bluuebunny/crossref_metadata_2025_split huggingface dataset:
Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors
Authors: Schröder Mariska A M , Turcu Adina F , O’Day Patrick , van Herwaarden Antonius E , Span Paul N , Auchus Richard J , Sweep Fred C G J , Claahsen-van der Grinten Hedi L 
Published: May 2021

Abstract
Testicular adrenal rest tumors (TART) are a common complication in male patients with classic 21-hydroxylase deficiency (21OHD). TART are considered to have steroid-producing properties and may contribute to the androgen excess in 21OHD patients. This study aims to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. Steroids were measured in left (n=7) and right (n=4) spermatic vein- and simultaneously taken peripheral plasma (n=7) samples from seven men with 21OHD and TART using liquid chromatography-tandem mass spectrometry. In addition, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. Compared to peripheral blood of 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cell-conditioned medium contained higher levels of testosterone, and lower levels of androstenedione and 11OHA4 after ACTH stimulation compared to adrenal cell-conditioned medium, indicating ACTH-induced production of testosterone in TART. TART cells also produced 11OHT after 48 h of ACTH stimulation. Thus, in patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vein- versus peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in-vitro results indicate that this metabolism is ACTH-sensitive.
Development of Deep Learning-Based Automatic Detection Algorithm for Adrenal Nodules on Contrast-Enhanced Abdominal CT Scans
Authors: Ahn Chang Ho , Kim Tae Woo , Jo Kyungmin , Kong Sung Hye , Kim Jinhee , Kim Taesung , Shin Chan Soo , Choo Jaegul , Kim Jung Hee 
Published: May 2021

Abstract
Objective: Adrenal nodules are often incidentally detected on abdominal computed tomography (CT) scans due to their asymptomatic nature. We aimed to develop an automatic detection program for adrenal nodules on abdominal CT scans using deep learning algorithms. Methods: We retrospectively analyzed abdominal CT scans performed at two university-affiliated hospitals (n = 483 and n = 514, respectively) from 2006 to 2019. This dataset was randomly divided into training set (181 CTs without adrenal nodule and 362 CTs with adrenal nodule) and test set (291 CTs without adrenal nodule and 163 CTs with adrenal nodule). All CT scans were contrast-enhanced and the phase with the highest contrast between adrenal gland and adjacent normal tissues was selected for multi-phase CT. The core algorithm of our deep learning algorithm for adrenal nodule (DLAAN) was MULAN (Multitask Universal Lesion Analysis Network) algorithm whose backbone was a convolutional neural network. DLAAN was composed of two stages. The first stage was to detect the CT slice where normal adrenal gland or adrenal nodule were located. The second stage was for fine localization of adrenal nodule on the corresponding CT slice. The performance of DLAAN was evaluated using the area under the receiver operating characteristic curve (AUROC) for patient-level classification and free-response ROC for nodule-level localization. The figure of merit for free-response ROC was calculated as an average sensitivity when 0.5, 1, 2, and 4 false positives per slice were allowed. Results: The AUROC of DLAAN was 0.927 (95% confidence interval: 0.900–0.955). With a threshold probability of 0.9, the sensitivity and specificity were 86.5% and 89.0%, respectively. When left and right adrenal nodules were analyzed separately, the AUROC was 0.910 for left adrenal nodule and 0.957 for right adrenal nodule, respectively. The accuracy of DLAAN according to the size of adrenal nodule was 0.890, 0.734, 0.981, 1.00 and 1.00 for no adrenal nodule, adrenal nodule sized 1–2 cm, 2–3 cm, 3–4 cm and &gt; 4 cm, respectively. The performance of DLAAN for the localization of adrenal nodule which was estimated by average sensitivity was 0.812. The number of CTs with at least one false positive nodule was 93/454 (20.5%). Conclusion: Our proof of concept study of deep learning-based automatic detection of adrenal nodule on contrast-enhanced abdominal CT scans showed high accuracy for both the classification of patients with or without adrenal nodule and the localization of adrenal nodule, although the performance of the algorithm decreased for small sized adrenal nodules. External validation with different CT settings and patient population is needed to assess the generalizability of our algorithm.
Safety Analysis of an Oral Testosterone Undecanoate (TU) Formulation Following 2 Years of Administration in Hypogonadal Men
Authors: Swerdloff Ronald S , Amory John K , Gittelman Marc , Seo B Woun , Rohowsky Nestor , Dudley Robert E 
Published: May 2021

