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Androgens are involved in the regulation of ovarian development during fetal/neonatal life. Environmental chemicals displaying anti-androgenic activities may affect multiple signal transduction pathways by blocking endogenous androgen action. The aim of the current study was to examine effects of the anti-androgen flutamide on the expression of coding transcripts and long non-coding RNAs (lncRNAs) in neonatal porcine ovaries. By employing RNA-Seq technology we aimed to extend our understanding of the role of androgens in neonatal folliculogenesis and examine the impact of the anti-androgen flutamide on ovarian function.
Flutamide (FLU) is a competitive antagonist of the androgen receptor which has been reported to induce severe liver injury in some patients. Several experimental models suggested that an episode of inflammation during drug treatment predisposes animals to tissue injury. The molecular cytotoxic mechanisms of FLU in isolated rat hepatocytes using an in vitro oxidative stress inflammation system were investigated in this study. When a nontoxic hydrogen peroxide (H2O2) generating system (glucose/glucose oxidase) with peroxidase or iron(II) [Fe(II)] (to partly simulate in vivo inflammation) was added to the hepatocytes prior to the addition of FLU, increases in FLU-induced cytotoxicity and lipid peroxidation (LPO) were observed that were decreased by 6-N-propyl-2-thiouracil or deferoxamine, respectively. N-Acetylcysteine decreased FLU-induced cytotoxicity in this system. Potent antioxidants, for example, Trolox ((±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), resveratrol (3,5,4'-trihydroxy-trans-stilbene), and DPPD (N,N'-diphenyl-1,4-phenylenediamine) also significantly decreased FLU-induced cytotoxicity and LPO and increased mitochondrial membrane potential (MMP) and glutathione (GSH) levels in the H2O2 generating system with peroxidase. TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl), a known reactive oxygen species (ROS) scavenger and superoxide dismutase mimetic, also significantly decreased toxicity caused by FLU in this system. These results raise the possibility that the presence or absence of inflammation may be another susceptibility factor for drug-induced hepatotoxicity.
Testosterone has been shown to worsen histological and neurological impairment during cerebral ischemia in animal models. Cell culture studies revealed that testosterone is implicated in protecting neural and glial cells against insults, and they started to elucidate testosterone pathways that underlie these protective effects. These studies support the hypothesis that testosterone can be neuroprotective throughout an episode of cerebral ischemia. Therefore, we evaluated the mechanisms underlying the shift between testosterone protective and deleterious effects via block testosterone aromatization and androgen receptors in rats subjected to 60-minute middle cerebral artery occlusion. Fifty rats were divided into five equal groups: gonadally intact male; castrated male; intact male + flutamide; intact male + letrozole; intact male + combination flutamide and letrozole. Our results indicated that castration has the ability to reduce histological damage and to improve neurological score 24 hours after middle cerebral artery occlusion. Moreover, flutamide improved histologic and neurological impairment better than castration. Letrozole induced increases in striatal infarct volume and seizures in gonadally intact rats. Combination of flutamide and letrozole showed that letrozole can reverse beneficial effects of flutamide. In conclusion, it seems that the beneficial effects of flutamide are the prevention of the deleterious effects and enhancement of neuroprotective effects of testosterone during cerebral ischemia.
We determined whether prostate specific antigen (PSA) would decrease with immediate antiandrogen switching from bicalutamide (BCL) to flutamide (FLT) in patients receiving combined androgen blockade for advanced prostate cancer. From 2002 to 2006, 20 patients who showed PSA failure after first-line hormonal therapy with a luteinizing hormone-release hormone (LH-RH) agonist and BCL were enrolled. All patients were immediately switched from BCL to FLT, administered with an LH-RH agonist, as second-line combined androgen blockade (CAB). We evaluated the PSA response to second-line CAB. Eight patients (40%) were responsive, showing PSA decreases of at least 50%. The median (range) duration of the PSA response was 18.4 (3-26) months. Second-line CAB using FLT was effective in 40% of patients who received first-line CAB using BCL. The lower Gleason scores at the initial prostate biopsy probably reflect the response to second-line CAB. Responders showed significantly better OS and CSS in the determination of any PSA decline and 40% PSA decline. The median OS duration in nonresponders and responders (40% PSA decline) was 1433 days versus 3617 days. It is concluded that an immediate switch from BCL to FLT is effective for some CRPC patients after first-line CAB using BCL.
