Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.

Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies, causing significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1,307 publicly available EBV genomes from cancer, non-malignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included the first NK/T-cell lymphoma (NKTCL) EBV genomes reported outside East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8- to 21.9- fold increased risk. We also observed frequent variations in EBV genomes affecting peptide sequences previously reported to bind common MHC alleles. Finally, we found several non-synonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.

Granulomatous lymphadenitis in Taiwan: Unraveling infantile peak and Bacillus Calmette-Guérin lymphadenitis.

BACKGROUND: Granulomatous lymphadenitis, a histopathological diagnosis, often indicates infections, such as those caused by mycobacterial and fungal agents. METHODS: We conducted an analysis of 1098 granulomatous lymphadenitis cases, examining age distribution, lymph node locations, and laterality. Molecular detection of Bacillus Calmette-Guérin (BCG) was performed on archived formalin-fixed paraffin-embedded tissue specimens. RESULTS: Our analysis revealed a bimodal age distribution, notably with a minor peak in infants. These infantile cases predominantly featured axillary involvement, frequently occurring on the left side. Positive rates of BCG identification decreased with age: <1 year, 71%; 1-2 year, 33%; 2-3 year, 13%; 3-4 year, 0%. Remarkably, only one of the 14 cases with molecularly confirmed BCG lymphadenitis had comments regarding BCG in the pathological report. Compared with patients born after 2016 (BCG at 5-8 months), those born before 2016 (BCG at birth) developed BCG lymphadenitis at a wider age range with right skewness (before 2016, 13 ± 11 months [range, 3-33 months] vs. after 2016, 10 ± 2 months [range, 8-13 months]). Four of the 14 BCG-positive cases had congenital heart disease. Seven patients received anti-tuberculosis drugs following surgical excision. No surgical complications were reported. CONCLUSIONS: BCG lymphadenitis constitutes a distinctive minor peak within the spectrum of granulomatous lymphadenitis in Taiwan. Pathologists should consider the possibility of BCG infection, especially in cases of infantile axillary, supraclavicular, neck lymphadenopathies on the left side. Moreover, BCG administration at 5-8 months may reduce delayed-onset BCG lymphadenitis.

High glucose enhances fibrosis in human annulus fibrosus cells by activating mTOR, PKCδ, and NF-κB signaling pathways.

Low back pain stands as a significant factor in disability, largely resulting from intervertebral disc degeneration (IVDD). High glucose (HG) levels have been implicated in the pathogenesis of IVDD. However, the detailed mechanism of HG in IVDD is largely unknown. Our clinical results revealed that fibrosis markers such as CTGF, Col1a1, ATF4, and EIF2 are highly expressed in advanced-stage IVDD patients. Stimulation of human annulus fibrosus cells (HAFCs) with HG, but not mannitol, promotes fibrosis protein production. Ingenuity Pathway Analysis in the GSE database found that the mTOR, PKCδ, and NF-κB pathways were significantly changed during IVDD. The mTOR, PKCδ, and NF-κB inhibitors or siRNAs all abolished HG-induced fibrosis protein production. In addition, treatment of HAFCs with HG enhances the activation of mTOR, PKCδ, and NF-κB pathways. Thus, HG facilitates fibrosis in IVDD through mTOR, PKCδ, and NF-κB pathways. These results underscore the critical role of HG as a fibrotic factor in the progression of IVDD.

Natural and Engineered Guide RNA-directed Transposition with CRISPR-Associated Tn7-like Transposons.

CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated nuclease) defense systems have been naturally coopted for guide RNA-directed transposition on multiple occasions. In all cases, cooption occurred with diverse elements related to the bacterial transposon Tn7. Tn7 tightly controls transposition; the transposase is activated only when special targets are recognized by dedicated target-site selection proteins. Tn7 and the Tn7-like elements that coopted CRISPR-Cas systems evolved complementary targeting pathways: one that recognizes a highly conserved site in the chromosome and a second pathway that targets mobile plasmids capable of cell-to-cell transfer. Tn7 and Tn7-like elements deliver a single integration into the site they recognize and also control the orientation of the integration event, providing future potential for use as programmable gene-integration tools. Early work has shown that guide RNA-directed transposition systems can be adapted to diverse hosts, even within microbial communities, suggesting great potential for engineering these systems as powerful gene-editing tools.

