PRMT5 mediated FUBP1 methylation accelerates prostate cancer progression.

Strategies beyond hormone-related therapy should need to be developed to improve prostate cancer mortalityfor better disease management. Here we show that FUBP1 and its methylation are essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppresses the development of prostate cancer. FUBP1 accelerated prostate cancer development across in various pre-clinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence shorter treatment durations in our patient cohort. Suppressed prostate cancer progression was observed in different various genetic mouse models expressing FUBP1 mutants deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, successfully disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in different various pre-clinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potentially therapeutic strategy for disease prostate cancer management.

Comprehensive analysis of the prognostic and immunological signature of TNFAIP8 family genes in human glioma.

TNFAIP8 family molecules have been recognized for their involvement in the progression of tumors across a range of cancer types. Emerging experimental data suggests a role for certain TNFAIP8 family molecules in the development of glioma. Nonetheless, the comprehensive understanding of the genomic alterations, prognostic significance, and immunological profiles of TNFAIP8 family molecules in glioma remains incomplete. In the study, using the comprehensive bioinformatics tools, we explored the unique functions of 4 TNFAIP8 members including TNFAIP8, TNFAIP8L1, TNFAIP8L2 and TNFAIP8L3 in glioma. The expressions of TNFAIP8, TNFAIP8L1, TNFAIP8L2, and TNFAIP8L3 were notably upregulated in glioma tissues compared to normal tissues. Furthermore, survival analysis indicated that elevated expression levels of TNFAIP8, TNFAIP8L1 and TNFAIP8L2 were correlated with unfavorable outcomes in terms of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) among glioma patients. Genetic modifications, such as mutations and copy number alterations, within the TNFAIP8 family exhibited a significant association with extended OS, DSS and PFS in individuals diagnosed with glioma. The findings suggest a noteworthy correlation between TNFAIP8 family members and the age and 1p/19q codeletion status of glioma patients. We also found that there were significant relationships between TNFAIP8 family expression and tumor immunity in glioma. Furthermore, functional annotation of TNFAIP8 family members and their co-expressed genes in gliomas was carried out using GO and KEGG pathway analysis. The GO analysis revealed that the primary biological processes influenced by the TNFAIP8 family co-expressed genes included cell chemotaxis, temperature homeostasis, and endocytic vesicle formation. Additionally, the KEGG analysis demonstrated that TNFAIP8 family co-expressed genes are involved in regulating various pathways such as inflammatory mediator regulation of TRP channels, pathways in cancer, prolactin signaling pathway, and Fc gamma R-mediated phagocytosis. Overall, the findings suggest that TNFAIP8 family members may play a significant role in the development of glioma and have the potential to serve as prognostic indicators and therapeutic targets for individuals with glioma.

Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3ßHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3ßHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3ßHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3ßHSD1 inhibitors as early intervention.

Relationship between Bladder Cancer, Nutritional Supply, and Treatment Strategies: A Comprehensive Review.

Bladder cancer (BC) is the predominant neoplasm affecting the urinary system and ranks among the most widespread malignancies globally. The causes of bladder cancer include genetic factors; age; sex; and lifestyle factors, such as imbalanced nutrition, obesity, and metabolic disorders. The lack of proper nutrient intake leads to the development of bladder cancer because insufficient nutrients are consumed to prevent this disease. The purpose of this review was to analyze the nutrients closely linked to the onset and advancement of bladder cancer and to explore the relationship between dietary nutrients and bladder cancer. Particular emphasis was placed on nutrients that are frequently ingested in daily life, including sugar, fat, protein, and others. The focus of this research was to analyze how nutritional intake before and after surgery affects the recovery process of patients who have been diagnosed with bladder cancer. This article seeks to increase awareness among both society and the medical community about the significance of implementing appropriate dietary nutrition to reduce the chances of developing bladder cancer, enhance perioperative care for patients with bladder cancer, and aid in their recuperation.

Rnd3 suppresses endothelial cell pyroptosis in atherosclerosis through regulation of ubiquitination of TRAF6.