Patients with polycystic ovary syndrome (PCOS), characterized by anovulation, hyperandrogenemia and polycystic ovaries, are still vulnerable to undergo recurrent pregnancy loss and premature labor even though the ovulatory process is pharmacologically recovered. However, its potential mechanism remains unknown. Thus, our aim was to investigate the effect and mechanism of hyperandrogenemia and flutamide (a non-steroidal anti-androgen) on the embryo implantation and pregnancy during mid-pregnancy.
With the objective to develop a potential 99mTc radiopharmaceutical for imaging the androgen receptor (AR) in prostate cancer, four ligands bearing the same pharmacophore derived from the AR antagonist flutamide were prepared, labeled with 99mTc, and their structures corroborated via comparison with the corresponding stable rhenium analogs. All complexes were obtained with high radiochemical purity. Three of the complexes were highly stable, and, due to their favorable physicochemical properties, were further evaluated using AR-positive and AR-negative cells in culture. All complexes exhibited considerable uptake in AR-positive cells, which could be blocked by an excess of flutamide. The efflux from the cells was moderate. They also showed significantly lower uptakes in AR-negative cells, indicating interactions with the AR receptor. However, the binding affinities were considerably reduced by the coordination to 99mTc, and the complex that exhibited the best biological behavior did not show sufficient specificity towards AR-positive cells.
Our present knowledge on interrelation between morphology/ultrastructure of mitochondria of the Leydig cell and its steroidogenic function is far from satisfactory and needs additional studies. Here, we analyzed the effects of blockade of androgen receptor, triggered by exposure to flutamide, on the expression of steroidogenic proteins (1) and ultrastructure of Leydig cells' constituents (2). We demonstrated that increase in the expression level of steroidogenic (StAR, CYP11A1, 3β-HSD, and CYP19A1) proteins (and respective mRNAs) in rat testicular tissue as well as elevation of intratesticular sex steroid hormone (testosterone and estradiol) levels observed in treated animals correspond well to morphological alterations of the Leydig cell ultrastructure. Most importantly, up-regulation of steroidogenic proteins' expression apparently correlates with considerable multiplication of Leydig cell mitochondria and subsequent formation of local mitochondrial networks. Interestingly, we showed also that the above-mentioned processes were associated with elevated transcription of Drp1 and Mfn2 genes, encoding proteins implicated in mitochondrial dynamics. Collectively, our studies emphasize the importance of mitochondrial homeostasis to the steroidogenic function of Leydig cells.
Flutamide is a widely used nonsteroidal antiandrogen for prostate cancer therapy, but its clinical application is restricted by the concurrent liver injury. Increasing evidence suggests that flutamide-induced liver injury is associated with oxidative stress, though the precise mechanism is poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidants including heme oxygenase-1 (HO-1). This study was designed to delineate the role of Nrf2/HO-1 in flutamide-induced hepatic cell injury. Our results showed that flutamide concentration dependently induced cytotoxicity, hydrogen peroxide accumulation, and mitochondrial dysfunction as indicated by mitochondrial membrane potential loss and ATP depletion. The protein expression of Nrf2 and HO-1 was induced by flutamide at 12.5 μM but was downregulated by higher concentrations of flutamide. Silencing either Nrf2 or HO-1 was found to aggravate flutamide-induced hydrogen peroxide accumulation and mitochondrial dysfunction as well as inhibition of the Nrf2 pathway. Moreover, preinduction of HO-1 by Copp significantly attenuated flutamide-induced oxidative stress and mitochondrial dysfunction, while inhibition of HO-1 by Snpp aggravated these deleterious effects. These findings suggest that flutamide-induced hepatic cell death and mitochondrial dysfunction is assoicated with inhibition of Nrf2-mediated HO-1. Pharmacologic intervention of Nrf2/HO-1 may provide a promising therapeutic approach in flutamide-induced liver injury.
