Miracle-dz/UniFAR-FTUs huggingface dataset:
Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

Multiple sclerosis (MS) is the most demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation. Oligodendrocyte progenitor cells (OPCs) are cycling cells in the developing and adult CNS that, under demyelinating conditions, migrate to the site of lesions and differentiate into mature oligodendrocytes to remyelinate damaged axons. However, this process fails during disease chronicization due to impaired OPC differentiation. Moreover, OPCs are crucial players in neuro-glial communication as they receive synaptic inputs from neurons and express ion channels and neurotransmitter/neuromodulator receptors that control their maturation. Ion channels are recognized as attractive therapeutic targets, and indeed ligand-gated and voltage-gated channels can both be found among the top five pharmaceutical target groups of FDA-approved agents. Their modulation ameliorates some of the symptoms of MS and improves the outcome of related animal models. However, the exact mechanism of action of ion-channel targeting compounds is often still unclear due to the wide expression of these channels on neurons, glia, and infiltrating immune cells. The present review summarizes recent findings in the field to get further insights into physio-pathophysiological processes and possible therapeutic mechanisms of drug actions.
Feasibility and Reliability Assessment of Video-Based Motion Analysis and Surface Electromyography in Children with Fragile X during Gait

Fragile X Syndrome (FXS), the leading form of inherited intellectual disability and autism, is characterized by specific musculoskeletal conditions. We hypothesized that gait analysis in FXS could be relevant for the evaluation of motor control of gait, and help the understanding of a possible correlation between functional and intellectual abilities. Typical deficits in executive control and hyperactivity have hampered the use of standard gait analysis. The aim of our study was to quantitatively assess musculoskeletal alterations in FXS children in standard ambulatory conditions, in a friendly environment. Ten FXS children and sixteen controls, with typical neurodevelopment, were evaluated through four synchronized video cameras and surface electromyography; lower limb joints rotations, spatiotemporal parameters, duration of muscle contraction, activation timing and envelope peaks were determined. Reliability and repeatability of the video based kinematics analysis was assessed with respect to stereophotogrammetry. The Kruskal–Wallis Test (p < 0.05) or SPM1D were used to compare different groups of subjects. Results show a consistently altered gait pattern associated with abnormal muscle activity in FXS subjects: reduced knee and excessive hip and ankle flexion, and altered duration and activity onset on all the recorded muscles (Rectus/Biceps Femoris, Tibialis Anterior, Gastrocnemius Lateralis). Results of this study could help with planning personalized rehabilitations.
Chemotherapy for Biliary Tract Cancer in 2021

Biliary tract cancer refers to a group of malignancies including cholangiocarcinoma, gallbladder cancer, and ampullary cancer. While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Adjuvant chemotherapy is used to prolong prognosis in some cases. Many unresectable cases are also treated with chemotherapy. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Evidence on chemotherapy for biliary tract cancer is recently on the increase. Combination chemotherapy with gemcitabine and cisplatin is currently the standard of care for first-line chemotherapy in advanced cases. Recently, FOLFOX also demonstrated efficacy as a second-line treatment. In addition, efficacies of isocitrate dehydrogenase inhibitors and fibroblast growth factor receptor inhibitors have been shown. In the adjuvant setting, capecitabine monotherapy has become the standard of care in Western countries. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have been evaluated in multiple clinical trials. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. In this article, we review the latest evidence of chemotherapy for biliary tract cancer.
The Receptor-Like Kinase ERECTA Confers Improved Water Use Efficiency and Drought Tolerance to Poplar via Modulating Stomatal Density

Poplar is one of the most important tree species in the north temperate zone, but poplar plantations are quite water intensive. We report here that CaMV 35S promoter-driven overexpression of the PdERECTA gene, which is a member of the LRR-RLKs family from Populus nigra × (Populus deltoides × Populus nigra), improves water use efficiency and enhances drought tolerance in triploid white poplar. PdERECTA localizes to the plasma membrane. Overexpression plants showed lower stomatal density and larger stomatal size. The abaxial stomatal density was 24–34% lower and the stomatal size was 12–14% larger in overexpression lines. Reduced stomatal density led to a sharp restriction of transpiration, which was about 18–35% lower than the control line, and instantaneous water use efficiency was around 14–63% higher in overexpression lines under different conditions. These phenotypic changes led to increased drought tolerance. PdERECTA overexpression plants not only survived longer after stopping watering but also performed better when supplied with limited water, as they had better physical and photosynthesis conditions, faster growth rate, and higher biomass accumulation. Taken together, our data suggest that PdERECTA can alter the development pattern of stomata to reduce stomatal density, which then restricts water consumption, conferring enhanced drought tolerance to poplar. This makes PdERECTA trees promising candidates for establishing more water use efficient plantations.
ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.
Treatment and Survival of Malignant Extracranial Germ Cell Tumours in the Paediatric Population: A Systematic Review and Meta-Analysis

