Miracle-dz/UniFAR-FTUs huggingface dataset:
Noninvasive PET Imaging of CDK4/6 Activation in Breast Cancer

The cell cycle is a progression of 4 distinct phases (G1, S, G2, and M), with various cycle proteins being essential in regulating this process. We aimed to develop a radiolabeled cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for breast cancer imaging. Our transfluorinated analog (18F-CDKi) was evaluated and validated as a novel PET imaging agent to quantify CDK4/6 expression in estrogen receptor (ER)–positive human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Methods: 18F-CDKi was synthesized and assayed against CDK4/6 kinases. 18F-CDKi was prepared with a 2-step automated synthetic strategy that yielded the final product with remarkable purity and molar activity. In vitro and in vivo biologic specificity was assessed in a MCF-7 cell line and in mice bearing MCF-7 breast tumors. Nonradioactive palbociclib was used as a blocking agent to investigate the binding specificity and selectivity of 18F-CDKi. Results: 18F-CDKi was obtained with an overall radiochemical uncorrected yield of 15% and radiochemical purity higher than 98%. The total time from the start of synthesis to the final injectable formulated tracer is 70 min. The retention time reported for 18F-CDKi and 19F-CDKi is 27.4 min as demonstrated by coinjection with 19F-CDKi in a high-pressure liquid chromatograph. In vivo blood half-life (weighted, 7.03 min) and octanol/water phase partition coefficient (1.91 ± 0.24) showed a mainly lipophilic behavior. 18F-CDKi is stable in vitro and in vivo (>98% at 4 h after injection) and maintained its potent targeting affinity to CDK4/6. Cellular uptake experiments performed on the MCF-7 breast cancer cell line (ER-positive and HER2-negative) demonstrated specific uptake with a maximum intracellular concentration of about 65% as early as 10 min after incubation. The tracer uptake was reduced to less than 5% when cells were coincubated with a molar excess of palbociclib. In vivo imaging and ex vivo biodistribution of ER-positive, HER2-negative MCF-7 breast cancer models showed a specific uptake of approximately 4% injected dose/g of tumor (reduced to ∼0.3% with a 50-fold excess of cold palbociclib). A comprehensive biodistribution analysis also revealed a significantly lower activation of CDK4/6 in nontargeting organs. Conclusion: 18F-CDKi represents the first 18F PET CDK4/6 imaging agent and a promising imaging agent for ER-positive, HER2-negative breast cancer.
Factors associated with the length of hospital stay of women undergoing cesarean section

ABSTRACT OBJECTIVE To evaluate whether age group, complications or comorbidities are associated with the length of hospitalization of women undergoing cesarean section. METHODS A cross-sectional study was carried out between June 2012 and July 2017, with 64,437 women undergoing cesarean section and who did not acquire conditions during their hospital stay. Hospital discharge data were collected from national health institutions, using the Diagnosis-Related Groups system (DRG Brasil®). The DRG referring to cesarean section with additional complications or comorbidities (DRG 765) and cesarean section without complications or associated comorbidities (DRG 766) were included in the initial diagnosis. The influence of age group and comorbidities or complications present at admission on the length of hospital stay was assessed based on the means of the analysis of variance. The size of the effect was verified by Cohen’s D, which allows evaluating clinical relevance. The criticality levels were identified using the Duncan test. RESULTS The longest length of hospital stay was observed in the age group from 15 to 17 years old and among those aged 45 years old or more. The hospital stay of women with complications or comorbidities at the time of admission was also longer. Moreover, it was noted that the increase in criticality level was associated with an increase in the mean length of hospital stay. CONCLUSIONS The length of hospital stay of women is higher among those belonging to the age group ranging from 15 to 17 years old and for those aged 45 years old or more. The presence of associated comorbidities, such as eclampsia, pre-existing hypertensive disorder with superimposed proteinuria and gestational hypertension (induced by pregnancy) with significant proteinuria increase the length of hospital stay. This study enabled the construction of distinct criticality level profiles based on the combination of age groups and the main comorbidities, which were directly related to the length of hospital stay.
Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye–Protein Interaction

Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)–targeted radiotracers, for example, 99mTc-labeled PSMA tracer analogs for radioguided surgery. The purpose of this study was to develop a second-generation 99mTc-labeled PSMA-targeted tracer incorporating a fluorescent dye. Methods: Several PSMA-targeted hybrid tracers were synthesized: glutamic acid-urea-lysine (EuK)-Cy5-mas3, EuK-(SO3)Cy5-mas3, EuK-Cy5(SO3)-mas3, EuK-(Ar)Cy5-mas3, and EuK-Cy5(Ar)-mas3; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas3) chelate to study the dye’s interaction with PSMA’s amphipathic entrance funnel. The compounds were evaluated for their photophysical and chemical properties and PSMA affinity. After radiolabeling with 99mTc, we performed in vivo SPECT imaging, biodistribution, and fluorescence imaging on BALB/c nude mice with orthotopically transplanted PC346C tumors. Results: The dye composition influenced the photophysical properties (brightness range 0.3–1.5 × 104 M−1 × cm−1), plasma protein interactions (range 85.0% ± 2.3%–90.7% ± 1.3% bound to serum, range 76% ± 0%–89% ± 6% stability in serum), PSMA affinity (half-maximal inhibitory concentration [IC50] range 19.2 ± 5.8–175.3 ± 61.1 nM) and in vivo characteristics (tumor-to-prostate and tumor-to-muscle ratios range 0.02 ± 0.00–154.73 ± 28.48 and 0.46 ± 0.28–5,157.50 ± 949.17, respectively; renal, splenic, and salivary retention). Even though all tracer analogs allowed tumor identification with SPECT and fluorescence imaging, 99mTc-EuK-(SO3)Cy5-mas3 had the most promising properties (e.g., half-maximal inhibitory concentration, 19.2 ± 5.8, tumor-to-muscle ratio, 5,157.50 ± 949.17). Conclusion: Our findings demonstrate the intrinsic integration of a fluorophore in the pharmacophore in PSMA-targeted small-molecule tracers. In this design, having 1 sulfonate on the indole moiety adjacent to EuK (99mTc-EuK-(SO3)Cy5-mas3) yielded the most promising tracer candidate for imaging of PSMA.
Therapeutic Applications of Pretargeting

Targeted therapies, such as radioimmunotherapy (RIT), present a promising treatment option for the eradication of tumor lesions. RIT has shown promising results especially for hematologic malignancies, but the therapeutic efficacy is limited by unfavorable tumor-to-background ratios resulting in high radiotoxicity. Pretargeting strategies can play an important role in addressing the high toxicity profile of RIT. Key to pretargeting is the concept of decoupling the targeting vehicle from the cytotoxic agent and administrating them separately. Studies have shown that this approach has the ability to enhance the therapeutic index as it can reduce side effects caused by off-target irradiation and thereby increase curative effects due to higher tolerated doses. Pretargeted RIT (PRIT) has been explored for imaging and treatment of different cancer types over the years. This review will give an overview of the various targeted therapies in which pretargeting has been applied, discussing PRIT with alpha- and beta-emitters and as part of combination therapy, plus its use in drug delivery systems.
Peripheral Brain-Derived Neurotrophic Factor and Contactin-1 Levels in Patients with Attention-Deficit/Hyperactivity Disorder