BACKGROUND: As the main pathological basis for various cardiovascular and cerebrovascular diseases, atherosclerosis has become one of the leading causes of death and disability worldwide. Emerging evidence has suggested that Rho GTPase Rnd3 plays an indisputable role in cardiovascular diseases, although its function in atherosclerosis remains unclear. Here, we found a significant correlation between Rnd3 and pyroptosis of aortic endothelial cells (ECs). METHODS: ApoeKO mice were utilized as a model for atherosclerosis. Endothelium-specific transgenic mice were employed to disrupt the expression level of Rnd3 in vivo. Mechanistic investigation of the impact of Rnd3 on endothelial cell pyroptosis was carried out using liquid chromatography tandem mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP) assays, and molecular docking. RESULTS: Evidence from gain-of-function and loss-of-function studies denoted a protective role for Rnd3 against ECs pyroptosis. Downregulation of Rnd3 sensitized ECs to pyroptosis under oxidized low density lipoprotein (oxLDL) challenge and exacerbated atherosclerosis, while overexpression of Rnd3 effectively prevented these effects. LC-MS/MS, Co-IP assay, and molecular docking revealed that Rnd3 negatively regulated pyroptosis signaling by direct interaction with the ring finger domain of tumor necrosis factor receptor-associated factor 6 (TRAF6). This leads to the suppression of K63-linked TRAF6 ubiquitination and the promotion of K48-linked TRAF6 ubiquitination, inhibiting the activation of NF-κB and promoting the degradation of TRAF6. Moreover, TRAF6 knockdown countered Rnd3 knockout-evoked exacerbation of EC pyroptosis in vivo and vitro. CONCLUSIONS: These findings establish a critical functional connection between Rnd3 and the TRAF6/NF-κB/NLRP3 signaling pathway in ECs, indicating the essential role of Rnd3 in preventing pyroptosis of ECs.

VAMP726 from maize and Arabidopsis confers pollen resistance to heat and UV radiation by influencing lignin content of sporopollenin.

Sporopollenin in the pollen cell wall protects male gametophytes from stresses. Phenylpropanoid derivatives, including guaiacyl (G) lignin units, are known to be structural components of sporopollenin, but the exact composition of sporopollenin remains to be fully resolved. We analyzed the phenylpropanoid derivatives in sporopollenin from maize and Arabidopsis by thioacidolysis coupled with nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS). The NMR and GC-MS results confirmed the presence of p-hydroxyphenyl (H), G, and syringyl (S) lignin units in sporopollenin from maize and Arabidopsis. Strikingly, H units account for the majority of lignin monomers in sporopollenin from these species. We next performed a genome-wide association study to explore the genetic basis of maize sporopollenin composition and identified a vesicle-associated membrane protein (ZmVAMP726) that is strongly associated with lignin monomer composition of maize sporopollenin. Genetic manipulation of VAMP726 affected not only lignin monomer composition in sporopollenin but also pollen resistance to heat and UV radiation in maize and Arabidopsis, indicating that VAMP726 is functionally conserved in monocot and dicot plants. Our work provides new insight into the lignin monomers that serve as structural components of sporopollenin and characterizes VAMP726, which affects sporopollenin composition and stress resistance in pollen.

Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma.

Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.

Expert consensus on the clinical application of totally implantable venous access devices in the upper arm (2022 Edition).

With the widespread adoption of ultrasound guidance, Seldinger puncture techniques, and intracardiac electrical positioning technology for the placement of peripherally inserted central catheters in recent years, an increasing number of medical staff and patients now accept peripheral placement of totally implantable venous access devices (TIVADs) in the upper arm. This approach has the advantage of completely avoiding the risks of hemothorax, pneumothorax, and neck and chest scarring. Medical specialties presently engaged in this study in China include internal medicine, surgery, anesthesiology, and interventional departments. However, command over implantation techniques, treatment of complications, and proper use and maintenance of TIVAD remain uneven among different medical units. Moreover, currently, there are no established quality control standards for implantation techniques or specifications for handling complications. Thus, this expert consensus is proposed to improve the success rate of TIVAD implantation via the upper-arm approach, reduce complication rates, and ensure patient safety. This consensus elaborates on the technical indications and contraindications, procedures and technical points, treatment of complications, and the use and maintenance of upper-arm TIVAD, thus providing a practical reference for medical staff.

Percutaneous Magnetic Resonance Imaging-Guided Coaxial Cutting Needle Biopsy of Pancreatic Lesions: Diagnostic Accuracy and Safety.