Simple Summary Germ cell tumours are a heterogeneous group of neoplasms and are predominantly midline tumours occurring from birth to late adulthood. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis or platinum-resistant disease. The aim of our systematic review was to explore survival rates internationally over the past two decades in order to better define future practice and treatment strategies and also to define specific subgroups with inferior outcomes. The results of our systematic review describe the heterogeneous nature of germ cell tumours in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, subpopulations can be defined which have an inferior survival and where future research and more individualised treatment would help to improve survival. Abstract Objective: This systematic review and meta-analysis was performed to explore overall survival (OS) and event free survival (EFS) rates internationally over the past two decades and to define specific subgroups with inferior outcomes which may demand different treatment strategies. Methods: The search focused on malignant extracranial germ cell tumours (GCTs) in the paediatric population. The initial database search identified 12,556 articles; 32 articles were finally included in this review, comprising a total of 5095 patients. Results: The studies were heterogeneous, varying from single institution reports to large prospective trials. Older studies, describing eras where non-platinum-based chemotherapy regimens were used, showed clearly worse outcomes. Survival for stage I–II gonadal disease is excellent. On the other hand, patients with an initial alpha-fetoprotein (AFP) > 10,000 ng/mL or kU/L, age > 11 years and stage IV disease confer a survival disadvantage. For testicular disease in particular, lymphovascular invasion and certain histopathological subtypes, such as embryonal carcinoma (EC) and mixed malignant GCTs, survival is poorer. Survival data for sacrococcygeal and mediastinal GCTs show a heterogeneous distribution across studies in this review, independent of year of publication. Patients > 12 years presenting with a mediastinal GCT pose a subpopulation which fares worse than GCTs in other locations or age groups. This is independent of AFP levels, stage of disease or treatment protocol, and these patients may demand a different treatment strategy. Conclusions: This review describes the heterogeneous nature of GCTs in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, in line with the current developmental biology-based classification system, subpopulations can be defined which have an inferior EFS and OS and where future research and more individualised treatment would help to improve survival.
Correlations between Changes in Medical Opioid Dispensing and Contributions of Fentanyl to Opioid-Related Overdose Fatalities: Exploratory Analyses from Canada

Canada is experiencing an epidemic of opioid-related mortality, with increasing yet heterogeneous fatality patterns from illicit/synthetic (e.g., fentanyl) opioids. The present study examined whether differential provincial reductions in medical opioid dispensing following restrictive regulations (post-2010) were associated with differential contributions of fentanyl to opioid mortality. Annual provincial opioid dispensing totals in defined daily doses/1000 population/day, and change rates in opioid dispensing for the 10 provinces for (1) 2011–2018 and (2) “peak-year” to 2018 were derived from a pan-Canadian pharmacy-based dispensing panel. Provincial contribution rates of fentanyl to opioid-related mortality (2016–2019) were averaged. Correlation values (Pearson’s R) between provincial changes in opioid dispensing and the relative fentanyl contributions to mortality were computed for the two scenarios. The correlation between province-based changes in opioid dispensing (2011–2018) and the relative contribution of fentanyl to total opioid deaths (2016–2019) was −0.70 (t = 2.75; df = 8; p = 0.03); the corresponding correlation for opioid dispensing changes (“peak-year” to 2018) was −0.59 (t = −2.06; df = 8; p = 0.07). Provincial reductions in medical opioid dispensing indicated (near-)significant correlations with fentanyl contribution rates to opioid-related death totals. Differential reductions in pharmaceutical opioid availability may have created supply voids for nonmedical use, substituted with synthetic/toxic (e.g., fentanyl) opioids and leading to accelerated opioid mortality. Implications of these possible unintended adverse consequences warrant consideration for public health policy.
Development of Machine Learning Models for Prediction of Osteoporosis from Clinical Health Examination Data