A novel particulate delivery matrix based on ionically crosslinked casein (CAS) nanoparticles was developed for controlled release of the poorly soluble anticancer drug flutamide (FLT). Nanoparticles were fabricated via oil-in-water emulsification then stabilized by ionic crosslinking of the positively charged CAS molecules below their isoelectric point, with the polyanionic crosslinker sodium tripolyphosphate. With the optimal preparation conditions, the drug loading and incorporation efficiency achieved were 8.73% and 64.55%, respectively. The nanoparticles exhibited a spherical shape with a size below 100 nm and a positive zeta potential (+7.54 to +17.3 mV). FLT was molecularly dispersed inside the nanoparticle protein matrix, as revealed by thermal analysis. The biodegradability of CAS nanoparticles in trypsin solution could be easily modulated by varying the sodium tripolyphosphate crosslinking density. A sustained release of FLT from CAS nanoparticles for up to 4 days was observed, depending on the crosslinking density. After intravenous administration of FLT-CAS nanoparticles into rats, CAS nanoparticles exhibited a longer circulation time and a markedly delayed blood clearance of FLT, with the half-life of FLT extended from 0.88 hours to 14.64 hours, compared with drug cosolvent. The results offer a promising method for tailoring biodegradable, drug-loaded CAS nanoparticles as controlled, long-circulating drug delivery systems of hydrophobic anticancer drugs in aqueous vehicles.
Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti-androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti-androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full-thickness burn wound healing, mouse model, DHT/F-scaffold showed a significantly faster wound healing compared with F-scaffold or DHT-scaffold. Histology analysis confirmed that DHT/F-scaffold exhibited higher re-epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen-dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients.
Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.
Hypoxia is common with preterm birth and may lead to long-term effects on the adult hypothalamic-pituitary-adrenal (HPA) axis that are sexually dimorphic due to neonatal androgens. Although the adult rat adrenal does not express appreciable CYP17 activity, the neonatal rat adrenal may synthesize androgens that could be a critical local factor in the development of adrenal function. We evaluated these phenomena by pretreating the neonatal rats on postnatal days (PD) 1, 6, 13, 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 mg/kg or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to acute hypoxia and blood was sampled. We found that (a) in PD2 pups, flutamide augmented corticosterone responses in a sexually dimorphic pattern and without an increase in ACTH, (b) PD7 and PD14 pups had the smallest corticosterone response to hypoxia (c) PD21 pups had an adult-like corticosterone response to hypoxia that was sexually dimorphic, (d) flutamide attenuated ACTH responses in PD7 hypoxic pups, and (e) high-dose flutamide suppressed the HPA axis, FSH, and estradiol. Flutamide demonstrated mixed antagonist and agonist effects that changed during the first three weeks of neonatal life. We conclude that the use of flutamide in neonatal rats to evaluate androgen-induced programming of subsequent adult behavior is not optimal. However, our studies suggest neonatal androgens play a role in regulation of adrenal function that is sexually dimorphic and changes during early development.
