Histone demethylase enzymes KDM5A and KDM5B modulate immune response by suppressing transcription of endogenous retroviral elements.

Epigenetic factors, including lysine-specific demethylases such as the KDM5 paralogs KDM5A and KDM5B have been implicated in cancer and the regulation of immune responses. Here, we performed a comprehensive multiomic study in cells lacking KDM5A or KDM5B to map changes in transcriptional regulation and chromatin organization. RNA-seq analysis revealed a significant decrease in the expression of Krüppel-associated box containing zinc finger (KRAB-ZNF) genes in KDM5A or KDM5B knockout cell lines, which was accompanied by changes ATAC-seq and H3K4me3 ChIP-seq. Pharmacological inhibition of KDM5A and KDM5B catalytic activity with a pan-KDM5 inhibitor, CPI-455, did not significantly change KRAB-ZNF expression, raising the possibility that regulation of KRAB-ZNF expression does not require KDM5A and KDM5B demethylase activity. KRAB-ZNF are recognized suppressors of the transcription of endogenous retroviruses (ERVs) and HAP1 cells with KDM5A or KDM5B gene inactivation showed elevated ERV expression, increased dsRNA levels and elevated levels of immune response genes. Acute degradation of KDM5A using a dTAG system in HAP1 cells led to increased ERV expression, demonstrating that de-repression of ERV genes occurs rapidly after loss of KDM5A. Co-immunoprecipitation of KDM5A revealed an interaction with the Nucleosome Remodeling and Deacetylase (NuRD) complex suggesting that KDM5A and NuRD may act together to regulate the expression of ERVs through KRAB-ZNFs. These findings reveal roles of KDM5A and KDM5B in modulating ERV expression and underscore the therapeutic potential of using degraders of KDM5A and KDM5B to modulate tumor immune responses.

Motor-Cargo Structured Nanotractors for Augmented NIR Phototherapy via Gas-Boosted Tumor Penetration and Respiration-Impaired Mitochondrial Dysfunction.

Tumor microenvironment, characterized by dense extracellular matrix and severe hypoxia, has caused pronounced resistance to photodynamic therapy (PDT). Herein, it has designed an artificial nitric oxide (NO) nanotractor with a unique "motor-cargo" structure, where a photoswitching upconversion nanoparticle (UCNP) core serves as the optical engine to harvest NIR light and asymmetrically coated mesoporous silica (SiO2) shell acts as a cargo unit to load nitric oxide (NO) fuel molecule (RBS, Roussin's black salt) and PDT photosensitizer (ZnPc, zinc phthalocyanine). Upon illumination by 980 nm light, the UCNP emits blue light to excite RBS salt and release NO gas. On one hand, NO is used as the driving force to propel the particle with a high speed of ≈194 µm s-1 that generates significant rupture stress (over 0.95 kPa) on cell membrane to promote cellular endocytosis and intratumoral penetration. On the other hand, NO enables to alleviate tumor hypoxia by inhibiting cellular respiration as an oxygen conserver. When the excitation is subsequently switched to 808 nm light, the UCNP emits red light, triggering ZnPc to produce large amount of reactive oxygen species for PDT treatment. This study explores Janus-typed nanostructures for cell-particle interaction and gas-assisted phototherapy, opening avenues for versatile bioapplications.

PARP7 Inhibitors and AHR Agonists Act Synergistically Across a Wide-Range of Cancer Models.

Small molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated as a monotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. Here we demonstrate that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to the combination. Our data show that this synergistic response is dependent on AHR/ARNT and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wildtype and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.

Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as therapeutic target for biliary atresia.

BACKGROUND AND AIMS: Biliary atresia (BA) is a devastating fibroinflammatory biliary disease that is the leading indication for pediatric liver transplants worldwide. Although cholangiocytes are the primary target cells, the pathogenic mechanisms involving cholangiocytes remain elusive. Here, we aimed to characterize the pathogenic role of cholangiocytes in BA. APPROACH AND RESULTS: Integration of single-cell RNA sequencing of 12 liver tissues (from 9 BA and 3 controls) and the spatial transcriptome of another four liver sections (from 2 BA and 2 controls) provided a comprehensive spatial liver cell atlas of BA. In particular, we identified a cholangiocyte-enriched spatial niche with infiltration of activated HSCs, activated portal fibroblasts, macrovascular endothelial cells, and TREM2 + macrophages that were elevated in the portal triad of BA. This niche was positively correlated with bile duct profiles, liver fibrosis, and poor survival in 2 independent cohorts of patients with BA. Using integrative bioinformatics analyses to mine the cell-cell communication and regulatory network in BA cholangiocytes, we uncovered the fibroinflammatory phenotype of cholangiocytes with TNFSF12-TNFRSF12A as a significant signal. Genetic ablation or blockade of TNFRSF12A suppresses liver injury, inflammation, and bile duct profiles in a mouse model of disease. Using human biliary organoids, we revealed that BA organoids expressed higher levels of CCL2 in response to TNFSF12 stimulation and promoted monocyte chemotaxis via the CCL2-CCR2 axis. CONCLUSIONS: Pathogenic cholangiocytes-enriched niche identifies TNFRSF12A as a potential therapeutic target for BA.