Abstract
Introduction: An oral testosterone (T) replacement therapy (TRT) would be the preferred choice for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men for up to 2 years. Subjects and Methods: Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results: Overall, up to 81 subjects were available for evaluation. T concentration increased from 208.3 ± 102.4 ng/dL (Mean ± SD) at baseline (BL) to 470.1 ± 396.5 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests - ALT (28.0 ± 12.3 to 26.6 ± 12.8 U/L), AST (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL) throughout the two studies. At Day 270, one subject had an ALT level of 227 U/L, which was &gt; 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on Day 290, and the level dropped to 87 U/L, &lt; 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. There were not any significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (+2.52 ± 3.7% vs BL, p &lt; 0.001) and cuff systolic BP (+5.6 ± 15.0 mmHg vs BL, p = 0.006). The change in prostate-related growth variables and CV endpoints changed initially and stabilized throughout the 2 trials. For example, systolic BP consistently showed a mean increase from BL between 3 - 6 mmHg. Conclusion: This oral TU formulation is an effective long-term therapy for hypogonadal men and has a safety profile consistent with other approved T products. Notably, no evidence of liver toxicity was observed. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children.
Studying the Genomic Role of Cathepsin-D in ER+ Breast Cancer
Authors: Dianati Elham , Liaudet-coopman Emmanuelle , Mader Sylvie 
Published: May 2021

Abstract
Estrogen receptor alpha (ERα), a transcription factor implicated in induction of cell growth in breast cancer, is a therapeutic target that is expressed in &gt;70% of breast tumors. The transcriptional activity of ERα is controlled by ligands and increased through its interaction with co-activators such as the p160/SRC and p300/CBP families. In an attempt to identify the ligand-specific protein complexes involved in transcriptional regulation by ERα, BioID and TurboID screens were performed in two ER+ breast cancer cell lines, T-47D and ZR-75-1. Surprisingly, Cathepsin-D (Cath-D), a lysosomal aspartyl endoproteinase that is an ER target gene, was identified in these screens. Cath-D expression is associated with a poor prognosis and increased metastasis rate in breast cancer irrespective of its catalytic activities {Glondu, 2001 #119}[i]. Cath-D is localized in part to the nucleus where it interacts with TRPS1, a repressor of GATA-mediated transcription and modulator of ERα signaling {Bach, 2015 #117}[ii]. Co-silencing Cath-D and TRPS1 suppressed cell proliferation and inhibited growth under soft agar, suggesting that they cooperate to drive tumorigenesis {Bach, 2015 #117}[ii]. We hypothesized that Cath-D plays genomic as well as non-genomic roles in breast tumor aggressiveness and may alter ERα-mediated transcription. The nuclear localization of Cath-D was confirmed by immunofluorescence using different commercialized antibodies and observed in western blots of chromatin-bound fractions in three different ERα+ breast cancer cell lines, T-47D, ZR-75 and MCF-7. Specificity of the antibodies was confirmed using siRNA-mediated suppression of Cath-D. Moreover, Cath-D was also identified in proximity to TurboID-ERα by LC-MS after chromatin fractionation. The proximity of ERα and Cath-D both in the cytoplasm and nucleus was confirmed by proximity Ligation Assay (PLA) in three ER+ cell lines. Co-immunoprecipitation assays indicated physical interaction of Cath-D with ERα in T-47D cell extracts. Further, Cath-D was detected by ChIP-qPCR on estrogen response elements (EREs) of two ERα target genes, TFF1 and GREB1 in T-47D and ZR-75 cells. These results suggest that Cath-D can interact with ERα on DNA and play genomic roles in ER+ breast cancer cells. [i] Glondu, M., et al. (2001). “A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells.” Oncogene20(47): 6920-6929. [ii] Bach, A. S., et al. (2015). “Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells.” Oncotarget6(29): 28084-28103.
The Transcriptional Function of GRHL2 in Hormone-Dependent Breast Cancers
Authors: Reese Rebecca , Helzer Kyle , Alarid Elaine T 
Published: May 2021

