The value of 68Ga-PSMA PET/CT in the diagnosis of intracapsular prostate cancer with a poor prognosis.

OBJECTIVE: To evaluate the diagnostic value of 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) for intracapsular prostate cancer with a poor prognosis (PPC) and no extracapsular invasion or distant metastasis. METHODS: The PET/CT images and clinical data of 221 patients were retrospectively analyzed. These patients all had clear pathological results. The maximum standard uptake value (SUVmax) of the main lesions was measured at the postprocessing workstation and was tested for correlation with the pathological score. The diagnostic accuracy was calculated using the receiver operating characteristic (ROC) curve, and the best diagnostic threshold was calculated. The correlation between SUVmax and the International Society of Urological Pathology Grade Group (GG) was also analyzed. RESULTS: The pathological results of the 221 patients were 48 benign lesions and 173 malignant lesions, including 81 PPC. Low-, intermediate-, and high-risk prostate cancers made up 21.97% (38/173), 54.33% (94/173), and 23.70% (41/173) of the malignant lesions, respectively. SUVmax and GG were positively correlated (r = 0.54, P < 0.01). The best SUVmax thresholds for 68Ga-PSMA PET/CT for the diagnosis of intracapsular PC and PPC were 7.95 and 13.94, respectively; the specificities were 0.83 and 0.85, the negative predictive values were 0.55 and 0.87, and the areas under the ROC curves were 0.88 and 0.88, respectively. CONCLUSION: 68Ga-PSMA PET/CT has high specificity and NPV in the diagnosis of intracapsular PPC, but the sensitivity for the diagnosis of intracapsular low-risk PC is low, which may cause some cases to be undetected.

Anlotinib for Metastatic Progressed Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data.

Introduction: Pheochromocytomas (PCC) and paragangliomas (PGL) (collectively PPGL) are a type of rare hypervascular neuroendocrine tumors that are very challenging to treat. This study aimed to determine the efficacy and safety of the multi-tyrosine kinase inhibitor anlotinib for the treatment of locally advanced or metastatic (LA/M) PPGL. Methods: A total of 37 eligible patients with unresectable or progressive LA/M PPGL were enrolled. Of them, 27 patients received anlotinib alone (n = 19) or in combination (n = 8) with radionuclide therapies, including peptide receptor radionuclide therapy (PRRT) and iodine 131 meta-iodobenzylguanidine (131I-MIBG). The primary endpoints included objective response rate (ORR), defined as partial response (PR) or complete response (CR), and disease-control rate, defined as PR, CR, or stable disease (SD). The secondary endpoints were progression-free survival (PFS), duration of response, and drug safety. Results: In the efficacy evaluation for all 27 patients, the ORR was 44.44% (95% CI: 24.4%-64.5%) and disease-control rate was 96.29% (95% CI: 88.7%-100%). Twelve cases (44.44%) achieved PR, 14 (51.85%) SD. The median PFS was 25.2 months (95% CI: 17.2 months to not reached). PFS was shorter in the anlotinib monotherapy group than in the group receiving anlotinib in combination with radionuclide therapy (P = .2). There were no serious treatment-related AEs. Conclusion: Anlotinib monotherapy or in combination with radionuclide therapies shows promising efficacy and safety for the treatment of LA/M PCC and PGL. Multi-tyrosine kinase inhibitors might represent a novel therapeutic strategy for patients with PPGL; however, large-scale prospective randomized, blinded, controlled clinical research studies are required.

A Mettl16/m6A/mybl2b/Igf2bp1 axis ensures cell cycle progression of embryonic hematopoietic stem and progenitor cells.

Prenatal lethality associated with mouse knockout of Mettl16, a recently identified RNA N6-methyladenosine (m6A) methyltransferase, has hampered characterization of the essential role of METTL16-mediated RNA m6A modification in early embryonic development. Here, using cross-species single-cell RNA sequencing analysis, we found that during early embryonic development, METTL16 is more highly expressed in vertebrate hematopoietic stem and progenitor cells (HSPCs) than other methyltransferases. In Mettl16-deficient zebrafish, proliferation capacity of embryonic HSPCs is compromised due to G1/S cell cycle arrest, an effect whose rescue requires Mettl16 with intact methyltransferase activity. We further identify the cell-cycle transcription factor mybl2b as a directly regulated by Mettl16-mediated m6A modification. Mettl16 deficiency resulted in the destabilization of mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1 in vivo. Moreover, we found that the METTL16-m6A-MYBL2-IGF2BP1 axis controlling G1/S progression is conserved in humans. Collectively, our findings elucidate the critical function of METTL16-mediated m6A modification in HSPC cell cycle progression during early embryonic development.

Paternal cadmium exposure induces glucolipid metabolic reprogramming in offspring mice via PPAR signaling pathway.