Intervention strategies for management of comorbid depression among individuals with hypertension: a scoping review protocol.

INTRODUCTION: Hypertension and depression often coexisted, leading to poor health outcome and significant challenges in healthcare management. Since no guidelines or consensus are available for health professionals to manage this comorbidity, identifying interventions in current literature is crucial for gaining a clear picture of evidence and informing future research directions and clinical practice. This scoping review is designed to address this gap by systematically mapping the range of potential interventions for managing comorbid hypertension and depression. METHODS AND ANALYSIS: Following the Joanna Briggs Institute guidelines for scoping review, this review will comprehensively search databases including PUBMED, Embase, PsycINFO, CINAHL, Cochrane Library Databases, Chinese Biomedical Literature Database and Chinese National Knowledge Infrastructure. Grey literature will be sourced from Google Scholar. A year limit of January 2004-December 2023 will be applied to retrieve the most current peer-reviewed articles in English and Chinese language only. Two reviewers will individually screen and the process will be documented in Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews. This review will explore a range of non-pharmacological and multicomponent interventions including psychosocial support, educational programmes, telemedicine and integrated healthcare models. Data extraction will follow the Template for Intervention Description and Replication checklist to ensure detailed and standardised reporting of intervention components. The synthesis of findings will employ both quantitative and qualitative methods to provide a comprehensive overview of the intervention landscape. ETHICS AND DISSEMINATION: This scoping review, which involves secondary data analysis of publicly available sources, does not require ethical approval. Findings will be disseminated through peer-reviewed publications and presentations at relevant conferences. STUDY REGISTRATION: Open Science Framework registry (osf.io/j7gt8) in Centre for Open Science on 29 January 2024.

Lattice matching enables construction of CaS@NaYF4 heterostructure with synergistically enhanced water resistance and luminescence for antibiotic detection.

Rare earth (RE)-doped CaS phosphors have been widely used as light-emitting components in various fields. Nevertheless, the application of nanosized CaS particles is still significantly limited by their poor water resistance and weak luminescence. Herein, a lattice-matching strategy is developed by growing an inert shell of cubic NaYF4 phase on the CaS luminescent core. Due to their similarity in crystal structure, a uniform core-shell heterostructure (CaS:Ce3+@NaYF4) can be obtained, which effectively protects the CaS:Ce3+ core from degradation in aqueous environment and enhances its luminescence intensity. As a proof of concept, a label-free aptasensor is further constructed by combining core-shell CaS:Ce3+@NaYF4 and Au nanoparticles (AuNPs) for the ultrasensitive detection of kanamycin antibiotics. Based on the efficient FRET process, the detection linear range of kanamycin spans from 100 to 1000 nM with a detection limit of 7.8 nM. Besides, the aptasensor shows excellent selectivity towards kanamycin antibiotics, and has been successfully applied to the detection of kanamycin spiked in tap water and milk samples, demonstrating its high potential for sensing applications.

Mucosal-associated invariant T cells promote ductular reaction through amphiregulin in biliary atresia.