Brain-derived neurotrophic factor (BDNF) facilitates neuronal growth and plasticity, and is crucial for learning and memory. Contactin-1 (CNTN1) is a member of the subfamily of neural immunoglobulin and is involved in the formation of axon connections in the developing nervous system. This cross-sectional study investigates whether BDNF and CNTN1 affect susceptibility to attention deficit/hyperactivity disorder (ADHD). A total of 136 drug-naïve patients with ADHD (108 boys and 28 girls) and 71 healthy controls (45 boys and 26 girls) were recruited. Blood samples were obtained to measure the plasma levels of BDNF and CNTN1 in each child. We found that BDNF levels in the ADHD boys exceeded those in the control boys, but BDNF levels in the ADHD girls were lower than those in the control girls. Boys who had higher BDNF levels performed worse on the Wechsler Intelligence Scale for Children—Fourth Edition, but girls who had higher BDNF levels made fewer omission errors in the Conners’ Continuous Performance Test. However, CNTN1 level did not differ significantly between patients and controls, and were not correlated to ADHD characteristics, regardless of gender. The findings suggest BDNF may influence sex-specific susceptibility to ADHD, but CNTN1 was not associated with ADHD pathophysiology.
The Morphopathogenetic Aspects of Intraabdominal Adhesions in Children under One Year of Age

Background and Objectives: The morphopathogenesis of adhesions is a complex process, characterized by the accumulation of an extracellular matrix, inflammation and hypoxia. The regulatory role between morphopathogenic factors in adhesions has not yet been defined. The aim was to investigate the appearance of transforming growth factor beta (TGFβ), basic fibroblast growth factor (FGF-2), fibroblast growth factor receptor 1 (FGFR1), protein gene product 9.5 (PGP 9.5), chromogranin A (CgA), interleukin-1 alpha (IL-1α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor alpha (TNFα), matrix metaloproteinase-2 (MMP-2) and matrix metaloproteinase-2 tissue inhibitor (TIMP-2) in intraabdominal adhesions. Materials and Methods: The study material was obtained from 49 patients under one year of age with total or partial bowel obstruction. All factors were detected using immunohistochemistry methods and their relative distribution was evaluated by means of the semiquantitative counting method. Results: Intraabdominal adhesions are characterized by increased TGFβ, FGFR1 and decreased FGF-2, PGP 9.5, IL-1, IL-4, IL-8, TIMP-2 findings. The most significant changes observed were the remodulation of the extracellular matrix, promotion of neoangiogenesis and the maintenance of a prolonged inflammation. Conclusions: The increase in TGFβ, as well as the disbalance between MMP-2 and TIMP-2 proves an increased fibrosis in intraabdominal adhesions. Less detected FGF-2 and more prominent FGR1 findings points out a compensatory receptor stimulation in response to the lacking same factor. The decrease in PGP 9.5 indicate hypoxic injury and proves the stimulation of neoangiogenesis. An unpronounced IL-1 and marked IL-10 finding indicate the local tissue protection reaction, the decrease in IL-4 could be the direct cause of giant cells, but the decrease of IL-8 could confirm a delayed chemotaxis of inflammatory cells.
An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex

At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5′ triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3′→5′ through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5′ caps and destruction of faulty adducts in 5′→3′ fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.
Layered Double Hydroxide Fluoride Release in Dental Applications: A Systematic Review

This systematic review appraises studies conducted with layered double hydroxides (LDHs) for fluoride release in dentistry. LDH has been used as antacids, water purification in removing excess fluoride in drinking water and drug delivery. It has great potential for controlled fluoride release in dentistry, e.g., varnishes, fissure sealants and muco-adhesive strips, etc. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was followed with two reviewers performing a literature search using four databases: PubMed, Web of Science, Science Direct and Ovid Medline with no date restrictions. Studies including any LDH for ion/drug release in dentistry were included, while assessing the application of LDH and the value of the methodology, e.g., ion release protocol and the LDH production process. Results: A total of 258 articles were identified and four met the inclusion criteria. Based on two in vitro studies and one clinical study, LDH was previously studied in dental materials, such as dental composites and buccal muco-adhesive strips for fluoride release, with the latter studied in a clinical environment. The fourth study analysed LDH powder alone (without being incorporated into dental materials). It demonstrated fluoride release and the uptake of volatile sulphur compounds (VSC), which may reduce halitosis (malodour). Conclusion: LDHs incorporated in dental materials have been previously evaluated for fluoride release and proven to be clinically safe. LDHs have the potential to sustain a controlled release of fluoride (or other cariostatic ions) in the oral environment to prevent caries. However, further analyses of LDH compositions, and clinical research investigating any other cariostatic effects, are required.
Physical Condition Factors that Predict a Better Quality of Life in Women with Fibromyalgia

