Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics (PK) and Pharmacodynamics (PD) of Epoetin Alfa in Anemic Cancer Patients Receiving Cycling Chemotherapy.

Epoetin alfa is a recombinant human erythropoietin (EPO). The objective of this study was to compare the PK/PD of epoetin alfa after a fixed dose (40,000 IU) once weekly (QW) regimen to those after the weight based (150 IU/kg) 3 times per week (TIW) regimen for 4 weeks in healthy subjects and for 6 weeks in anemic cancer patients. In this randomized, open-label, parallel, multi-center study, PK profiles were determined during Week 1 and Week 3 in healthy subjects. For cancer patients, PK profiles were determined during Week 1 when patients were receiving chemotherapy and an optional one during Week 3 when patients were not receiving chemotherapy. Of the 33 enrolled cancer patients who received as least one dose of Epoetin alfa (safety population), 29 were evaluable for PK and 27 were evaluable for PD. Of the safety population (82% had solid tumors), ECOG scores were 0 (48%), 1 (42%), and 2 (9%). None of the patients had bone or kidney metastasis. Their ages and body weights ranged from 31–77 yrs (mean 59.2 yrs) and 50.9 –94.1 kg (mean 70.8 kg), respectively. Mean serum EPO concentrations in the cancer patients during Week 1 were higher than during Week 3. In general, the concentration-time profiles and PK parameters of anemic cancer subjects were different from those in healthy subjects during Week 1 but similar to healthy subjects during Week 3. Mean (SD) PK parameters are listed in following table. Epoetin alfa was safe and well tolerated after the two regimens in this study. The 40,000 IU QW regimen had a higher C max , higher exposure to epoetin alfa/erythropoietin in serum (in terms of AUC 0-7days ), and a lower clearance (CL/F) than the 150 IU/kg TIW regimen. Despite these PK differences, time-profiles of changes in PD parameters and their AUC (% reticulocytes, hemoglobin, and total RBCs) were similar. Mean (SD) PK parameters
A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients

Purpose: We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel. Patients and Methods: Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines. Results: Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). Overall survival (P = 0.59) and relapse-free survival (P = 0.55) did not differ between the two arms. Conclusions: The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity.
Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology

Objective: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). Methods: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. Results: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery. Conclusions: The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT.
Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization

Pharmacological concentrations of melatonin reduce reperfusion arrhythmias, but less is known about the antiarrhythmic protection of the physiological circadian rhythm of melatonin. Bilateral surgical removal of the superior cervical ganglia irreversibly suppresses melatonin rhythmicity. This study aimed to analyze the cardiac electrophysiological effects of the loss of melatonin circadian oscillation and the role played by myocardial melatonin membrane receptors, SERCA2A, TNFα, nitrotyrosine, TGFβ, KATP channels, and connexin 43. Three weeks after bilateral removal of the superior cervical ganglia or sham surgery, the hearts were isolated and submitted to ten minutes of regional ischemia followed by ten minutes of reperfusion. Arrhythmias, mainly ventricular tachycardia, increased during reperfusion in the ganglionectomy group. These hearts also suffered an epicardial electrical activation delay that increased during ischemia, action potential alternants, triggered activity, and dispersion of action potential duration. Hearts from ganglionectomized rats showed a reduction of the cardioprotective MT2 receptors, the MT1 receptors, and SERCA2A. Markers of nitroxidative stress (nitrotyrosine), inflammation (TNFα), and fibrosis (TGFβ and vimentin) did not change between groups. Connexin 43 lateralization and the pore-forming subunit (Kir6.1) of KATP channels increased in the experimental group. We conclude that the loss of the circadian rhythm of melatonin predisposes the heart to suffer cardiac arrhythmias, mainly ventricular tachycardia, due to conduction disorders and changes in repolarization.
Preterm delivery: a single hospital experience

