Miracle-dz/UniFAR-FTUs huggingface dataset:
Delineation of the Molecular Mechanisms of Nucleoside Recognition by Cytidine Deaminase through Virtual Screening

Cytidine deaminase (EC 3.5.4.5, CDA), an enzyme of the pyrimidine salvage pathways, is responsible for the degradation and inactivation of several cytidine‐based antitumor drugs such as cytarabine, gemcitabine, decitabine, and azacytidine. Thus, CDA inhibitors are highly sought after as compounds to be co‐administered with said drugs to improve their effectiveness. Alternatively, the design of antitumor drugs not susceptible to the action of CDA is also regarded as an attractive solution. Herein we describe a virtual screen for CDA ligands based on chemical similarity and molecular docking. The campaign led to the identification of three novel inhibitors and one novel substrate, with a 19 % hit rate, and allowed a significant extension of the structure–activity relationships, also in light of the compounds that resulted inactive. The most active compound identified through the screen is the inhibitor pseudoisocytidine, which has the potential to serve as a lead for highly stable compounds. The study also delineated the detrimental effect of 5‐aza and 6‐aza substitutions, the incompatibility of the presence of an amino group at the 3′‐position, as well as the presence of very strict steric requirements around the 2′‐arabino position and, even more, the N4‐position. Importantly, these features can be exploited for the design of novel anti‐neoplastic agents resistant to the action of CDA.
Retrogressed (burned-out) testicular germ cell tumor disguising as duodenal gastrointestinal stromal tumor

Oncology, Gastroenterology and Hepatology Reports| Jul-Dec 2015 | Vol 4 | Issue 2 Sir, Testicular germ cell tumors (TGCT) most often present as masses in the testes but may uncommonly present with symptoms pertaining to the sites of their metastases. In the latter situation, the primary lesion may be clinically unapparent due to small size, central location or a true burned‐out/regressed tumor. The primary tumor can be overlooked in this clinical scenario which may lead to inappropriate patient management.
Toward the Discovery of Novel Anti‐HIV Drugs. Second‐Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti‐HIV Activity: Synthesis, Structure–Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD‐box RNA helicase DDX3 led to the design and synthesis of second‐generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV‐1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure–activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti‐HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV‐1 host cofactors.
Cannabinoid CB2 receptor attenuates morphine‐induced inflammatory responses in activated microglial cells

BACKGROUND AND PURPOSE Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states. In the present study, we characterized the signal transduction pathways mediated by cannabinoid CB2 and µ‐opioid receptors in quiescent and LPS‐stimulated murine microglial cells.
Peripheral neural targets in obesity

Interest in pharmacological treatments for obesity that act in the brain to reduce appetite has increased exponentially over recent years, but failures of clinical trials and withdrawals due to adverse effects have so far precluded any success. Treatments that do not act within the brain are, in contrast, a neglected area of research and development. This is despite the fact that a vast wealth of molecular mechanisms exists within the gut epithelium and vagal afferent system that could be manipulated to increase satiety. Here we discuss mechano‐ and chemosensory pathways from the gut involved in appetite suppression, and distinguish between gastric and intestinal vagal afferent pathways in terms of their basic physiology and activation by enteroendocrine factors. Gastric bypass surgery makes use of this system by exposing areas of the intestine to greater nutrient loads resulting in greater satiety hormone release and reduced food intake. A non‐surgical approach to this system is preferable for many reasons. This review details where the opportunities may lie for such approaches by describing nutrient‐sensing mechanisms throughout the gastrointestinal tract.
RISK OF RETINAL VEIN OCCLUSION WITH CENTRAL SEROUS CHORIORETINOPATHY