What physical qualities can predict the quality of life (QoL) in women with fibromyalgia (FM)? QoL is a very complex outcome affected by multiple comorbidities in people with fibromyalgia. This study aims to determine which physical qualities can predict the quality of life in women with FM. Also, a comparison between the physical qualities of women with FM and healthy counterparts was conducted. In total, 223 women participated in this cross-sectional study, 123 with FM, with ages ranging between 45 and 70 years. The study was conducted at several fibromyalgia associations and specialized medical units. QoL was measured as the main outcome. In addition, functional capacity, muscular strength, maintenance of thoracic posture, postural control, flexibility, pain threshold, and anxiety were measured. Prediction of the QoL was conducted with multiple linear regression analysis and comparison between groups, using the Mann–Whitney U test. There were significant differences between groups in all the variables measured (p < 0.01). The multiple linear regression model showed that factors influencing QoL in women with FM for all the variables measured were functional capacity, handgrip strength and bicep strength, maintenance of thoracic posture, pain threshold, and anxiety (R2 = 0.53, p < 0.05). To conclude, women with FM show a significantly lower QoL than their healthy counterparts, and the factors that predict their perceived QoL are functional capacity, muscular strength, postural maintenance, pain threshold, and anxiety.
Intake, digestibility, and performance of lambs fed spineless cactus cv. Orelha de Elefante Mexicana

Objective To evaluate the effects of the carmine cochineal-resistant spineless cactus genotypes cv. Orelha de Elefante Mexicana (Opuntia) and Miúda (Nopalea) on the intake and digestibility of nutrients, ingestive behavior, performance, and ultrasound measurements of growing lambs. Methods Thirty-six male (non-castrated) Santa Inês lambs were used, with an average age of 6 months and an initial average weight of 22.0±2.9 kg. They were distributed in a completely randomized design with 3 treatments (Tifton hay, Nopalea and Opuntia) and 12 replications, using initial weight as a covariate. The experimental period was 86 days, with the first 30 days used for the adaptation of the animals to the facilities, diets and management, and the remaining 56 days used for evaluation and data collection. Results The intake and apparent digestibility of dry matter (DM), organic matter (OM), crude protein (CP), neutral detergent fiber (NDF), total carbohydrates (TC), non-fibrous carbohydrates (NFC), and total digestible nutrients (TDN) showed a significant difference (p<0.05) as a function of the diets, with the Nopalea treatment (p<0.05) increasing DM intake (g/kg and % body weight [BW]), CP, TDN, and TC digestibility, whereas the Tifton hay diet led to a high (p<0.001) neutral detergent fiber corrected for ash and protein (NDFap) g/d intake, NDFap (BW %) and digestibility of said nutrient. There was no effect of treatments (p>0.05) on feeding time, however, rumination time and total chewing time were higher (p<0.05) for animals fed Tifton hay. The performance of the animals was similar (p>0.05). For the ultrasound measurements, Nopalea promoted an increase in the final loin eye area, compared to Tifton hay. Conclusion The use of spineless cactus variety Miúda leads to the greater intake and digestibility of nutrients. The evaluated carmine cochineal-resistant spineless cactus genotypes are alternatives for semi-arid regions as they do not negatively affect the performance of growing lambs.
Radiomics: Data Are Also Images