PURPOSE: To appraise the diagnostic performance of magnetic resonance imaging-guided percutaneous coaxial cutting needle biopsy of pancreatic lesions using a 0.4-T open magnetic resonance imaging scanner with optical tracking navigation. MATERIALS AND METHODS: This retrospective study included 158 patients who underwent magnetic resonance imaging-guided pancreatic lesion biopsy procedures from May 2019 to December 2020. Two to four specimens were collected from each patient. Pathological diagnosis and clinical follow-ups were conducted to establish the final diagnosis. The procedures were evaluated for sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and complications. The Cardiovascular and Interventional Radiological Society of Europe guidelines were used to classify complications. RESULTS: Biopsy pathology revealed 139 pancreatic tumor malignancies and 19 benign pancreatic lesions. Finally, 151 patients were diagnosed with pancreatic malignancy and 7 with benign disease confirmed by surgery, re-biopsy, and clinical follow-up. The sensitivity, specificity, positive and negative predictive value, and accuracy for diagnosis of pancreatic diseases were 92.1%, 100%, 100%, 36.8%, and 92.4%, respectively. The biopsy accuracy was significantly related to the size (≤ 2 cm, 76.2%; 2-4 cm, 94.0%; > 4 cm, 96.2%, P = .02) and not the lesion's location (head of pancreas, 90.7%; neck of pancreas, 88.9%; body of pancreas, 94.3%; tail of pancreas, 96.7%, P = .73). Minor complications included two patients experiencing mild abdominal pain and two with a minor occurrence of hemorrhage. CONCLUSIONS: Percutaneous magnetic resonance imaging-guided pancreatic lesion biopsy combined with optical navigation has high diagnostic accuracy and is safe for clinical practice. Level of Evidence Level 4, Case-series.

Clinical spectrum and prognosis of pathologically confirmed atypical tumefactive demyelinating lesions.

To describe the clinical spectrum and prognosis of atypical tumefactive demyelinating lesions (TDLs), which were confirmed by pathology. A total of 11 patients were diagnosed with atypical TDLs confirmed by brain biopsy and surgery between January 2006 and December 2017. The clinical spectrum and prognosis in these patients were analyzed. The patients' ages ranged from 29 to 62 years, with a mean age of 48.9 years; 72.7% were males. The Expanded Disability Status Scale (EDSS) of the patients with first onset was 2.36. Most of the patients started with limb numbness and weakness (45.5%) or alalia (27.2%). The mean time from symptom onset to biopsy or surgery was 12.9 days (3-30 days). Most of the patients had solitary lesions (72.7%), supratentorial lesions (90.9%, particularly predominant in the frontal, temporal, and parietal lobes), moderate edema (63.6%), mild mass effect (54.5%), and patchy lesions (54.5%). Among them, three patients were positive for myelin basic protein (MBP) and one patient was positive for myelin oligodendrocyte glycoprotein (MOG). The patients were followed up for an average of 6.9 years (2-14 years), and recurrent TDLs were observed in 2 patients. Except for the 2 patients who relapsed, only 1 of the 9 patients died; the other 8 patients improved or maintained the status quo (the EDSS scores were lower or unchanged). The patients did not have any serious nervous system injury at onset, and the main presentation included extremity weakness, headache or dizziness, and alalia. The most common form was patchy on MRI enhancement. Cerebrospinal fluid and demyelination test can be an indicator of TDLs, and seizures may be a poor prognostic indicator. Most atypical TDLs have monophasic courses and good outcomes. The effect of neurosurgery alone was good in our group, and the effect of surgery on atypical TDLs can be further studied.

Application effect of preoperative chemoradiotherapy combined with rehabilitation nursing in patients with rectal cancer surgery.

To study the effect of preoperative chemoradiotherapy combined with rehabilitation nursing in patients with rectal cancer surgery. 106 cases of rectal cancer patients in our hospital were selected. 53 cases in each group were treated with surgical treatment combined with rehabilitation nursing treatment and preoperative radiotherapy and chemotherapy combined with surgical treatment and rehabilitation nursing treatment in the study group. The T stage (ypT) and N stage (ypN) downgrading rates of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 were compared between the two groups after treatment. The 5-year cumulative survival rate, recurrence rate and the positive rate of Bax and antigen identified by monoclonal antibody Ki-67 (Ki-67) expression were detected. T stage downgrading rate and N stage downgrading rate were 77.36% (41/53) 35.85% (19/53) in control group and 94.34% (50/53) 64.15% (34/53) in research group, respectively. The CEA and CA19-9 levels measured at the end of surgery and one month after nursing in both groups were lower than those before treatment. After treatment, scores of quality of life indicators in both groups increased. The positive rates of Bax and Ki-67Ki-67 were significantly different between the two groups after treatment (P < 0.05). Preoperative chemoradiotherapy combined with rehabilitation nursing has obvious effect on patients with rectal cancer surgery, and has obvious advantages in inhibiting tumor growth, destroying tumor survival immune environment and reducing surgical complications, which can improve the prognosis and is worthy of clinical application. It could provide a potential treatment for patients with rectal cancer.