BACKGROUND: Biliary atresia (BA) is a neonatal fibro-inflammatory cholangiopathy with ductular reaction as a key pathogenic feature predicting poor survival. Mucosal-associated invariant T (MAIT) cells are enriched in human liver and display multiple roles in liver diseases. We aimed to investigate the function of MAIT cells in BA. METHODS: First, we analyzed correlations between liver MAIT cell and clinical parameters (survival, alanine transaminase, bilirubin, histological inflammation and fibrosis) in two public cohorts of patients with BA (US and China). Kaplan-Meier survival analysis and spearman correlation analysis were employed for survival data and other clinical parameters, respectively. Next, we obtained liver samples or peripheral blood from BA and control patients for bulk RNA sequencing, flow cytometry analysis, immunostaning and functional experiments of MAIT cells. Finally, we established two in vitro co-culture systems, one is the rhesus rotavirus (RRV) infected co-culture system to model immune dysfunction of human BA which was validated by single cell RNA sequencing and the other is a multicellular system composed of biliary organoids, LX-2 and MAIT cells to evaluate the role of MAIT cells on ductular reaction. FINDINGS: Liver MAIT cells in BA were positively associated with low survival and ductular reaction. Moreover, liver MAIT cells were activated, exhibited a wound healing signature and highly expressed growth factor Amphiregulin (AREG) in a T cell receptor (TCR)-dependent manner. Antagonism of AREG abrogated the proliferative effect of BA MAIT cells on both cholangiocytes and biliary organoids. A RRV infected co-culture system, recapitulated immune dysfunction of human BA, disclosed that RRV-primed MAIT cells promoted cholangiocyte proliferation via AREG, and further induced inflammation and fibrosis in the multicellular system. INTERPRETATION: MAIT cells exhibit a wound healing signature depending on TCR signaling and promote ductular reaction via AREG, which is associated with advanced fibrosis and predictive of low survival in BA. FUNDING: This work was funded by National Natural Science Foundation of China grant (82001589 and 92168108), National Key R&D Program of China (2023YFA1801600) and by Basic and Applied Basic Research Foundation of Guangdong (2020A1515110921).

Fructose intake from sugar-sweetened beverages is associated with a greater risk of hyperandrogenism in women: UK Biobank cohort study.

OBJECTIVE: To assess the association between fructose consumption and serum sex hormone-binding globulin (SHBG), (free) testosterone, and risk of hyperandrogenism in a population-based cohort. DESIGN: An observational and genetic association study in participants of the UK Biobank (n = 136 384 and n = 383 392, respectively). METHODS: We assessed the relationship of (1) the intake of different sources of fructose (ie, total, fruit, fruit juice, and sugar-sweetened beverages [SSBs]) and (2) rs2304681 (a missense variant in the gene encoding ketohexokinase, used as an instrument of impaired fructose metabolism), with SHBG, total and free testosterone levels, and risk of hyperandrogenism (free androgen index >4.5). RESULTS: The intake of total fructose and fructose from fruit was associated with higher serum SHBG and lower free testosterone in men and women and lower risk of hyperandrogenism in women. In contrast, fructose intake from SSB (≥10 g/day) was associated with lower SHBG in men and women and with higher free testosterone levels and risk of hyperandrogenism in women (odds ratio [OR]: 1.018; 95% confidence interval [CI]: 1.010; 1.026). Carriers of the rs2304681 A allele were characterized by higher circulating SHBG (both men and women), lower serum free testosterone (women), and a lower risk of biochemical hyperandrogenism (OR: 0.997, 95% CI: 0.955; 0.999; women) and acne vulgaris (OR: 0.975, 95% CI: 0.952; 0.999; men and women combined). CONCLUSIONS: The consumption of ≥10 g/day fructose from SSB, corresponding to ≥200 mL serving, is associated with a 2% higher risk of hyperandrogenism in women. These observational data are supported by our genetic data.

Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. METHODS: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. RESULTS: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/ß-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). CONCLUSIONS: ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

A TGF-ß-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-ß cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-ß of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-ß. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

ShallowHRD status acts as an effective prognostic predictor in ovarian cancer patients treated by poly (ADP-ribose) polymerase inhibitors (PARPis).

PURPOSE: Homologous recombination deficiency (HRD) plays a crucial role in ovarian cancer patients who are treated with Poly (ADP-ribose) polymerase inhibitors (PARPis). It could be defined as a prognosis biomarker. However, many high throughput sequencing methods for evaluating HRD, including HRDetect (WGS 10X), SigMA (WGS 40X or panel 1000X), and scarHRD (WGS 30X), are technically complex, time and data-storage consuming, and costly. Herein, we aimed to develop a low-cost method by low sequencing coverage to identify HRD status for precision medication. METHODS: We utilized ShallowHRD, a software tool to evaluate tumor HRD based on whole genome sequencing (WGS) at low coverage (1X), and established a novel scoring system, ShallowHRD score system. RESULTS: Compared with negative ShallowHRD status (ShallowHRD score < 15 or BRCAwild), positive ShallowHRD status (ShallowHRD score ≥ 15 or BRCAmut) presented favorable survival after being treated with PARPis. CONCLUSION: The ShallowHRD status is a good biomarker for predicting prognosis, which could help guide the clinical application of PARPis in ovarian cancer patients by a cost-effective, time and data-storage saving method.