Flutamide, a widely used nonsteroidal anti-androgen, but not its bioisostere bicalutamide, has been associated with idiosyncratic drug-induced liver injury. Although the susceptibility factors are unknown, mitochondrial injury has emerged as a putative hazard of flutamide. To explore the role of mitochondrial sensitization in flutamide hepatotoxicity, we determined the effects of superimposed drug stress in a murine model of underlying mitochondrial abnormalities. Male wild-type or heterozygous Sod2(+/-) mice were injected intraperitoneously with flutamide (0, 30 or 100 mg/kg/day) for 28 days. A kinetic pilot study revealed that flutamide (100 mg/kg/day) caused approximately 10-fold greater exposure than the reported therapeutic mean plasma levels. Mutant (5/10), but not wild-type, mice in the high-dose group exhibited small foci of hepatocellular necrosis and an increased number of apoptotic hepatocytes. Hepatic GSSG/GSH, protein carbonyl levels, and serum lactate levels were significantly increased, suggesting oxidant stress and mitochondrial dysfunction. Measurement of mitochondrial superoxide in cultured hepatocytes demonstrated that mitochondria were a significant source of flutamide-enhanced oxidant stress. Indeed, mitochondria isolated from flutamide-treated Sod2(+/-) mice exhibited decreased aconitase activity as compared to vehicle controls. A transcriptomics analysis using MitoChips revealed that flutamide-treated Sod2(+/-) mice exhibited a selective decrease in the expression of all complexes I and III subunits encoded by mitochondrial DNA. In contrast, Sod2(+/-) mice receiving bicalutamide (50 mg/kg/day) did not reveal any hepatic changes. These results are compatible with our concept that flutamide targets hepatic mitochondria and exerts oxidant stress that can lead to overt hepatic injury in the presence of an underlying mitochondrial abnormality.
Ovarian follicular atresia is regulated by androgens directly via androgen receptors and indirectly after conversion to estrogens. The balance between proliferation and cell apoptosis is crucial for the physiological functioning of the follicles. The disorder between these processes leads to reproductive failure, such as cyst formation. Recent research suggests maternally or neonatally mediated effects of antiandrogen flutamide on reproductive functions during adulthood. Therefore, the current study was performed to determine whether late gestational or neonatal exposure to flutamide influences proliferation and apoptosis rates in large antral follicles of adult porcine ovary. These periods are critical in ovarian biology and may determine female fertility in adulthood. Flutamide was injected into pregnant gilts between days 80 and 88 of gestation, and into female piglets between days 2 and 10 postnatally. The ovaries were collected from treated and control adult pigs, and healthy large antral follicles were excised. In large antral follicles, granulosa and theca cells revealed elevated (p<0.001) proliferation index measured by immunolocalization of Ki-67 following maternal and neonatal flutamide exposure. The percentage of apoptotic granulosa cells detected using TUNEL assay significantly decreased (p<0.01) after flutamide administration, that paralleled with down-regulation (p<0.01) of caspase-3 protein expression. Moreover, plasma testosterone decreased (p<0.001) in flutamide-treated animals, whereas 17β-estradiol was elevated following flutamide exposure. The present research indicates increased proliferation and diminished apoptosis rates within large antral follicles of adult pigs following prenatal and neonatal flutamide administration, which might influence the normal development of the follicles and pigs fertility as a consequence.
The dynamic cross-talk between epididymal cells is hormonally regulated and, in part, through direct cell-to-cell interactions. To date, no information is available regarding possible impact of anti-androgens on the proteins involved in the gap junctional communication within the boar epididymis. Thus, a question arised whether prenatal or postnatal exposure to an anti-androgen flutamide alters the expression of gap junction protein - connexin43 (Cx43) and androgen receptor (AR) expression in the caput, corpus and cauda epididymis and leads to delayed effects on morphology and function of adult pig epididymis.