Comparison of the 2022 world health organization classification and international consensus classification in myelodysplastic syndromes/neoplasms.

In 2022, two novel classification systems for myelodysplastic syndromes/neoplasms (MDS) have been proposed: the International Consensus Classification (ICC) and the 2022 World Health Organization (WHO-2022) classification. These two contemporary systems exhibit numerous shared features but also diverge significantly in terminology and the definition of new entities. Thus, we retrospectively validated the ICC and WHO-2022 classification and found that both systems promoted efficient segregation of this heterogeneous disease. After examining the distinction between the two systems, we showed that a peripheral blood blast percentage ≥ 5% indicates adverse survival. Identifying MDS/acute myeloid leukemia with MDS-related gene mutations or cytogenetic abnormalities helps differentiate survival outcomes. In MDS, not otherwise specified patients, those diagnosed with hypoplastic MDS and single lineage dysplasia displayed a trend of superior survival compared to other low-risk MDS patients. Furthermore, the impact of bone marrow fibrosis on survival was less pronounced within the ICC framework. Allogeneic transplantation appears to improve outcomes for patients diagnosed with MDS with excess blasts in the ICC. Therefore, we proposed an integrated system that may lead to the accurate diagnosis and advancement of future research for MDS. Prospective studies are warranted to validate this refined classification.

Transcriptomic Analysis Reveals Intrinsic Abnormalities in Endometrial Polyps.

Endometrial polyps (EPs) are benign overgrowths of the endometrial tissue lining the uterus, often causing abnormal bleeding or infertility. This study analyzed gene expression differences between EPs and adjacent endometrial tissue to elucidate intrinsic abnormalities promoting pathological overgrowth. RNA sequencing of 12 pairs of EPs and the surrounding endometrial tissue from infertile women revealed 322 differentially expressed genes. Protein-protein interaction network analysis revealed significant alterations in specific signaling pathways, notably Wnt signaling and vascular smooth muscle regulation, suggesting these pathways play critical roles in the pathophysiology of EPs. Wnt-related genes DKK1 and DKKL1 were upregulated, while GPC3, GREM1, RSPO3, SFRP5, and WNT10B were downregulated. Relevant genes for vascular smooth muscle contraction were nearly all downregulated in EPs, including ACTA2, ACTG2, KCNMB1, KCNMB2, MYL9, PPP1R12B, and TAGLN. Overall, the results indicate fundamental gene expression changes promote EP formation through unrestrained growth signaling and vascular defects. The intrinsic signaling abnormalities likely contribute to clinical symptoms of abnormal uterine bleeding and infertility common in EP patients. This analysis provides molecular insights into abnormal endometrial overgrowth to guide improved diagnostic and therapeutic approaches for this troublesome women's health condition. Confirmation of expanded cohorts and further investigations into implicated regulatory relationships are warranted.

Antrodia cinnamomea prevents ovariectomized-promoted bone loss by inhibiting osteoclast formation.

Osteoporosis is a common bone disease in aging populations, particularly in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are linked with a variety of adverse effects. Antrodia cinnamomea extracts (ACE) are highly renowned for their anticancer, antioxidative, and anti-inflammatory properties. However, whether ACE-enriched anti-osteoporosis functions are largely unknown. In a preclinical animal model, we found that ovariectomy significantly decreased bone volume in the ovariectomized (OVX) rats. Administration of ACE antagonized OVX-induced bone loss. In addition, ACE reversed OVX-reduced biomechanical properties. The serum osteoclast marker also showed improvement in the ACE-treated group. In the cellular model, it was indicated that ACE inhibits RANKL-induced osteoclast formation. Taken together, ACE seems to be a hopeful candidate for the development of novel anti-osteoporosis treatment.