In industrialized societies, the prevalence of metabolic diseases has substantially increased over the past few decades, yet the underlying causes remain unclear. Cadmium (Cd) is a hazardous heavy metal and pervasive environmental endocrine disruptor. Here, we investigate the effects of paternal Cd exposure on offspring glucolipid metabolism. Paternal Cd exposure (1 mg kg-1 body weight) impaired glucose tolerance, increased random serum glucose and fasting serum insulin, elevated serum total cholesterol, and low-density lipoprotein in offspring mice. Untargeted metabolomics analysis of male offspring liver tissue revealed that paternal Cd exposure can affect offspring glucolipid metabolic reprogramming, which involved biosynthesis of phenylalanine, tyrosine and tryptophan, biosynthesis of unsaturated fatty acids, metabolism of linoleic acid, arachidonic acid and α-linolenic acid. Transcriptome sequencing of male offspring liver tissue showed that arachidonic acid metabolism, AMPK signaling pathway, PPAR signaling pathway and adipocytokine signaling pathway were significantly inhibited in the Cd-exposed group. The mRNA expression levels of PPAR signaling pathway related genes (Acsl1, Cyp4a14, Cyp4a10, Cd36, Ppard and Pck1) were significantly decreased. The protein expression levels of ACSL1, CD36, PPARD and PCK1 were also significantly reduced. Collectively, our findings suggest that paternal Cd exposure affect offspring glucolipid metabolic reprogramming via PPAR signaling pathway.

Non-invasive Prenatal Diagnosis of Chromosomal Aneuploidies and Microdeletion Syndrome Using Fetal Nucleated Red Blood Cells Isolated by Nanostructure Microchips.

Detection of detached fetal nucleated red blood cells (fNRBCs) in the maternal peripheral blood may serve as a prospective testing method competing with the cell-free DNA, in non-invasive prenatal testing (NIPT). Methods: Herein, we introduce a facile and effective lab-on-a-chip method of fNRBCs detection using a capture-releasing material that is composed of biotin-doped polypyrrole nanoparticles. To enhance local topographic interactions between the nano-components and fNRBC, a specific antibody, CD147, coated on the nanostructured substrate led to the isolation of fNRBCs from maternal peripheral blood. Subsequently, an electrical system was employed to release the captured cells using 0.8 V for 15 s. The diagnostic application of fNRBCs for fetal chromosomal disorders (Trisomy 13/21/18/X syndrome, microdeletion syndrome) was demonstrated. Results: Cells captured by nanostructured microchips were identified as fNRBCs. Twelve cases of chromosomal aneuploidies and one case of 18q21 microdeletion syndrome were diagnosed using the fNRBCs released from the microchips. Conclusion: Our method offers effective and accurate analysis of fNRBCs for comprehensive NIPT to monitor fetal cell development.

Decidual vascular endothelial cells promote maternal-fetal immune tolerance by inducing regulatory T cells through canonical Notch1 signaling.

Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro. Moreover, under in vitro Treg cell induction condition with agonistic antibodies and transforming growth factor (TGF)-ß, DVECs promoted Treg cell differentiation from non-Treg conventional T cells. Consistent with the promotion of Treg cell maintenance and differentiation, Treg cell-associated gene expression such as TGF-ß, Epstein-Barr-induced gene-3, CD39 and glucocorticoid-induced tumor necrosis factor receptor was also increased in the presence of DVECs. Further study revealed that DVECs expressed Notch ligands such as Jagged-1, Delta-like protein 1 (DLL-1) and DLL-4, while Treg cells expressed Notch1 on their surface. The effects of DVECs on Treg cells was inhibited by siRNA-induced knockdown of expression of Jagged-1 and DLL-1 in DVECs. Downregulation of Notch1 in Treg cells using lentiviral shRNA transduction decreased Foxp3 expression in Treg cells. Adoptive transfer of Notch1-deficient Treg cells increased abortion rate in a murine semiallogeneic pregnancy model. Taken together, our study suggests that maternal DVECs are able to maintain decidual Treg cell identity and promote Treg cell differentiation through activation of Notch1 signal pathway in Treg cells and subsequently inhibit the immune response against semiallogeneic fetuses and preventing spontaneous abortion.

Two novel mutations in the C-terminal region of centrosomal protein 290 (CEP290) result in classic Joubert syndrome.

Joubert syndrome is a neurologic disorder with a pathognomonic "molar tooth sign" on brain imaging. The purpose of this study was to identify potential mutations in a Chinese patient with Joubert syndrome by targeted massively parallel sequencing. Taking advantage of high-throughput DNA sequencing technologies, 18 Joubert-causing genes of a Chinese patient with classic Joubert syndrome were sequenced at a time, and 2 novel variants in the CEP290 gene (c.7323_7327delAGAAG and c.6012-2A>G) were identified in this patient. Sanger validation showed that 2 variants were inherited from each parents, respectively. Both variants are located in the C-terminal region of the CEP290 protein and are predicted to be deleterious. The results support that the combination of targeted genes enrichment and next-generation sequencing is valuable molecular diagnostic tool and suitable for clinical application.