatment on prognosis were analyzed for 34 patients after exclusion of 4 patients who could not receive curative treatment. At a median follow-up of 40.9 months, the mean (± SD) progression-free survival (PFS) and overall survival (OS) were 66.6% ± 8.3% and 45.9% ± 8.7% at 2 years and 44.2% ± 9.9% and 34.2% ± 8.9% at 5 years, respectively. The metastasis stage at diagnosis (M0-1 vs M2-4) (HR 2.68, 95% CI 1.08-6.65; p = 0.0338) and gross tumor resection (yes vs no) (HR 3.49, 95% CI 1.01-12.1; p = 0.0481) were prognostic factors for PFS but not for OS. Postoperative chemotherapy was performed in all 34 cases. High-dose chemotherapy was performed in 19 (55.8%) of 34 patients and showed a positive impact on OS (HR 0.31, 95% CI 0.11-0.86; p = 0.0254); the most commonly used regimen was a double-conditioning regimen of thiotepa plus melphalan. Local radiotherapy had a positive impact on both PFS and OS; however, craniospinal irradiation (CSI) performed in 12 patients as the primary therapy was associated with a poor outcome. Disseminated recurrence within 12 months from diagnosis was the most common pattern of treatment failure regardless of CSI. CONCLUSIONS There has been an improvement in outcomes for pediatric ATRT patients since the introduction of multimodal therapy in Japan, mainly in patients without metastases. Even if selection bias is taken into consideration, CSI did not contribute to an improved prognosis. Novel treatment approaches are required for pediatric ATRT patients with metastases.