Kikuchi disease in acute leukaemia: a distinct clinical syndrome with HLA association.

AIMS: To report the clinicopathological features of Kikuchi disease in patients with acute leukaemia, emphasising similarities among cases. METHODS AND RESULTS: In a cohort of 454 Kikuchi disease patients, we identified three cases of concurrent acute leukaemia. These patients shared similar clinical traits, with Kikuchi disease emerging approximately a month after induction chemotherapy onset, featuring neck-region lymphadenopathy. Notably, two patients were middle-aged, deviating from the typical age distribution of Kikuchi disease. Histologically, these cases aligned with typical Kikuchi disease. Negative immunohistochemical stains (CD34, CD117, ERG, TdT) indicated the absence of extramedullary leukaemic infiltration. Herpes simplex virus immunohistochemical staining was also negative. Significantly, a human leucocyte antigen (HLA) association was observed in these three cases. HLA-B*15:01, C*04:01, and DRB1*04:06 were more prevalent in these patients compared to the general population (compared with three independent control cohorts: Taiwanese Han Chinese (n = 504), Tzu Chi Taiwanese bone marrow donors (n = 364) and Hong Kong Chinese (n = 5266)). CONCLUSIONS: Our study underscores the unique link between Kikuchi disease and acute leukaemia, characterised by specific features and HLA associations. This underlines Kikuchi disease as a possible differential diagnosis in pertinent clinical scenarios. Furthermore, this syndrome offers insights into postchemotherapy immunology in acute leukaemia, enhancing comprehension.

IL-17 promotes IL-18 production via the MEK/ERK/miR-4492 axis in osteoarthritis synovial fibroblasts.

The concept of osteoarthritis (OA) as a low-grade inflammatory joint disorder has been widely accepted. Many inflammatory mediators are implicated in the pathogenesis of OA. Interleukin (IL)-18 is a pleiotropic cytokine with versatile cellular functions that are pathogenetically important in immune responses, as well as autoimmune, inflammatory, and infectious diseases. IL-17, a proinflammatory cytokine mainly secreted by Th17 cells, is upregulated in OA patients. However, the role of IL-17 in OA progression is unclear. The synovial tissues collected from healthy donors and OA patients were used to detect the expression level of IL-18 by IHC stain. The OA synovial fibroblasts (OASFs) were incubated with recombinant IL-17 and subjected to Western blot, qPCR, and ELISA to examine IL-18 expression level. The chemical inhibitors and siRNAs which targeted signal pathways were used to investigate signal pathways involved in IL-17-induced IL-18 expression. The microRNAs which participated IL-18 expression were surveyed with online databases miRWalk and miRDB, followed by validation with qPCR. This study revealed significantly higher levels of IL-18 expression in synovial tissue from OA patients compared with healthy controls, as well as increased IL-18 expression in OASFs from rats with severe OA. In vitro findings indicated that IL-17 dose-dependently promoted IL-18 production in OASFs. Molecular investigations revealed that the MEK/ERK/miR-4492 axis stimulated IL-18 production when OASFs were treated with IL-17. This study provides novel insights into the role of IL-17 in the pathogenesis of OA, which may help to inform OA treatment in the future.

Surgical Phase Duration in Robot-Assisted Partial Nephrectomy: A Surgical Data Science Exploration for Clinical Relevance.