Objectives: The aim of this study was to evaluate relation of preterm delivery with mother´s age, premature rupture of amniotic sac, number of spontaneous vaginal deliveries or Cesarean sections (C-sections), Apgar score in the first and the fifth minute, as well as birth weight of newborns. Methods: The study was retrospective, comparative, and data were obtained at the Clinic of Obstetrics and Gynecology of the University Clinical Centre Sarajevo for the period from October 2013 through February 2014. The sample was divided into two groups based on the timing of delivery: preterm delivery group (before 37th week of pregnancy) and term delivery group (after 37th week of pregnancy). The standard methods of descriptive statistics and the univariate analysis were performed. Results: Univariate analysis showed that there was no significant association of mother´s age with preterm delivery (OR=1.02, CI: 0.94, 1.10; p=0.72). Rupture of fetal membranes was 4.53 (OR=4.53, CI:1.95, 10.51, p<0.001) while C-section was 9.8 (OR=9.80, CI: 3.34, 36.14; p<0.001) times more frequent in preterm compared to term delivery group. Severely depressed Apgar score (0-3) was 84% (OR=1.84, CI: 1.01, 03.35; p=0.046) more frequent in the first and 52% (OR=1.52, CI: 0.72, 2.98; p=0.29) more frequent in the fifth minute after preterm compared to term delivery. Low birth weight (<2500g) was associated with preterm delivery group (OR=3.78, CI: 1.75, 9.33, p<0.001). Conclusion: Significant association of preterm deliveries with rupture of fetal membranes, C-section, severely depressed one-minute Apgar score (0-3) and low birth weight was documented. Keywords: premature membranes rupture, Apgar score, Cesarean section
Thermoresponsive Hydrogel Induced by Dual Supramolecular Assemblies and Its Controlled Release Property for Enhanced Anticancer Drug Delivery.

Supramolecular hydrogels based on inclusion complexation between cyclodextrins (CDs) and polymers have attracted much interest due to their potential for biomedical applications. It is also attractive to incorporate stimuli-responsive properties into the system to create "smart" hydrogels. Herein, a poly(N-isopropylacrylamide) (PNIPAAm) star polymer with a β-CD core and an adamantyl-terminated poly(ethylene glycol) (Ad-PEG) polymer were synthesized. They self-assembled into a thermoresponsive pseudo-block copolymer through a host-guest complexation, and formed supramolecular micelles with the change of environment temperature. Subsequently, an injectable polypseudorotaxane-based supramolecular hydrogel was formed between α-CD and the PEG chains of the pseudo-block copolymer. The hydrogel had a unique network structure involving two types of supramolecular self-assemblies between cyclodextrins and polymers, i.e., the host-guest complexation between β-CD units and adamantyl groups, and the polypseudorotaxane formation between α-CD and PEG chains. We hypothesize that the dual supramolecular hydrogel formed at room temperature may be enhanced by increasing the temperature over the lower critical solution temperature (LCST) of PNIPAAm, due to the hydrophobic interactions of PNIPAAm segments. Further, if the hydrogel is applied for sustained delivery of hydrophobic drugs, the copolymer dissolved from the hydrogel could micellize and continue to serve as micellar drug carriers with the drug encapsulated in the hydrophobic core. Rheological tests revealed that the hydrophobic interactions of the PNIPAAm segments could significantly enhance the strength of the hydrogel when temperature increased from 25 to 37 °C. As compared to hydrogels formed by α-CD and PEG only, the sustained release property of this thermoresponsive hydrogel for an anticancer drug, doxorubicin (DOX), was improved at 37 °C. The hydrogel dissolved slowly and released the pseudo-block copolymer in the forms of micelles that continued to serve as drug carriers with DOX encapsulated in the hydrophobic core, achieving a better cellular uptake and anticancer effect than free DOX controls even in multidrug resistant cancer cells. According to these findings, the dual supramolecular hydrogel developed in this work with remarkable thermoresponsive properties might have potential for sustained anticancer drug delivery with enhanced therapeutic effect in multidrug resistant cancer cells.
Honokiol ameliorates oxidative stress-induced DNA damage and apoptosis of c2c12 myoblasts by ROS generation and mitochondrial pathway

ABSTRACT Honokiol is one of the main active components of Magnolia officinalis, and has been demonstrated to have multiple pharmacological activities against a variety of diseases. Recently, this phenolic compound is known to have antioxidant activity, but its mechanism of action remains unclear. The purpose of the current study was to evaluate the preventive effects of honokiol against oxidative stress-induced DNA damage and apoptosis in C2C12 myoblasts. The present study found that honokiol inhibited hydrogen peroxide (H2O2)-induced DNA damage and mitochondrial dysfunction, while reducing reactive oxygen species (ROS) formation. The inhibitory effect of honokiol on H2O2-induced apoptosis was associated with the up-regulation of Bcl-2 and down-regulation of Bax, thus reducing the Bax/Bcl-2 ratio that in turn protected the activation of caspase-9 and -3, and inhibition of poly (ADP-ribose) polymerase cleavage, which was associated with the blocking of cytochrome c release to the cytoplasm. Collectively, these results demonstrate that honokiol defends C2C12 myoblasts against H2O2-induced DNA damage and apoptosis, at least in part, by preventing mitochondrial-dependent pathway through scavenging excessive ROS.
Gene Expression Analysis of Fruit Bromelain in Ripening of Ananas comosus Cultivar MD 2