Primary suprasellar germinoma: A series of 15 cases.

Primary suprasellar germinoma (PSG) is a rare malignant tumor of the central nervous system. This study aimed to explore the clinical characteristics, treatment protocol, and prognosis of patients with PSG. This case series retrospectively analyzed the clinical data of patients with PSG in Tianjin Huanhu Hospital diagnosed between January 2016 and December 2021. Fifteen patients with an average age of 19.6 years were included, in which nine of them were males. The mean duration between initial symptoms and admission was 17.0 months. The mean follow-up was 40.8 months. Ten patients had polydipsia and polyuria, visual impairments were observed in 8 patients, and 2 cases (13.3%) had symptoms both from suprasellar and pineal regions. All 15 cases were histopathologically confirmed as germinoma through craniotomy or biopsy. Most patients (80%) underwent radiotherapy combined with chemotherapy. During follow-up, all the patients showed a reduction in tumor size, especially in the bifocal cases. Symptoms of polydipsia, polyuria, and visual impairment were markedly relieved to different degrees. All patients had recovered well at discharge. Patients with polydipsia and polyuria took desmopressin daily. A histological confirmation by open biopsy through craniotomy or endoscopic biopsy might be recommended for PSG to start the appropriate treatments. Patients with PSG will usually have a good prognosis, but attention should be paid to the treatment of endocrine deficiencies.

OpNAC1 transcription factor regulates the biosynthesis of the anticancer drug camptothecin by targeting loganic acid O-methyltransferase in Ophiorrhiza pumila.

Camptothecin (CPT) is an anticancer pentacyclic quinoline alkaloid widely used to treat cancer patients worldwide. However, the biosynthetic pathway and transcriptional regulation of camptothecin are largely unknown. Ophiorrhiza pumila, the herbaceous plant from the Rubiaceae family, has emerged as a model plant for studying camptothecin biosynthesis and regulation. In this study, a high-quality reference genome of O. pumila with estimated size of ~456.90 Mb was reported, and the accumulation level of camptothecin in roots was higher than that in stems and leaves. Based on its spatial distribution in the plant, we examined gene functions and expression by combining genomics with transcriptomic analysis. Two loganic acid O-methyltransferase (OpLAMTs) were identified in strictosidine-producing plant O. pumila, and enzyme catalysis assays showed that OpLAMT1 and not OpLAMT2 could convert loganic acid into loganin. Further knock-out of OpLAMT1 expression led to the elimination of loganin and camptothecin accumulation in O. pumila hairy roots. Four key residues were identified in OpLAMT1 protein crucial for the catalytic activity of loganic acid to loganin. By co-expression network, we identified a NAC transcription factor, OpNAC1, as a candidate gene for regulating camptothecin biosynthesis. Transgenic hairy roots and biochemical assays demonstrated that OpNAC1 suppressed OpLAMT1 expression. Here, we reported on two camptothecin metabolic engineering strategies paving the road for industrial-scale production of camptothecin in CPT-producing plants.

IGFBP2 Drives Regulatory T Cell Differentiation through STAT3/IDO Signaling Pathway in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies. Elevated regulatory T cell (Treg) infiltration has a potent immunosuppressive function in tumor biology, which contributes to low survival in PDAC. Nonetheless, the crosstalk between malignant cells and tumor-infiltrating Tregs in PDAC is not well understood. Here, clinical data demonstrates that the insulin-like growth factor binding protein 2 (IGFBP2) is associated with Treg accumulation in the microenvironment of PDAC in humans. Additionally, IGFBP2 increases Treg infiltration in the tumor microenvironment and promotes disease progression in mouse PDAC. Bioinformatic analysis and mechanistic assessment reveals IGFBP2 upregulated indoleamine 2, 3-dioxygenase (IDO) by activating signal transducer and activator of transcription 3 (STAT3) signaling in PDAC cells, thus inducing Treg differentiation and an immunosuppressive tumor microenvironment. These findings provide mechanistic insights into an important molecular pathway that promotes an immunosuppressive microenvironment, which suggests the IGFBP2 axis as a potential target for improved immune response in PDAC.