(1) Background: Surgical phases form the basic building blocks for surgical skill assessment, feedback, and teaching. The phase duration itself and its correlation with clinical parameters at diagnosis have not yet been investigated. Novel commercial platforms provide phase indications but have not been assessed for accuracy yet. (2) Methods: We assessed 100 robot-assisted partial nephrectomy videos for phase durations based on previously defined proficiency metrics. We developed an annotation framework and subsequently compared our annotations to an existing commercial solution (Touch Surgery, Medtronic™). We subsequently explored clinical correlations between phase durations and parameters derived from diagnosis and treatment. (3) Results: An objective and uniform phase assessment requires precise definitions derived from an iterative revision process. A comparison to a commercial solution shows large differences in definitions across phases. BMI and the duration of renal tumor identification are positively correlated, as are tumor complexity and both tumor excision and renorrhaphy duration. (4) Conclusions: The surgical phase duration can be correlated with certain clinical outcomes. Further research should investigate whether the retrieved correlations are also clinically meaningful. This requires an increase in dataset sizes and facilitation through intelligent computer vision algorithms. Commercial platforms can facilitate this dataset expansion and help unlock the full potential, provided that the phase annotation details are disclosed.

Omentin-1 ameliorates the progress of osteoarthritis by promoting IL-4-dependent anti-inflammatory responses and M2 macrophage polarization.

Osteoarthritis (OA) is a prevalent joint disease commonly associated with aging and obesity, which can lead to pain, stiffness, joint dysfunction, and disability. Omentin-1 (also called intelectin-1) is a newly discovered adipokine, which plays a protective role in suppressing the secretion of pro-inflammatory cytokines. Based on data from the Gene Expression Omnibus (GEO) dataset and clinical samples obtained at our institution revealed, determined that omentin-1 and IL-4 (an anti-inflammatory cytokine) levels were significantly lower in OA patients than in normal controls. Omentin-1 was shown to induce IL-4-depedent anti-inflammatory responses and M2 macrophage polarization in OA synovial fibroblasts via the PI3K, ERK, and AMPK pathways. Administering omentin-1 was shown to block cartilage degradation and bone erosion resulting from anterior cruciate ligament transection by inhibiting the production of pro-inflammatory cytokines and promoting M2 macrophage polarization in vivo. Our findings indicate omentin-1 as a promising therapeutic avenue for the treatment for OA.

Necrosis in lymph nodes and their differential diagnoses: application of reticulin staining.

This study aimed to enhance the histopathological diagnosis of necrotic lymph node specimens. A chart review was conducted, revealing that the most common causes of lymph node necrosis were Kikuchi disease (33%), granulomatous inflammation (25%), metastasis (17%), and lymphomas (12%). Histological analysis of necrotic tissue in 333 specimens demonstrated significant differences between the four diseases. The necrotic tissue of Kikuchi disease was amorphous, and hypercellular, and exhibited karyorrhexis and congestion. Granulomatous inflammation presented amorphous necrotic tissue with a nodular-like pattern. Metastasis exhibited heterogeneous morphology that varied between cancer types. Lymphomas displayed extensive necrosis with ghost cells, congestion, and bubbles. Reticulin staining patterns also differed between diseases. Kikuchi disease and lymphomas exhibited preserved reticular fiber networks in the necrotic tissue, resembling the viable tissue. Granulomatous inflammation and metastasis showed disrupted reticular fiber networks in the necrotic tissue. Based on these findings, histological features and reticulin staining patterns can aid in diagnosing Kikuchi disease, granulomatous inflammation, metastasis, and lymphomas in necrotic lymph node specimens.

Nesfatin-1 stimulates BMP5 expression and osteoclastogenesis in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease marked by immune cell activation and chronic inflammation in the synovium accompanied by osteoclast activation and local joint destruction. Increased levels of the adipokine nesfatin-1 in RA synovium are associated with proinflammatory cytokines. Our analysis of datasets from the Gene Expression Omnibus (GEO) database and synovial tissue samples from RA patients revealed that these had higher levels of nesfatin-1 and osteoclast markers compared with normal synovium. These findings were the same in tissue samples from mice with collagen-induced arthritis (CIA) and normal healthy controls. RNA sequencing analysis revealed that nesfatin-1 increased levels of bone morphogenetic protein-5 (BMP5) expression via JAK/STAT signaling in RA synovial fibroblasts. Finally, we found that nesfatin-1 short hairpin RNA reduced BMP5 and osteoclast formation in CIA mice. These findings provide new insights into the pathogenesis of RA.