Osteoporosis is treatable but often overlooked in clinical practice. We aimed to construct prediction models with machine learning algorithms to serve as screening tools for osteoporosis in adults over fifty years old. Additionally, we also compared the performance of newly developed models with traditional prediction models. Data were acquired from community-dwelling participants enrolled in health checkup programs at a medical center in Taiwan. A total of 3053 men and 2929 women were included. Models were constructed for men and women separately with artificial neural network (ANN), support vector machine (SVM), random forest (RF), k-nearest neighbor (KNN), and logistic regression (LoR) to predict the presence of osteoporosis. Area under receiver operating characteristic curve (AUROC) was used to compare the performance of the models. We achieved AUROC of 0.837, 0.840, 0.843, 0.821, 0.827 in men, and 0.781, 0.807, 0.811, 0.767, 0.772 in women, for ANN, SVM, RF, KNN, and LoR models, respectively. The ANN, SVM, RF, and LoR models in men, and the ANN, SVM, and RF models in women performed significantly better than the traditional Osteoporosis Self-Assessment Tool for Asians (OSTA) model. We have demonstrated that machine learning algorithms improve the performance of screening for osteoporosis. By incorporating the models in clinical practice, patients could potentially benefit from earlier diagnosis and treatment of osteoporosis.
Cooperative Object Transportation Using Curriculum-Based Deep Reinforcement Learning

This paper presents a cooperative object transportation technique using deep reinforcement learning (DRL) based on curricula. Previous studies on object transportation highly depended on complex and intractable controls, such as grasping, pushing, and caging. Recently, DRL-based object transportation techniques have been proposed, which showed improved performance without precise controller design. However, DRL-based techniques not only take a long time to learn their policies but also sometimes fail to learn. It is difficult to learn the policy of DRL by random actions only. Therefore, we propose two curricula for the efficient learning of object transportation: region-growing and single- to multi-robot. During the learning process, the region-growing curriculum gradually extended to a region in which an object was initialized. This step-by-step learning raised the success probability of object transportation by restricting the working area. Multiple robots could easily learn a new policy by exploiting the pre-trained policy of a single robot. This single- to multi-robot curriculum can help robots to learn a transporting method with trial and error. Simulation results are presented to verify the proposed techniques.
Hearing Outcomes and Complications of Cochlear Implantation in Elderly Patients over 75 Years of Age

Objective: Populations are aging in many countries, and the proportion of elderly people with severe to profound hearing loss is increasing in parallel with the increasing average life span. The objective of this study was to investigate the outcomes of cochlear implant (CI) surgery in elderly patients compared to those in younger patients. Methods: The outcomes of CI surgery were retrospectively investigated for 81 adults (32 men and 49 women) who underwent CI surgery at our hospital. They were divided according to age at the time of implantation into the younger group (<75 years of age; n = 49) or elderly group (≥75 years of age; n = 32). Results: The mean sentence recognition score on the CI-2004 Japanese open-set test battery (±standard deviation) was 82.9% ± 24.1 in the younger group and 81.9% ± 23.2 in the elderly group, with no significant difference between the groups (Mann–Whitney U test). The incidence of major complications that required surgical treatment was not significantly different between the groups (4.1% vs. 6.2%, respectively). Thus, there were no severe complications that could affect general health status in either group. Three patients in each group died for reasons unrelated to CI surgery during follow-up. The proportion of patients who were alive and continued to use the CI five years after surgery was 92.8% and 91.5%, respectively. Conclusion: Our results show good speech recognition and a low incidence of major complications in elderly patients. This comprehensive report on the outcomes of CI surgery in elderly patients will be helpful to the elderly with severe to profound hearing loss when deciding whether to undergo CI surgery.
Nutritional Therapy in Pediatric Crohn’s Disease—Are We Going to Change the Guidelines?