Fruit bromelain is a proteolytic enzyme harbouring cysteine catalytic residue found abundantly in pineapple fruit. The expression of cysteine proteases is usually regulated during fruit ripening. In the present study, we aimed to study the expression and proteolytic activity level of fruit bromelain during the ripening stage of A. comosus cultivar MD 2. The gene expression of fruit bromelain was investigated via relative gene expression analysis using qPCR while the proteolytic activity of fruit bromelain was analysed via enzymatic assay using casein as a substrate. The qPCR analysis revealed that the expression of fruit bromelain was down-regulated 10-fold in ripe pineapple fruits. Besides that, the unripe pineapple fruits [1.9101 ± 0.0831 U/mL] had a higher proteolytic activity than the ripe MD 2 pineapple fruits [1.1333 ± 0.0896 U/mL]. This result showed that the function of fruit bromelain may be related to the protection of young pineapple fruits during the fruit development stage.
Conhecimentos de escolares e funcionários da Rede Pública de Ensino sobre as parasitoses intestinais

O desconhecimento ou nível insatisfatório de informações sobre as enteroparasitoses e sua prevenção, aliados ao baixo nível socioeconômico, educacional e insuficiência de saneamento básico, têm sido apontados como fatores de risco para a aquisição dessas infecções. Neste estudo foram averiguados os conhecimentos de estudantes do 3º ao 7º ano do Ensino Fundamental e dos funcionários de sete escolas Municipais de Niterói, RJ, Brasil. Foram aplicados questionários, e as respostas foram avaliadas como adequadas, inadequadas, incompletas, não soube responder ou não respondeu. Entre os 335 estudantes, observou-se conhecimento mediano sobre habitat (47,5 %), prevenção (48,4 %) e sintomatologia (45,1 %). Desses, 43,3 % demonstraram conhecimento inadequado sobre transmissão. E 51,6 % dos estudantes fizeram associação de verminoses com vermes, e somente 2,7 % apresentaram conhecimento sobre protozoários. Em 62 funcionários, observou-se conhecimento adequado sobre definição, exemplos, habitat, transmissão, sintomatologia e prevenção. Tais resultados evidenciaram a ocorrência de informações fragmentadas sobre a infecção por enteroparasitos entre os escolares e mais corretas entre os funcionários. Torna-se importante efetuar melhor abordagem do tema, referente aos conteúdos de ciências, e ampliar este arcabouço teórico para interferir na difusão da informação e na formação de cidadãos críticos.
From Intelligent Energy Management to Value Economy through a Digital Energy Currency: Bahrain City Case Study

The transition of the energy system into a more efficient state requires innovative ideas to finance new schemes and engage people into adjusting their behavioural patterns concerning consumption. Effective energy management combined with Information and Communication Technologies (ICTs) open new opportunities for local and regional authorities, but also for energy suppliers, utilities and other obligated parties, or even energy cooperatives, to implement mechanisms that allow people to become more efficient either by producing and trading energy or by reducing their energy consumption. In this paper, a novel framework is proposed connecting energy savings with a digital energy currency. This framework builds reward schemes where the energy end-users could benefit financially from saving energy, by receiving coins according to their real consumption compared to the predicted consumption if no actions were to take place. A pilot appraisal of such a scheme is presented for the case of Bahrain, so as to simulate the behaviour of the proposed framework in order for it to become a viable choice for intelligent energy management in future action plans.
LncRNA GUSBP5-AS promotes EPC migration and angiogenesis and deep vein thrombosis resolution by regulating FGF2 and MMP2/9 through the miR-223-3p/FOXO1/Akt pathway

Long non-coding RNAs (lncRNAs) play an essential role in multitudinous physiological and pathological processes, including vascular disease. We previously showed that lncRNA GUSBP5-AS (enst00000511042) is upregulated in endothelial progenitor cells (EPCs) of deep veni thrombosis (DVT) patients. Here, we investigate the role and mechanism of GUSBP5-AS in EPCs and DVT. Using the DVT model, we found that GUSBP5-AS significantly reduced the thrombus size and weight and enhanced the homing ability of EPC to DVT sites to promote resolution and recanalization of thrombus. GUSBP5-AS promoted cell cycle progression, proliferation, migration and invasion in EPCs, enhanced EPC angiogenesis in vitro and in vivo, and inhibited apoptosis. Strikingly, this study showed that GUSBP5-AS was unbalanced and modulated Forkhead Box Protein O1 (FOXO1) in EPCs in patients with DVT by interacting with miR-223-3p. Mechanistically, GUSBP5-AS functions as a sponge of miR-223-3p, which targets FOXO1. Both GUSBP5-AS knockdown and miR-223-3p overexpression remarkably inhibited angiogenesis, migration and invasion in EPCs. Additionally, our data suggested that GUSBP-AS activated the Akt pathway and enhanced fibroblast growth factor 2 (FGF2), matrix metalloproteinase-2/9 (MMP2/9) and F-actin expression. Taken together, this study indicates that GUSBP5-AS modulates angiogenesis, proliferation and homing ability of EPCs via regulating FGF2 and MMP2/9 expression through the miR-223-3p/FOXO1/Akt pathway, which may provide a new direction for the development of DVT therapeutics.
The Effect of Counterfactual Information on Outcome Value Coding in Medial Prefrontal and Cingulate Cortex: From an Absolute to a Relative Neural Code