Abstract
The Grainyhead-like protein family, composed of GRHL1, GRHL2, and GRHL3, are nuclear transcription factors that regulate epithelial differentiation. GRHL2 has been associated with several nuclear hormone receptors, including progesterone receptor (PR), androgen receptor (AR), and more recently, estrogen receptor (ER). In breast cancer, GRHL2 has been shown to both activate ER-dependent enhancers through FOXA1 and MLL3-mediated deposition of the activating histone mark H3K4me1 and repress enhancers via inhibition of the histone acetyltransferase p300. Cistromic analysis by our group of ER phosphorylated at serine 118 (pS118-ER), a form of transcriptionally active ER, found an enrichment of the GRHL motif near pS118-ER binding sites. Despite these findings, the direct relationship between GRHL2 and ER transcriptional function and how that relationship influences ER-positive breast cancer growth and differentiation is not well-defined. To explore the relationship between GRHL2 and pS118-ER further, we used transcriptomic and cistromic analysis of ER-positive cells lacking GRHL2 to determine the impact of the loss of GRHL2 on cellular and transcriptional responses to estrogen. This analysis identified a subset of genes that are controlled by both GRHL2 and estrogen. In addition, CRISPR engineered T47D cells lacking a portion of the GRHL2 transactivation domain (ΔTAD) demonstrate reduced nuclear ER levels and reduced ER chromatin occupancy. Gene expression analysis of ΔTAD-GRHL2 cells showed increased GRHL3 expression, and ChIP analysis revealed increased Pol II occupancy at the GRHL3 promoter, suggesting that there may be a compensatory mechanism within the GRHL family to regulate the transcriptome. Finally, ΔTAD-GRHL2 mutants reduced growth and colony formation relative to wild-type controls. Together, this work will provide an understanding of how transcriptionally active ER and GRHL2 selectively cooperate to regulate transcription, growth, and differentiation in ER-positive breast cancer.
Differential Genomic Interactions Drive Progesterone Receptor Isoform Specific Functions in Breast Cancer
Authors: Doan Tram B , Graham J Dinny , Tehan Mariah , Guild Barbara J , Clarke Christine L 
Published: May 2021

Abstract
Progesterone is critical for normal breast development and function, and has been shown to stimulate proliferation of normal breast epithelial cells by increasing stem and progenitor cell numbers. Breast cancer incidence is increased in women exposed to progesterone analogues in combined estrogen plus progestin hormone replacement therapy, but not in women taking estrogen alone. Classical progesterone signaling is mediated through the nuclear progesterone receptor (PR), which occurs as two related but functionally different isoforms, PRA and PRB. PRA and PRB are co-expressed equally in normal breast tissue but become dysregulated in breast cancer where PRA often becomes predominant. PRA predominance in breast cancer is associated with poorer outcome and higher risk of distant metastasis in tamoxifen treated patients. We show using integrated analysis of ChIP-seq, ATAC-seq and transcriptomic profiling in a breast cancer cell line model of acquired PRA predominance that: 1) PRA and PRB have different requirements with regard to chromatin accessibility; 2) PRA predominance reshapes the PR cistrome and the associated transcriptome to affect genes not normally regulated by PR when PRA and PRB are equivalently expressed, possibly through assisted loading with multiple other transcription factors; 3) Genes regulated by PR only when PRA is predominant are associated with poorer breast cancer outcome and involved in multiple cancer-associated pathways including those that regulate cell proliferation and adhesion. Our data suggest a mechanism for the poorer disease outcome seen in breast cancers with a predominance of PRA.
LBD Dimerization of the Androgen Receptor but Not N/C Interaction Is Crucial for Normal Male Development in Mice
Authors: El Kharraz Sarah , Helsen Christine , Dubois Vanessa , Libert Claude , Poutanen Matti , Claessens Frank 
Published: May 2021