Predictive model containing gene signature and shear wave elastography to predict patient outcomes after Kasai surgery in biliary atresia.

AIMS: Infants with biliary atresia (BA) are treated with Kasai portoenterostomy (KPE) surgery, but many BA patients need subsequent salvage liver transplants. The aim of this study is to develop a comprehensive gene-clinical model based on two-dimensional shear wave elastography (2DSWE), liver gene expression, and other clinical parameters to predict response to KPE for BA patients. METHODS: Differentially expressed gene patterns between liver samples of BA (n = 102) and non-BA control (n = 14) were identified using RNA sequencing analysis. Biliary atresia patients were then randomly assigned to training and validation cohorts. Gene classifier based on the differentially expressed genes was built in the training cohort. Nomogram models with and without gene classifier were further constructed and validated for predicting native liver survival of BA patients. The utility of the nomograms was compared by C-index. RESULTS: Using the least absolute shrinkage and selection operator model, we generated a nine-gene prognostic classifier. The nomogram based on the nine-gene classifier, age, preoperative 2DSWE, and albumin had the better C-index compared to gene classifier alone in the training cohort (0.83 [0.76-0.90] vs. 0.69 [0.61-0.77], p = 0.003) and the validation cohort (0.74 [0.67-0.82] vs. 0.62 [0.55-0.70], p = 0.001). Using risk scores developed from the nomogram, the 12-month survival rates of BA patients with native liver were 35.7% (95% confidence interval [CI], 22.7-56.3) in the high-risk group and 80.8% (95% CI, 63.4-100.0) in the low-risk group in the validation cohort. CONCLUSIONS: The comprehensive genetic-clinical nomogram based on preoperative 2DSWE, liver gene expression, and other clinical parameters can accurately predict response to KPE.

Intratumoral erythroblastic islands restrain anti-tumor immunity in hepatoblastoma.

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1+ macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.

Ex vivo tumor dissection followed by kidney autotransplantation in bilateral wilms tumor.

Introduction: Successful management of bilateral Wilm's tumor (BWT) involves a radical resection while preserving enough normal kidney tissue. Nephron-sparing surgery often results in an R1/R2 resection with a high recurrence rate in children with huge or multiple tumors, or tumors proximity to the renal hilum. In contrast, kidney autotransplantation can completely resect the tumor while maintaining homeostasis and preserving the patient's healthy kidney tissues. Methods: We summarized the clinical data of 8 synchronous BWT patients who underwent kidney autotransplantation at the First Affiliated Hospital of Sun Yat-sen University from 2018 to 2020. Ex vivo tumor resection and kidney autotransplantions were performed on 11 kidneys. The baseline characteristics, perioperative management, and survival status were reported. Results: Nephron-sparing surgeries were performed on 5 kidneys in vivo. Among all the 8 patients, six of them (75%) received staged operation and the other 2 patients (25%) received single-stage operation. No residual tumors were found on the postoperative imaging in all the 8 patients. In total, 6 (75%) patients occurred complications after the autotransplantation, among which, 2 (33.3%) patients had complication of Clavien-Dindo grade IIIa, and 4 (66.7%) patients had complication of grade < 3. During the 38 months of follow-up, 87.5% (7/8) of patients were tumor-free survival with normal renal function. One patient died from renal failure without tumor recurrence. Discussion: Therefore, our study indicated that autologous kidney transplantation can be an option for patients with complex BWT if the hospital's surgical technique and perioperative management conditions are feasible.

Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance.

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.

Gonadal Y-chromosome mosaicism with 45, X Turner syndrome complicated with bilateral HCG-secreting gonadoblastoma.