Purpose: To investigate the risk of retinal vein occlusion (RVO) after central serous chorioretinopathy (CSCR). Methods: The study included 2882 CSCR patients and 17,292 control patients matched by age, sex, number of visits to an ophthalmologist, diabetes mellitus, hypertension, and hyperlipidemia from January 2001 to December 2010 from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected until December 2011. Cox proportional hazard regression analysis was used to obtain the adjusted hazard ratio for RVO. The RVO-free survival rate was calculated using Kaplan–Meier analysis. Results: There was a significantly higher risk of RVO in CSCR patients than in controls (incidence rate ratio = 3.07, 95% confidence interval = 1.86–5.07). After adjustment for potential confounders, the adjusted hazard ratio for developing RVO in the CSCR patients was 3.15 times higher than that of the controls (adjusted hazard ratio = 3.15, 95% confidence interval = 1.91–5.21). Conclusion: Central serous chorioretinopathy increases the risk of RVO. For CSCR patients, the authors recommend thorough retinal vessel evaluation, regular follow-up, and education regarding RVO for patients with CSCR.
Weightlifting Training and Hormonal Responses in Adolescent Males: Implications for Program Design

THE ROLE OF STRENGTH training for youth has received considerable attention in recent years. In this age of overzealous parents and coaches, an increasing concern has been for what constitutes an appropriate training program for youth. Although it is clear that many elite athletes begin their training at a young age, one must always be concerned for the welfare of the child. Although not all champions begin training for their respective sports at a very young age, it is becoming increasingly common to start serious training during adolescence (the age from the onset of puberty to adulthood), and in the case of sports such as gymnastics, at an even younger age. In weightlifting, for instance, it is likely that an earlier start to training is partly responsible for the dominance that Eastern European and Asian countries display. So, how old must a child be before such difficult training demands are placed on them? Should they specialize in one activity, or should they include many different sports and activities to provide a broad training experience? Furthermore, what type of training program is best during adolescence? Although not all of these questions are easily answered, the main purpose of this article is to take a brief look at what physiology can tell us about training tolerance during adolescence. It is readily apparent that many different factors contribute to elite performances in any sport or activity. This article will focus on the insights gained from the sport of weightlifting (i.e., snatch, clean and jerk). Most of the athletes in the studies reviewed here specialize in weightlifting training. Because this is the only lifting sport that is included in the Olympic Games, much research has been performed regarding its physiology. Although not all youth who participate in resistance training perform these exercises, data from these studies may still provide the best opportunity to examine how adolescents respond to stressful weight-training programs. In the pursuit of excellence, talent identification programs have been developed to identify potentially elite performers for weightlifting (6, 7). Although this is certainly a critical step in developing top-notch performers in any sport, such testing has not yet addressed the issues of desire or capacity for the required training. Additionally, a coach or trainer must also be concerned with creating the proper psychological environment to optimize an individual's motivation and increase participant retention in the program (11). Certainly, a major concern is the physical safety of the training of weightlifting. To date, the data indicate that the weightlifting-training programs are as safe or safer than most other youth sport activities and that such training is not detrimental to the young athlete (4). Although all these considerations are important for resistance training of young athletes, the focus of the remainder of this article will be on monitoring the training tolerance of junior-aged weightlifters.
Neoangiogenesis after direct intramyocardial implantation of bone marrow-derived stem cells in a patient with severe coronary artery disease ineligible for percutaneous or surgical revascularization

Bone marrow-derived stem cells (BMSC) may be an alternative for the treatment of patients with severe coronary artery disease ineligible for either percutaneous or surgical revascularization. This case report presents a 65-year-old male patient with untreatable angina pectoris (Canadian Cardiovascular Society Class III) and severe coronary artery disease. A mixture of BMSC containing approximately 3×106 CD34+ cells was directly injected into preoperatively determined ischemic regions of the myocardium by median sternotomy. At baseline, at 3 months, and at 1 year of follow-up, echocardiography (demonstrating wall motions of 16 segments), single-photon emission computed tomography, and coronary angiography (at baseline and at 1 year) were performed to assess myocardial perfusion, left ventricular (LV) function and coronary anatomy. The patient reached Canadian Cardiovascular Society Class I after 6 months of cell implantation. The ejection fraction increased from 34% to 37% at the third month and 40% at 1 year of follow-up. At 1 year of follow-up, preoperatively akinetic mid-base septum and anteroseptal regions progressed to mild hipokinesia and severe hypokinetic mid-base-apical anterior regions and apical lateral-inferior regions became normokinesia. Single-photon emission computed tomography revealed a visible improvement in anterior and lateral segments at 1 year of follow-up. Coronary angiography showed newly developed collateral arteries at 1 year of follow-up. BMSC transplantation in a patient with severe coronary artery disease resulted in increase of LV ejection fraction, an increase of the perfusion of ischemic myocardial regions, and improvement in wall motion defects without any adverse events.
Brain mapping in neuro-oncology: what is the future?