This study was carried out to clarify the central effects of neuropeptide Y (NPY) on gonadotropin and prolactin (PRL) release in the male rat and to evaluate the hypothesis that it may play a role in negative feedback regulation of gonadotropin secretion in the male. NPY (4 micrograms in 2 microliters 0.9% NaCl) or an equal volume of saline was microinjected into the third cerebral ventricle of conscious, unrestrained rats and its effects on plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH) and PRL concentrations, and the gonadotropin response to LH-releasing hormone (LHRH) were measured by radioimmunoassay in noncastrated, castrated (3 days before the experiment) rats or animals treated with flutamide, an androgen receptor blocker (10 mg/kg b.w. per day subcutaneously for 3 days). Blood samples were drawn periodically from a Silastic catheter in the external jugular vein just before and for 120 min after intraventricular injections. At 90 min after injection 25 ng of LHRH were infused intravenously and 3 additional blood samples were withdrawn at 10-min intervals after the injection. Normal male rats responded to NPY with a decrease in plasma LH concentrations at 60 min. Plasma LH was significantly lower at 120 min than values in the saline-injected controls. At that time there was a significant 2-fold augmentation of their response to LHRH. In contrast, NPY elevated plasma FSH significantly versus values in controls at 15 and 30 min after injection, but the FSH release in response to LHRH was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)
Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper-Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y1), zeta potential (Y2), drug entrapment efficiency (Y3), and the cumulative drug release after 24 h (Y4) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles' spherical shape with bilayer structure. Values of dependent variables were 748.6 nm, -48.60 mV, 72.8% and 72.2% for Y1, Y2, Y3 and Y4, respectively. The optimized FLT-loaded niosomes exerted high cytotoxic efficacy against human prostate cancer cell line (PC-3) with an IC50 value of 0.64 ± 0.04 µg/mL whilst, it was 1.88 ± 0.16 µg/mL for free FLT. Moreover, the IC50 values on breast cancer cell line (MCF-7) were 0.27 ± 0.07 µg/mL and 4.07 ± 0.74 µg/mL for FLT-loaded niosomes and free FLT, respectively. The permeation of the optimized FLT-loaded niosomes through the rabbit intestine showed an enhancement ratio of about 1.5 times that of the free FLT suspension. In vivo pharmacokinetic study displayed an improvement in oral bioavailability of the optimized niosomal formulation with AUC and Cmax values of 741.583 ± 33.557 μg/mL × min and 6.950 ± 0.45 μg/mL compared to 364.536 ± 45.215 μg/mL × min and 2.650 ± 0.55 μg/mL for the oral FLT suspension. With these promising findings, we conclude that encapsulation of FLT in cholesterol-loaded nanovesicles enhanced its anticancer activity and oral bioavailability which endorse its use in the management of prostate cancer.
The androgen receptor antagonist, flutamide, is strongly associated with idiosyncratic drug-induced liver injury (DILI). Following administration, flutamide undergoes extensive first-pass metabolism to its primary metabolite, 2-hydroxyflutamide. Flutamide is a known mitochondrial toxicant; however there has been limited investigation into the potential mitochondrial toxicity of 2-hydroxyflutamide and its contribution to flutamide-induced liver injury. In this study we have used the acute glucose or galactose-conditioning of HepG2 cells to compare the mitochondrial toxicity of flutamide, 2-hydroxyflutamide and the structurally-related, non-hepatotoxic androgen receptor antagonist, bicalutamide. Compound-induced changes in mitochondrial oxygen consumption rate were assessed using Seahorse technology. Permeabilization of cells and delivery of specific substrates and inhibitors of the various respiratory complexes provided more detailed information on the origin of mitochondrial perturbations. These analyses were supported by assessment of downstream impacts including changes in cellular NAD(+)/NADH ratio. Bicalutamide was not found to be a mitochondrial toxicant, yet flutamide and 2-hydroxyflutamide significantly reduced basal and maximal respiration. Both flutamide and 2-hydroxyflutamide significantly reduced respiratory complex I-linked respiration, though 2-hydroxyflutamide also significantly decreased complex II and V-linked respiration; liabilities not demonstrated by the parent compound. This study has identified for the first time, the additional mitochondrial liabilities of the major metabolite, 2-hydroxyflutamide compared with its parent drug, flutamide. Given the rapid production of this metabolite upon administration of flutamide, but not bicalutamide, we propose that the additional mitochondrial toxicity of 2-hydroxyflutamide may fundamentally contribute to the idiosyncratic DILI seen in flutamide-treated, but not bicalutamide-treated patients.
Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.
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