We report a rare case of bilateral HCG-secreting gonadoblastomas (Gb) in a 5.25-year-old girl of 45, X Turner syndrome (TS) with gonadal Y chromosome mosaicism. The clinical data were summarized, and the literatures were reviewed. The patient had enlarged breasts for 2 years and 3 months, with elevated ß-HCG of blood found for 8 months. The level of ß-HCG of cerebrospinal fluid, cranial MRI, chest and abdominal CT, and pelvic MRI were normal. After surgical gonad exploration, biopsy and excision, gonad venous blood hormone examination and SRY gene detection of gonad tissue, the diagnosis was confirmed as HCG-secreting Gb (bilateral) and TS (45, X) with gonad Y chromosome mosaicism. The patient received 4 courses of chemotherapy, and regular outpatient follow-up. At 9 months after gonadectomy, there was no clinical, laboratory, or radiological evidence of recurrence. We reported a nonclassical case of 45, X Turner syndrome (TS) with gonadal Y chromosome mosaicism, who presented with breast development as the first manifestation and then virilization due to bilateral HCG-secreting gonadoblastomas. Detection of serum ß-HCG and AFP is requisite for the diagnosis of precocious puberty, karyotyping is important for virilizing phenotypic female, and virilization in Turner syndrome implies the existence of Y chromosome(substance) (peripheral blood or tissue mosaicism) and the occurrence of gonadal tumors.

Analysis of circRNA and miRNA expression profiles in IGF3-induced ovarian maturation in spotted scat (Scatophagus argus).

Insulin-like growth factor 3 (IGF3) induces ovarian maturation in teleosts; however, research on its molecular regulatory mechanism remains deficient. Circular RNAs (circRNAs) and microRNAs (miRNAs) are involved in various biological processes, including reproduction. In this study, circRNAs and miRNAs involved in IGF3-induced ovarian maturation were evaluated in spotted scat (Scatophagus argus). In ovarian tissues, we identified 176 differentially expressed (DE) circRNAs and 52 DE miRNAs between IGF3 treatment and control groups. Gene Ontology (GO) enrichment analyses showed that host genes of DE circRNAs and target genes of DE miRNAs were enriched for various processes with a high degree of overlap, including cellular process, reproduction, reproductive process, biological adhesion, growth, extracellular region, cell junction, catalytic activity, and transcription factor activity. Enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included cell adhesion molecules, ECM-receptor interaction, regulation of actin cytoskeleton, focal adhesion, cell cycle, Hedgehog signaling pathway, phosphatidylinositol signaling system, PI3K-Akt signaling pathway, Apelin signaling pathway, Notch signaling pathway, insulin signaling pathway, and Rap1 signaling pathway. A circRNA-miRNA-mRNA regulatory network was constructed, including DE genes involved in reproduction (e.g., oocyte maturation, oocyte meiosis, and ECM remodeling), such as ccnd2, hecw2, dnm2, irs1, adam12, and cdh13. According to the regulatory network and tissue distribution, we identified one circRNA (Lachesis_group5:6245955|6270787) and three miRNAs (novel_miR_622, novel_miR_980, and novel_miR_64) that may exert regulatory effects in IGF3-induced ovarian maturation in S. argus. Taken together, this study provides a novel insight into the molecular mechanisms by which IGF3 functions in ovaries and highlights the effects of circRNAs and miRNAs in reproduction in S. argus.

Bench surgery with autotransplantation for bilateral Wilms tumor-A feasible technique for renal sinus invasion.

Purpose: Bilateral Wilms tumor (BWT) with renal sinus invasion requires extremely difficult surgical care. This study presents an alternative strategy for tumor removal while at the same time preserving the renal parenchyma. Materials and methods: In total, 9 cases of synchronous BWT were admitted to our hospital between May 2016 to Aug 2020. We retrospectively reviewed the clinical data, surgical technique, and functional and oncological outcomes of these cases. Results: The 9 cases included 3 males and 6 females, with a median age of 12 months at surgery (range 7-40). A total of 14 kidney units had renal sinus invasion (77.8%), whereas multifocal neoplasms were observed in 7 units (38.9%). The local stage distribution revealed 1 kidney with stage I, 10 kidneys with stage II, and 7 kidneys with stage III. Nephron-sparing surgery was performed on 15 kidney units (83.3%), among which 13 (72.2%) underwent bench surgery with autotransplantation (BS-AT), whereas 2 (11.1%) were subjected to tumor enucleation in vivo. Urinary leakage was the most prevalent postoperative complication. We observed negative margins. During the mean follow-up of 28.4 months, 2 patients (22.2%) succumbed from sepsis and renal failure, respectively, whereas the other 7 (77.8%) survived without recurrence. Survivors experienced an estimated glomerular filtration rate of 81 ± 15.4 ml/(min × 1.73 m2). The endpoint renal volume of 9 renal units receiving BS-AT significantly increased (P = 0.02). Conclusions: In summary, the surgical management of bilateral Wilms tumor requires meticulous operative approach and technique. Besides, BS-AT provides a viable alternative to nephron-sparing surgery for BWT patients with renal sinus invasion.