Abstract
The androgen receptor (AR) is a nuclear receptor with a main role in the development and maintenance of the male phenotype. To execute its role as transcription factor, the AR forms homodimers. Three dimerization modes have been described for the AR: one via the DNA binding domain, a second via the ligand binding domain (LBD) and a third via interactions between the LBD and the aminoterminus of the AR (N/C). Based exclusively on in vitro data, all three dimerization modes seem to contribute to full AR activity, albeit to a different extent. The in vivo role of the dimerization modes, however, remains unknown. To study the physiological relevance, we generated two mouse models using a CRISPR/Cas9 approach, in which either the N/C interaction (ARNoC) or LBD dimerization (ARLmon) was disrupted. Surprisingly, the male ARNoC mice have a normal phenotype, indicating that the N/C interaction is not crucial for male development. In contrast, ARLmon males have an external female phenotype with cryptorchid testes and high levels of circulating testosterone (T), androstenedione and luteinizing hormone (LH) (6-, 13- and 45-fold higher, respectively). They have no prostate, seminal vesicles or epididymis, illustrating the importance of LBD dimerization during male development. Phenotyping the ARLmon model furthermore provided evidence of a crucial role for the AR in bone homeostasis as well as steroidogenesis. The ARLmon males display a severe bone phenotype, similar to that of complete AR knockout (ARKO) mice. The bone phenotype of ARKO was postulated to be mainly due to lower estrogen levels. However, in contrast to ARKO mice, ARLmon mice have high circulating levels of T, which can still function as prohormone for estradiol and support bone function via the ERα. Immunohistological analysis of ARLmon testes showed hyperplasia of the Leydig cells and residual spermatogenesis. Analysis of the steroidogenic pathway revealed that while the expression of most genes is increased, the expression of Hsd17b3, encoding the enzyme responsible for conversion of androstenedione into T, is low in ARLmon testis. Reporter assays confirmed that the promotor of this gene is indeed upregulated by the AR itself. In conclusion, our work uncovers the physiological role of the N/C interaction and LBD dimerization of the AR. It furthermore demonstrates a direct role for AR in male bone development independent of T aromatization into estrogens. Finally, we show that the AR controls the final step in the synthesis of its own ligand. In contrast to the in vitro data, N/C interaction is not crucial for male development in vivo. The ARLmon model illustrates that LBD dimerization could be an excellent new therapeutic target for inhibiting AR activity for example in advanced prostate cancer that has developed resistance to the current AR-targeting therapies.
Mapping of Corticosteroids in Murine Kidneys Using Mass Spectrometry Imaging
Authors: Stasinopoulos Ioannis , Khan Shazia , MacKay Logan C , Brown Roger W , Bailey Matthew J , Andrew Ruth 
Published: May 2021