In recent years, there has been a significant increase in the incidence of Crohn’s disease. Despite significant medical progress, the treatment options available today do not meet the needs of all patients. Recent reports indicate that external environmental factors, including diet, are key in the pathomechanism of the disease. It was proven that the so-called Western dietary pattern is associated with an increased risk of disease. In the pediatric population, exclusive enteral nutrition is the only nutritional therapy option recommended today with proven high efficacy in inducing remission. Recent publications that indicate at least comparable efficacy and significantly better tolerability of a specialised elimination diet, the Crohn’s Disease Exclusion Diet (CDED), provide the basis for a change in recommendations. This article discusses the mechanism of action, principles of use, and scientific evidence evaluating the efficacy of CDED in the treatment of children with Crohn’s disease.
Are spine metastasis survival scoring systems outdated and do they underestimate life expectancy? Caution in surgical recommendation guidance.

OBJECTIVE Survival scoring systems for spine metastasis (SPM) were designed to help surgical practice. The authors sought to validate the prognostic accuracy of the main preoperative scoring systems for SPM. METHODS It was hypothesized that true patient survival in SPM was better than that predicted using prognosis scores. To investigate this hypothesis, the authors designed a French national retrospective study of a prospectively collected multicenter database involving 739 patients treated for SPM between 2014 and 2017. RESULTS In this series, the median survival time for all patients from an SPM diagnosis was 17.03 ± 1.5 months. Sensitivity and specificity were estimated using the area under the curve (AUC). The AUC of Tomita's prognosis score was the lowest and poorest (0.4 ± 0.023, range 0.35-0.44), whereas the AUC of the Tokuhashi score was the highest (0.825). The Lei score presented an AUC of 0.686 ± 0.022 (range 0.64-0.7), and the Rades score showed a weaker AUC (0.583 ± 0.020, range 0.54-0.63). Differences among AUCs were all statistically significant (p < 0.001). The modified Bauer score and the Rades score had the highest rate of agreement in predicting survival, with a weighted Cohen's kappa of 0.54 and 0.41, respectively, indicating a moderate agreement. The revised Tokuhashi and Lei scores had a fair rate of agreement (weighted Cohen's kappa = 0.24 and 0.22, respectively). The van der Linden and Tomita scores demonstrated the worst performance, with only a "slight" rate of agreement (weighted Cohen's kappa = 0.19 and 0.16, respectively) between what was predicted and the actual survival. CONCLUSIONS The use of prognostic scoring systems in the estimation of survival in patients with SPM has become obsolete and therefore underestimates survival. Surgical treatment decisions should no longer be based on survival estimations alone but must also take into account patient symptoms, spinal instability, and quality of life.
Birchen and Blue Leonesa sperm cryopreservation: a new technique for evaluating the integrity of cockerel sperm membranes

ABSTRACT 1. Birchen and Blue Leonesa are two endangered chicken breeds mainly raised in Curueño Valley in North Spain. The establishment of a germplasm bank to guarantee the preservation of these breeds is needed. However, cockerels from different breeder flocks can show variance in semen cryoresistance. 2. The following work focused on the sperm characterisation and cryopreservation of Birchen and Blue Leonesa cockerels from four different breeders. A total of 30 semen pools were analysed. Besides conventional sperm analysis, including motility by computer-aided sperm analysis (CASA) and DNA fragmentation by TUNEL, the present study tested a double staining method (MitoTrackerTM Green FM/propidium iodide). This gave simultaneous assessment of plasma and acrosomal and mitochondrial membranes, which were previously validated by SYBR-14/PI, CASA, aniline blue and TUNEL. 3. No significant differences were found among fresh semen variables between breeds and breeders. For post-thawed variables, significant differences (P < 0.05) were found between breeders in sperm viability (58.0 ± 1.90 breeder D vs. 35.2 ± 7.41 breeder A, 37.2 ± 4.09 breeder B and 22.3 ± 5.92 breeder C) and DNA fragmentation (62.4 ± 9.91 breeder C vs. 31.8 ± 7.08 breeder B and 24.5 ± 5.49 breeder D). The lowest DNA fragmentation values for semen from breeder D birds were coincident with higher integrity of the mitochondrial membrane. 4. The results revealed higher sperm cryoresistance in the cockerels from one of the breeders, possibly due to differences in management system (e.g. diet, housing, control of stress elements and pathogens, reproduction practices or maintenance of genetic diversity). These differences may determine the sperm freezability, and thus the effectiveness of developing a germplasm bank.