TRAF7-targeted HOXA5 acts as a tumor suppressor in prostate cancer progression and stemness via transcriptionally activating SPRY2 and regulating MEK/ERK signaling.

Homeobox A5 (HOXA5), a homeodomain transcription factor, is considered a tumor suppressor in cancer progression; however, its function in prostate cancer (PCa) remains unclear. This study focused on the relevance of HOXA5 in PCa progression. We identified the downregulation of HOXA5 in PCa tissues based on the TCGA database and further verified in 30-paired PCa and adjacent normal tissues. Functional studies revealed that HOXA5 upregulation impaired the stem-like characteristics and malignant behaviors of PCa cells in vitro and in vivo. Mechanistically, HOXA5 was found to be regulated by tumor necrosis factor receptor-associated factor 7 (TRAF7), a putative E3-ubiquitin ligase. We observed that TRAF7 was overexpressed in PCa and subsequently enhanced the degradation of HOXA5 protein via its ubiquitin ligase activity, contributing to the acquisition of an aggressive PCa phenotype. For its downstream mechanism, we demonstrated that sprouty RTK signaling antagonist 2 (SPRY2) served as a downstream target of HOXA5. HOXA5 could directly bind to the SPRY2 promoter, thereby regulating the SPRY2-mediated MEK/ERK signaling pathway. Silencing SPRY2 largely compromised the tumor-suppressive effect of HOXA5 in PCa progression and cancer stemness. Our findings highlight the previously-underappreciated signaling axis of TRAF7-HOXA5-SPRY2, which provides a novel prognostic and therapeutic target for PCa treatment.

Responses of cherry radish to different types of microplastics in the presence of oxytetracycline.

Croplands have become a hotspot for antibiotic and microplastic (MP) pollution. However, little is known regarding their combined effects on crops. In this study, the individual and combined effects of oxytetracycline (OTC) and three MPs (i.e., polypropylene (PP), polyamide (PA), and polyvinylchloride (PVC)) on cherry radish were investigated using pot experiments. Individually, OTC (50 mg kg-1), PA (2%, w/w), and PP (2%, w/w) induced negligible effects on cherry radish biomass and the root/shoot ratio. However, PVC (2%, w/w) significantly inhibited cherry radish growth; that is, its shoot and root fresh weight decreased by 46.2% and 81.1%, respectively. In the combined exposure groups, OTC alleviated the adverse effects of PVC on the cherry radish leaf number and shoot fresh weight. This was linked to that OTC increased the content of photosynthetic pigments. Superoxide dismutase activity in cherry radish roots was inhibited to different extents in all treatment groups except for the PA and PVC treatments. Malondialdehyde (MDA) content in cherry radish roots increased in all treatment groups, suggesting that both OTC and MPs caused oxidative damage to cherry radish root cells, therefore inhibiting cherry radish root growth. However, the presence of OTC non-significantly changed the effects of MPs on cherry radish roots. Irrespective of OTC presence, MPs induced a reduction in the root/shoot ratio of cherry radish, suggesting that the inhibitory effect of MPs on cherry radish roots was stronger than that on shoots. These findings contribute to the evaluation of the phytotoxicity of antibiotics and MPs in soil-vegetable systems.

Clinical heterogeneity and intrafamilial variability of Joubert syndrome in two siblings with CPLANE1 variants.

BACKGROUND: Joubert syndrome (JBTS) is a rare genetic disorder that is characterized by midbrain-hindbrain malformations. Multiple variants in genes that affect ciliary function contribute to the genetic and clinical heterogeneity of JBTS and its subtypes. However, the correlation between genotype and phenotype has not been elucidated due to the limited number of patients available. METHODS: In this study, we observed different clinical features in two siblings from the same family. The older sibling was classified as a pure JBTS patient, whereas her younger sibling displayed oral-facial-digital defects and was therefore classified as an oral-facial-digital syndrome type VI (OFD VI) patient. Next, we performed human genetic tests to identify the potential pathogenic variants in the two siblings. RESULTS: Genetic sequencing indicated that both siblings harbored compound heterozygous variants of a missense variant (c.1067C>T, p.S356F) and a frameshift variant (c.8377_8378del, p.E2793Lfs*24) in CPLANE1 (NM_023073.3). CONCLUSION: This study reports that two novel CPLANE1 variants are associated with the occurrence of JBTS and OFD VI. These results help elucidate the intrafamilial phenotypic variability associated with CPLANE1 variants.

Identification of two novel pathogenic variants of PIBF1 by whole exome sequencing in a 2-year-old boy with Joubert syndrome.

BACKGROUND: Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. CASE PRESENTATION: A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. CONCLUSION: In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.

Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome.

BACKGROUND: Joubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid-hindbrain malformation called the "molar tooth sign" on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS. METHODS: Whole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT-PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690). RESULTS: We identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode. CONCLUSION: Our study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.

Clinical Features and Long-Term Outcome of Primary Intracranial Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumors: 14 Cases From a Single Institution.

OBJECTIVE: Primary intracranial Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare, and only a few studies have reported >4 cases of this disease. The purpose of this study was to explore the clinical features, treatment, and outcome of primary intracranial ES/pPNETs. METHODS: The clinical data of 14 patients who had been surgically treated from February 2003 to November 2017 and in whom immunohistochemical staining results had confirmed the diagnosis of primary intracranial ES/pPNETs were retrospectively analyzed. Kaplan-Meier survival analysis was used to estimate the survival rate and the median survival time (MST). RESULTS: Gross total resection (GTR) was achieved in 7 cases, and subtotal resection was performed in 7 cases. During follow-up, 10 (71.4%) patients had local recurrence and 3 (21.4%) patients had distant metastasis. The overall 1-, 2-, and 5-year survival rates were 78.6%, 47.6%, and 19.0%, respectively. Kaplan-Meier survival analysis showed that postoperative radiotherapy was a significant prognostic factor for longer MST (P = 0.034). GTR and radiotherapy with or without adjuvant chemotherapy yielded the highest 2-year survival rate (100%). Three patients who underwent GTR, radiotherapy, and chemotherapy had the highest 2-year survival rates (100%) and the longest MST (48 months). CONCLUSIONS: Primary intracranial ES/pPNETs have an aggressive clinical course, with a high tendency for local recurrence and distant metastasis. Radiotherapy plays a significant role in improving the survival of patients. GTR combined with radiotherapy and chemotherapy may be the most beneficial treatment modality.

Receptor-mediated glutamate release from volume sensitive channels in astrocytes.

Several lines of work have shown that astrocytes release glutamate in response to receptor activation, which results in a modulation of local synaptic activity. Astrocytic glutamate release is Ca(2+)-dependent and occurs in conjunction with exocytosis of glutamate containing vesicles. However, astrocytes contain a millimolar concentration of cytosolic glutamate and express channels permeable to small anions, such as glutamate. Here, we tested the idea that astrocytes respond to receptor stimulation by dynamic changes in cell volume, resulting in volume-sensitive channel activation, and efflux of cytosolic glutamate. Confocal imaging and whole-cell recordings demonstrated that astrocytes exhibited a transient Ca(2+)-dependent cell volume increase, which activated glutamate permeable channels. HPLC analysis revealed that glutamate was released in conjunction with other amino acid osmolytes. Our observations indicate that volume-sensitive channel may constitute a previously uncharacterized target for modulation of astrocyte-neuronal interactions.