Mesenchymal stem cell-derived extracellular vesicles attenuate tPA-induced blood-brain barrier disruption in murine ischemic stroke models.

Intracerebral hemorrhage following blood-brain barrier (BBB) disruption resulting from thrombolysis of ischemic stroke with tissue plasminogen activator (tPA) remains a critical clinical problem. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are promising nanotherapeutic agents that have the potential to repair the BBB after ischemic stroke; however, whether they can attenuate BBB disruption and hemorrhagic transformation after tPA thrombolysis is largely unknown. Here, we observed that MSC-EVs efficiently passed through the BBB and selectively accumulated in injured brain regions in ischemic stroke model mice in real time using aggregation-induced emission luminogens (AIEgens), which exhibit better tracking ability than the commercially available tracer DiR. Moreover, tPA administration promoted the homing of MSC-EVs to the ischemic brain and increased the uptake of MSC-EVs by astrocytes. Furthermore, the accumulated MSC-EVs attenuated the tPA-induced disruption of BBB integrity and alleviated hemorrhage by inhibiting astrocyte activation and inflammation. Mechanistically, miR-125b-5p delivered by MSC-EVs played an indispensable role in maintaining BBB integrity by targeting Toll-like receptor 4 (TLR4) and inhibiting nuclear transcription factor-kappaB (NF-κB) signaling in astrocytes. This study provides a noninvasive method for real-time tracking of MSC-EVs in the ischemic brain after tPA treatment and highlights the potential of MSC-EVs as thrombolytic adjuvants for ischemic stroke. STATEMENT OF SIGNIFICANCE: Although tPA thrombolysis is the most effective pharmaceutical strategy for acute ischemic stroke, its clinical application and therapeutic efficacy are challenged by tPA-induced BBB disruption and hemorrhagic transformation. Our study demonstrated that MSC-EVs can act as an attractive thrombolytic adjuvant to repair the BBB and improve thrombolysis in a mouse ischemic stroke model. Notably, by labeling MSC-EVs with AIEgens, we achieved accurate real-time imaging of MSC-EVs in the ischemic brain and therapeutic visualization. MSC-EVs inhibit astrocyte activation and associated inflammation through miR-125b-5p/TLR4/NF-κB pathway. Consequently, we revealed that MSC-EVs combined with tPA thrombolysis may be a promising approach for the treatment of ischemic stroke in clinical setting.

Exosomes derived from pericardial adipose tissues attenuate cardiac remodeling following myocardial infarction by Adipsin-regulated iron homeostasis.

As a vital adipokine, Adipsin is closely associated with cardiovascular risks. Nevertheless, its role in the onset and development of cardiovascular diseases remains elusive. This study was designed to examine the effect of Adipsin on survival, cardiac dysfunction and adverse remodeling in the face of myocardial infarction (MI) injury. In vitro experiments were conducted to evaluate the effects of Adipsin on cardiomyocyte function in the face of hypoxic challenge and the mechanisms involved. Our results showed that Adipsin dramatically altered expression of proteins associated with iron metabolism and ferroptosis. In vivo results demonstrated that Adipsin upregulated levels of Ferritin Heavy Chain (FTH) while downregulating that of Transferrin Receptor (TFRC) in peri-infarct regions 1 month following MI. Adipsin also relieved post-MI-associated lipid oxidative stress as evidenced by decreased expression of COX2 and increased GPX4 level. Co-immunoprecipitation and immunofluorescence imaging prove a direct interaction between Adipsin and IRP2. As expected, cardioprotection provided by Adipsin depends on the key molecule of IRP2. These findings revealed that Adipsin could be efficiently delivered to the heart by exosomes derived from pericardial adipose tissues. In addition, Adipsin interacted with IRP2 to protect cardiomyocytes against ferroptosis and maintain iron homeostasis. Therefore, Adipsin-overexpressed exosomes derived from pericardial adipose tissues may be a promising therapeutic strategy to prevent adverse cardiac remodeling following ischemic heart injury.