Adaptive coding of stimuli is well documented in perception, where it supports efficient encoding over a broad range of possible percepts. Recently, a similar neural mechanism has been reported also in value-based decision, where it allows optimal encoding of vast ranges of values in PFC: neuronal response to value depends on the choice context (relative coding), rather than being invariant across contexts (absolute coding). Adaptive coding of stimuli is well documented in perception, where it supports efficient encoding over a broad range of possible percepts. Recently, a similar neural mechanism has been reported also in value-based decision, where it allows optimal encoding of vast ranges of values in PFC: neuronal response to value depends on the choice context (relative coding), rather than being invariant across contexts (absolute coding). Additionally, value learning is sensitive to the amount of feedback information: providing complete feedback (both obtained and forgone outcomes) instead of partial feedback (only obtained outcome) improves learning. However, it is unclear whether relative coding occurs in all PFC regions and how it is affected by feedback information. We systematically investigated univariate and multivariate feedback encoding in various mPFC regions and compared three modes of neural coding: absolute, partially-adaptive and fully-adaptive. Twenty-eight human participants (both sexes) performed a learning task while undergoing fMRI scanning. On each trial, they chose between two symbols associated with a certain outcome. Then, the decision outcome was revealed. Notably, in one-half of the trials participants received partial feedback, whereas in the other half they got complete feedback. We used univariate and multivariate analysis to explore value encoding in different feedback conditions. We found that both obtained and forgone outcomes were encoded in mPFC, but with opposite sign in its ventral and dorsal subdivisions. Moreover, we showed that increasing feedback information induced a switch from absolute to relative coding. Our results suggest that complete feedback information enhances context-dependent outcome encoding. SIGNIFICANCE STATEMENT This study offers a systematic investigation of the effect of the amount of feedback information (partial vs complete) on univariate and multivariate outcome value encoding, within multiple regions in mPFC and cingulate cortex that are critical for value-based decisions and behavioral adaptation. Moreover, we provide the first comparison of three possible models of neural coding (i.e., absolute, partially-adaptive, and fully-adaptive coding) of value signal in these regions, by using commensurable measures of prediction accuracy. Taken together, our results help build a more comprehensive picture of how the human brain encodes and processes outcome value. In particular, our results suggest that simultaneous presentation of obtained and foregone outcomes promotes relative value representation.
A case of severe psoriasis in a 84‐year‐old women successfully treated with ixekizumab

Dear Editor, Psoriasis is a chronic inflammatory skin disease showing a high impact on quality of life for its aesthetic and psychological implications which also affect patient-physician relationship and, consequently, adherence to treatments. In 3% to 13% of cases psoriasis may directly develop in elderly age and ~15% of these elderly subjects have moderate-to-severe disease. Conventional systemic therapies can be highly risky or even contraindicated in elderly psoriatic patients, shifting physicians' attention to biologics. However, efficacy and safety of biologics in patients ≥65 years are not clearly described. Even if few data are available for anti-TNF-α and anti-IL12/23 use in geriatric patients, more studies are needed for anti-IL17. Herein we report the case of an 84-year-old Caucasian female with severe plaque psoriasis. The patient was suffering from plaque-type psoriasis for 3 years, previously treated with methotrexate and narrow band UVB phototherapy. When referring to our clinic, she was affected by a severe and widespread form of plaque psoriasis (psoriasis area and severity index [PASI]: 22—body surface area: 60%), associated with severe itching (visual analogue scale for itching [VAS]: 8) that resulted in a reduction of the quality of life (dermatology life quality index [DLQI]: 25) (Figure 1a). The patient was also suffering from hypertension, and depression. Treatment with standard dose ixekizumab led to achieve complete remission (PASI100) after only 4 weeks (Figure 1b), with complete resolution of itching symptoms (VAS:0). A huge improvement was also observed for DLQI which decreased from 25 (at week 0) to 0 (at week 4). These results are still maintained at