Surgery is the first treatment in neuro-oncology. However, brain gliomas are frequently located within eloquent areas. Therefore, in order to maximize the extent of resection while preserving cerebral functions, owing to major interindividual anatomo–functional variability across patients, functional mapping is now mandatory. Preoperative functional neuroimaging allows a better understanding of the individual organization of brain networks, leading to optimized surgical indications and planning. Intrasurgical cortical and subcortical stimulation, often carried out in awake patients, enables assessment of the performance of online anatomo–functional correlations, with increased resection according to functional boundaries. Postoperative functional neuroimaging following recovery, regularly carried out after active rehabilitation, provides information regarding cerebral plasticity over time, possibly opening the door to another surgery(ies). In summary, brain mapping allows surgical removal in eloquent area.
Structure–Activity Relationships of Organofluorine Inhibitors of β‐Amyloid Self‐Assembly

A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of β‐amyloid (Aβ) self‐assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of Aβ oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF3‐C‐OH and CF3‐C‐NH groups that were proposed to be binding units in our previous studies. A broad range of potential small‐molecule inhibitors were synthesized by combining various carbocyclic and heteroaromatic rings with an array of substituents, generating a total of 106 molecules. The compounds were tested by standard methods such as thioflavin‐T fluorescence spectroscopy for monitoring fibril formation, biotinyl Aβ1–42 single‐site streptavidin‐based assays for observing oligomer formation, and atomic force microscopy for morphological studies. These assays revealed a number of structures that show significant inhibition against either Aβ fibril or oligomer formation. A detailed analysis of the structure–activity relationship of anti‐fibril and ‐oligomer properties is provided. These data present further experimental evidence for the distinct nature of fibril versus oligomer formation and indicate that the interaction of the Aβ peptide with chiral small molecules is not stereospecific in nature.
Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer

Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST. Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented. Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.
Update on the efficacy and safety of combination ezetimibe plus statin therapy

Abstract The primary aim of lipid-related cardiovascular disease (CVD) risk management is the lowering of LDL-C levels. Numerous studies have shown that statins, which inhibit cholesterol biosynthesis, effectively reduce serum LDL-C and subsequent CVD risk. Ezetimibe is an LDL-C-lowering drug that inhibits the absorption of dietary and biliary cholesterol through its interaction with the intestinal Niemann–Pick C1-like 1 sterol transporter. When combined with statin therapy, the complementary inhibition of cholesterol absorption and synthesis with these two agents is highly effective in not only reducing LDL-C, but also in improving serum levels of other lipid fractions and reducing high-sensitivity C-reactive protein levels compared with either agent alone. This article summarizes the most current clinical data available on the lipid-altering efficacy and safety of ezetimibe coadministered with statins in patients with hypercholesterolemia and in other diverse populations. In addition, the impact of ezetimibe on surrogate imaging, clinical outcome measures and other potential effects that may translate into CVD risk reduction are also described. An assessment of the full clinical significance of ezetimibe therapy will depend on the results of cardiovascular outcomes trials anticipated during the next few years.
Eficacia del hierro aminoquelado en comparación con el sulfato ferroso como fortificante de un complemento alimentario en preescolares con deficiencia de hierro, Medellín, 2011