Inhibition of macrophage-derived foam cells by Adipsin attenuates progression of atherosclerosis.

Phagocytosis of oxidized low-density lipoprotein (OxLDL) by macrophages yields "foam cells" and serves as a hallmark of atherosclerotic lesion. Adipsin is a critical component of the complement activation pathway. Recent evidence has indicated an obligatory role for Adipsin in pathological models including ischemia-reperfusion and sepsis. Adipsin levels are significantly decreased in patients with asymptomatic carotid atherosclerosis, implying the role for Adipsin as a potential marker of asymptomatic carotid atherosclerosis. This study was designed to evaluate the role for Adipsin in atherosclerosis and the mechanisms involved using both in vivo and in vitro experiments. ApoE-/-/AdipsinTg mice were constructed and were fed a high-fat diet for 12 weeks. Compared with ApoE-/- mice, area of the sclerotic plaques was reduced, along with lower macrophage deposition within the plaque in ApoE-/-/AdipsinTg mice. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were stimulated with oxLDL (50 µg/ml). Adenovirus vectors containing the Adipsin gene were transfected into macrophages. Lipid accumulation was observed by Oil red O staining. Western blot and reverse transcription-polymerase chain reaction data revealed that Adipsin overexpression inhibited oxLDL-induced lipid uptake and foam cell formation and upregulation of CD36 and PPARγ in Ad-Adipsin-transfected macrophages. In addition, the PPARγ-specific agonist GW1929 reversed Adipsin overexpression-evoked inhibitory effect on lipid uptake. These results demonstrate unequivocally that Adipsin inhibits lipid uptake in a PPARγ/CD36-dependent manner and prevents the formation of foam cells, implying that Adipsin may be a potential therapeutic target against atherosclerosis.

Fumarate hydratase gene germline variants and mosaicism associated with pheochromocytoma and paraganglioma.

Fumarate hydratase (FH) catalyzes the conversion of fumaric acid to L-malic acid. Heterozygous variants of the human fumarate hydratase gene (FH) predispose to hereditary leiomyomatosis and renal cell cancer and, rarely, pheochromocytoma/paraganglioma (PPGL). No mosaic variant in FH has been reported yet. Using next-generation sequencing, five individuals with FH variants were found in 319 PPGL patients. Immunohistochemistry staining and loss of heterozygosity analysis in tumor tissues were performed to determine the pathogenicity of the variants. Deep targeted sequencing was performed on the peripheral blood DNA of a pheochromocytoma (PCC) patient with uterine leiomyomas. Finally, two of the five variants were found to be pathogenic. A germline variant (c.817G>A, p.Ala273Thr) was found in a patient with a PPGL family history. A mosaic variant (c.206G>A, p.Gly69Asp) with an allelic ratio of 5% in blood DNA was confirmed in the PCC patient with uterine leiomyomas. No metastatic PPGL was observed in the two PPGL patients with FH pathogenic variants. In summary, we report mosaicism in FH and the first PPGL pedigree with an FH pathogenic germline variant. Both germline variants and mosaicism should be taken into account during genetic testing.

Kinesin family member 15 can promote the proliferation of glioblastoma.

Glioblastoma is one of the most dangerous tumors for patients in clinical practice at present, and since glioblastoma originates from the brain, it will have a serious impact on patients. Therefore, more effective clinical therapeutic targets are still needed at this stage. Kinesin family member 15 (KIF15) promotes proliferation in several cancers, but its effect on glioblastoma is unclear. In this study, differentially expressed gene analysis and network analysis were performed to identify critical genes affecting glioma progression. The samples were divided into a KIF15 high-expression group and KIF15 low-expression group, and the association between FIK15 expression level and clinical characteristics was summarized and analyzed by performing medical data analysis; the effect of KIF15 on glioblastoma cell proliferation was detected by employing colony formation and MTT assays. The effect of KIF15 on tumor growth in mice was determined. It was found that KIF15 was a potential gene affecting the progression of glioblastoma. In addition, KIF15 was highly expressed in glioblastoma tumor tissues, and KIF15 was correlated with tumor size, clinical stage and other clinical characteristics. After the KIF15 gene was knocked out, the proliferation ability of glioblastoma was significantly inhibited. KIF15 also contributed to the growth of glioblastoma tumors in mice. Therefore, we found KIF15 to be a promising clinical therapeutic target.