The aim of this review is to provide readers with an update on the state of the art, pitfalls, solutions for those pitfalls, future perspectives, and challenges in the quickly evolving field of radiomics in nuclear medicine imaging and associated oncology applications. The main pitfalls were identified in study design, data acquisition, segmentation, feature calculation, and modeling; however, in most cases, potential solutions are available and existing recommendations should be followed to improve the overall quality and reproducibility of published radiomics studies. The techniques from the field of deep learning have some potential to provide solutions, especially in terms of automation. Some important challenges remain to be addressed but, overall, striking advances have been made in the field in the last 5 y.
Deficiency in Androgen Receptor Aggravates the Depressive-Like Behaviors in Chronic Mild Stress Model of Depression

While androgen receptor (AR) and stress may influence the development of the major depressive disorder (MDD), the detailed relationship, however, remains unclear. Here we found loss of AR accelerated development of depressive-like behaviors in mice under chronic mild stress (CMS). Mechanism dissection indicated that AR might function via altering the expression of miR-204-5p to modulate the brain-derived neurotrophic factor (BDNF) expression to influence the depressive-like behaviors in the mice under the CMS. Adding the antiandrogen flutamide with the stress hormone corticosterone can additively decrease BDNF mRNA in mouse hippocampus mHippoE-14 cells, which can then be reversed via down-regulating the miR-204-5p expression. Importantly, targeting this newly identified AR-mediated miR-204-5p/BDNF/AKT/MAPK signaling with small molecules including 7,8-DHF and fluoxetine, all led to alter the depressive-like behavior in AR knockout mice under CMS exposure. Together, results from these preclinical studies conclude that decreased AR may accelerate the stress-induced MDD via altering miR-204-5p/BDNF/AKT/MAPK signaling, and targeting this newly identified signaling may help in the development of better therapeutic approaches to reduce the development of MDD.
Comparison of the Utility of RP-TLC Technique and Different Computational Methods to Assess the Lipophilicity of Selected Antiparasitic, Antihypertensive, and Anti-inflammatory Drugs

The aim of this study was to assess the lipophilicity of selected antiparasitic, antihypertensive and non-steroidal anti-inflammatory drugs (NSAIDs) by means of reversed phase–thin layer chromatography (RP-TLC) as well by using Soczewiński–Wachtmeister’s and J. Ościk’s equations. The lipophilicity parameters of all examined compounds obtained under various chromatographic systems (i.e., methanol-water and acetone-water, respectively) and those determined on the basis of Soczewiński-Wachtmeister’s and Ościk’s equations (i.e., RMWS and RMWO) were compared with the theoretical ones (e.g., AlogPs, AClogP, milogP, AlogP, MlogP, XlogP2, XlogP3) and the experimental value of the partition coefficient (logPexp). It was found that the RMWS parameter may be a good alternative tool in describing the lipophilic nature of biologically active compounds with a high and low lipophilicity (i.e., antihypertensive and antiparasitic drugs). Meanwhile, the RMWO was more suitable for compounds with a medium lipophilicity (i.e., non-steroidal anti-inflammatory drugs). The chromatographic parameter φ0(a) can be helpful for the prediction of partition coefficients, i.e., AClogP, XlogP3, as well as logPexp of examined compounds.
Automated CT bone segmentation using statistical shape modelling and local template matching

Abstract Accurate CT bone segmentation is essential to develop chair-side manufacturing of implants based on additive manufacturing. We herewith present an automated method able to accurately segment challenging bone regions, while simultaneously providing anatomical correspondences. The method was evaluated on demanding regions: normal and osteoarthritic scapulae, healthy and atrophied mandibles, and orbital bones. On average, results were accurate with surface distances of approximately 0.5 mm and average Dice coefficients >90%. Since anatomical correspondences are propagated during the segmentation process, this approach can directly yield anatomical measurements, provide design parameters for personalized surgical instruments, or determine the bone geometry to manufacture patient-specific implants.