Introduction: Iron depleted deposits are the first link in the chain of events leading to iron deficiency which is the most prevalent nutritional shortage and main cause of anemia worldwide. This situation can be prevented through food fortification. Objective: To compare the efficacy of amino acid chelate iron with ferrous sulfate as fortifier of a dietaryc omplement in preschoolers with iron deficiency. Materials and methods: This study was a blinded clinical trial with randomized groups. We analyzed 56 preschoolers with iron deficiency (ferritin < 24 ng/ml) that received 13 g of milk with 12.5 mg of iron, either amino acid chelate or in the ferrous sulfate form. After two months, hemoglobin, hematocrit and serum ferritin concentrations were measured. Results: In the ferrous sulfate group, ferritin concentration increased from 18.8 ng/ml to 24.1 ng/ml,while the variation was of 18.4 ng/ml to 29.7 ng/ml in the amino acid chelate group, with statistically differences in both cases. Serum ferritin was different between groups, being higher in iron aminoacid chelate group (p=0.022). Hemoglobin and hematocrit levels did not change after the intervention. Adverse reactions in the ferrous sulfate group were 35.7%, compared with 42.9% in the iron amino acidc helate group; 5 children had respiratory tract infection, without statistical differences. Conclusions: Both compounds increased serum ferritin concentration, with a higher increase in thosewho were given milk with iron amino acid chelate. There were no differences in the adverse reactionsand infections incidences between the groups. doi: http://dx.doi. org/10.7705/biomedica.v33i3. 775
Perfil metabólico y deterioro de órganos diana en hipertensos esenciales según el control de la presión arterial en la consulta

BACKGROUND AND OBJECTIVE To evaluate the degree of metabolic control and end-organ damage in a group of hypertensive patients with poor and good blood pressure (BP) control in primary health care centers. PATIENTS AND METHODS Observational study with diagnostic intervention, performed in 16 primary care centers of Burgos (Spain). 207 patients (120 with good BP control and 87 with poor BP control) with pharmacological treatment were included in the study. The following parameters were determined: clinic history, casual BP, 24-h ambulatory blood pressure monitoring (ABPM), electrocardiography, and clinic analysis in plasma and 24-hour urine. RESULTS The 32% and 31% of patients respectively were receiving combined pharmacological treatment. No significant differences were detected between the two groups for the levels of c-HDL > 130 mg/dl (62% vs. 62%), microalbuminuria (5% vs. 10%) and basal glucose levels > 126 mg/dl (105 vs. 15%). There was a significant proportion of patients with poor clinical BP control with left ventricular hypertrophy (13% vs. 34%; p < 0,001), impaired renal function (3% vs. 11%; p < 0,05), mean hematocrit value (41,9 +/- 4,5 vs. 43,7 +/- 3,5; p < 0,01) and different degree on BP control by ABPM (1,6% vs. 16%: p < 0,01). CONCLUSIONS Our hypertensive patients with poor BP clinical control showed more end-organ damage than those with good control, although they have a similar metabolic profile. The access to ABPM by primary health care centers could modify the therapeutic management in a significant subgroup of hypertensive patients with poor BP control.
OUTCOMES AFTER LASER VERSUS COMBINED LASER AND BEVACIZUMAB TREATMENT FOR TYPE 1 RETINOPATHY OF PREMATURITY IN ZONE I

Purpose: To investigate the anatomical and refractive outcomes in patients with Type 1 retinopathy of prematurity in Zone I. Methods: The medical records of 101 eyes of 51 consecutive infants with Type 1 retinopathy of prematurity in Zone I were analyzed. Infants were treated by conventional laser photocoagulation (Group I), combined intravitreal bevacizumab injection and Zone I sparing laser (Group II), or intravitreal bevacizumab with deferred laser treatment (Group III). The proportion of unfavorable anatomical outcomes including retinal fold, disc dragging, retrolental tissue obscuring the view of the posterior pole, retinal detachment, and early refractive errors were compared among the three groups. Results: The mean gestational age at birth and the birth weight of all 51 infants were 24.3 ± 1.1 weeks and 646 ± 143 g, respectively. In Group I, an unfavorable anatomical outcome was observed in 10 of 44 eyes (22.7%). In contrast, in Groups II and III, all eyes showed favorable anatomical outcomes without reactivation or retreatment. The refractive error was less myopic in Group III than in Groups I and II (spherical equivalent of −4.62 ± 4.00 D in Group I, −5.53 ± 2.21 D in Group II, and −1.40 ± 2.19 D in Group III; P < 0.001). Conclusion: In Type 1 retinopathy of prematurity in Zone I, intravitreal bevacizumab with concomitant or deferred laser therapy yielded a better anatomical outcome than conventional laser therapy alone. Moreover, intravitreal bevacizumab with deferred laser treatment resulted in less myopic refractive error.