Abstract
Renal sodium reabsorption is important for blood pressure homeostasis and is physiologically regulated by aldosterone; glucocorticoids may also contribute. Abnormal steroid hormone activity within the kidney contributes to hypertension but the mechanisms are not fully defined. Molecular profiling of receptors and metabolising enzymes indicates that steroid hormone action is compartmentalised within the kidney. Ambient steroid concentrations are a critical factor governing bioactivity at a cellular level, but this is largely unknown, and the kidney remains a “black box”. Mass spectrometry imaging (MSI) was applied recently to localise steroids in brain and testes, and here is applied to kidney. Image reconstruction permits characterisation and co-registration of kidney histological regions based on regional markers detectable by MSI. Our aim was to map and quantify glucocorticoids and aldosterone in different histological zones (cortex, medulla) of murine kidneys, using an optimised MSI method. This approach has the potential to map steroids within functional zones of the kidney, providing fundamental new information relevant to hormone action in health and in disease. Cryosections of male C57BL6 mouse kidneys (age 12 weeks, n=6) were subject to MSI following derivatisation using Girard T reagent and α-cyano-4-hydroxycinnamic acid matrix application. Images were reconstructed, and methods optimised to enhance signal and limit diffusion of analytes of interest. Matrix assisted laser desorption/ionisation (MALDI) was used as a sampling method, coupled to Fourier Transform Ion cyclotron mass spectrometry. Ions with m/z 458.3010, 460.3166 and 474.2957 were detected, using MALDI, in renal sections, close to the predicted masses of 458.3013 (Δppm=0.65), 460.3169 (Δppm=0.65), and 474.2962 (Δppm=1.05), for derivatives of 11-dehydrocorticosterone, corticosterone and aldosterone respectively. Untargeted evaluation of ions was conducted to find regional markers that would allow definition of kidney histological zones. The Heat maps generated indicated that corticosterone intensity was higher in the inner cortex area close to the corticomedullary junction than the rest of the kidney. In contrast 11-dehydrocorticosterone was detected mainly in medulla and aldosterone signal was equally strong in medulla and outer cortex. Thus, MSI can be used map the sites where glucocorticoid and mineralocorticoids are most active in regulating renal tubular function. Co-localisation of steroids of interest with zonal markers by MSI permits steroid mapping in functional renal zones of the kidney. This approach provides fundamental new insights into the physiological control of sodium transport by steroids and opens doors to understanding changes in disorders of blood pressure. The project was supported and funded by Kidney Research UK.
Association of Thyroid Function With Suicide Ideation/Attempt -A Systematic Review and Meta-analysis
Authors: Toloza Bonilla Freddy Jean Karlo , Mao Yuanjie , Menon Lakshmi P , George Gemy Maria , Borikar Madhura , Owen Richard R , Maraka Spyridoula 
Published: May 2021

Abstract
Background: Thyroid disorders are very prevalent and could affect virtually the entire human body, including cognitive and psychiatric domains. However, the relationship between thyroid dysfunction and suicide is still controversial. Material and Methods: A systematic review and meta-analysis was conducted to describe the association of thyroid function with suicide ideation/attempt in adults. A comprehensive search from databases’ inception (MEDLINE, EMBASE, Cochrane, PsycINFO, PsycArticles, PSYNDEX and Scopus) to July 20, 2018 was conducted with no language restrictions. We included studies that reported mean values and standard deviation (SD) of thyroid hormone levels [Thyroid-stimulant hormone (TSH), free T4 (FT4), free T3 (FT3), total T4 (TT4), and total T3 (TT3)] in patients with suicide ideation/attempt compared with controls. Four reviewers worked independently and in duplicate for assessment of inclusion criteria, data extraction, and assessment of risk of bias. The mean value and SD of the thyroid function tests were used to calculate the mean difference for each subgroup. Random-effects models for meta-analyses were applied. Results: Overall, 2278 articles were identified, and 13 observational studies met the inclusion criteria. These studies involved 2651 participants, including 817 participants diagnosed with suicidal ideation/attempt. Group sizes of patients with suicide ideation/attempt ranged from 7 to 122 participants with mean age ranging from 23 to 49 years. Control group sizes ranged from 8 to 464 participants with mean age ranging from 24 to 50 years. Two studies included only women, two studies included only men, and 9 studies included both (% female range: 29 to 78%). Patients with suicide ideation/attempt had lower levels of FT3 (-0.19 pg/mL; P=0.04) and TT4 (-0.23 µg/dL; P=0.05) compared to controls. There were no differences in TSH, TT3 or FT4 levels between groups. In a subgroup analysis comparing current suicidal ideation vs current suicidal attempt vs history of suicidal ideation/attempt with the control group, there were no differences in any of the thyroid function tests. None of the included studies compared rates of overt/subclinical thyroid disease among groups. The overall risk of bias of the included studies was low-to-moderate. Conclusions: There is scarce evidence regarding the association of thyroid disorders and suicide. We found statistically significant lower thyroid hormone levels in patients with suicidal ideation/attempt. The clinical implications of this finding remain unknown and further research is needed to evaluate the association of thyroid disorders with suicide.