Multiple adaptations underly co-option of a CRISPR surveillance complex for RNA-guided DNA transposition.

CRISPR-associated transposons (CASTs) are natural RNA-directed transposition systems. We demonstrate that transposon protein TniQ plays a central role in promoting R-loop formation by RNA-guided DNA-targeting modules. TniQ residues, proximal to CRISPR RNA (crRNA), are required for recognizing different crRNA categories, revealing an unappreciated role of TniQ to direct transposition into different classes of crRNA targets. To investigate adaptations allowing CAST elements to utilize attachment sites inaccessible to CRISPR-Cas surveillance complexes, we compared and contrasted PAM sequence requirements in both I-F3b CAST and I-F1 CRISPR-Cas systems. We identify specific amino acids that enable a wider range of PAM sequences to be accommodated in I-F3b CAST elements compared with I-F1 CRISPR-Cas, enabling CAST elements to access attachment sites as sequences drift and evade host surveillance. Together, this evidence points to the central role of TniQ in facilitating the acquisition of CRISPR effector complexes for RNA-guided DNA transposition.

Visfatin upregulates VEGF-C expression and lymphangiogenesis in esophageal cancer by activating MEK1/2-ERK and NF-κB signaling.

Lymph node metastasis is a recognized prognostic factor in esophageal cancer. Adipokines, including visfatin, and the molecule vascular endothelial growth factor (VEGF)-C, are implicated in lymphangiogenesis, but whether any association exists between esophageal cancer, adipokines and VEGF-C is unknown. We examined the relevance of adipokines and VEGF-C in esophageal squamous cell carcinoma (ESCC) in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. We found significantly higher levels of visfatin and VEGF-C expression in esophageal cancer tissue than in normal tissue. Immunohistochemistry (IHC) staining identified that higher levels of visfatin and VEGF-C expression were correlated with advanced stage ESCC. Visfatin treatment of ESCC cell lines upregulated VEGF-C expression and VEGF-C-dependent lymphangiogenesis in lymphatic endothelial cells. Visfatin induced increases in VEGF-C expression by activating the mitogen-activated protein kinase kinases1/2-extracellular signal-regulated kinase (MEK1/2-ERK) and Nuclear Factor Kappa B (NF-κB) signaling cascades. Transfecting ESCC cells with MEK1/2-ERK and NF-κB inhibitors (PD98059, FR180204, PDTC, and TPCK) and siRNAs inhibited visfatin-induced increases in VEGF-C expression. It appears that visfatin and VEGF-C are promising therapeutic targets in the inhibition of lymphangiogenesis in esophageal cancer.

Nodal reactive proliferation of monocytoid B-cells may represent atypical memory B-cells.

BACKGROUND: Reactive lymphadenopathies such as toxoplasmosis and cytomegalovirus lymphadenitis are associated with monocytoid cell proliferation. Monocytoid cells are B-lymphocytes with an undetermined subset. METHODS: Using digital spatial profiling whole transcriptome analyses, this study compared monocytoid and control B-cells. The B-cell subset of monocytoid cells was assigned according to gene expression profiles. RESULTS: This study identified 466 differentially expressed genes between monocytoid and control B-cells. The cellular deconvolution algorithm identified monocytoid cells as memory B-cells instead of as naïve B-cells. A comparison of the upregulated genes revealed that atypical memory B-cells had the largest number of genes overlapping with monocytoid cells compared with other memory B-cell subsets. Atypical memory B-cell markers, namely TBX21 (T-bet), FCRL4 (IRTA1), and ITGAX (CD11c), were all upregulated in monocytoid cells. Similar to atypical memory B-cells, monocytoid cells exhibited (1) upregulated transcription factors (TBX21, TOX), (2) upregulated genes associated with B-cell inhibition (FCRL5, FCRL4) and downregulated genes associated with B-cell activation (PIK3CG, NFKB1A, CD40), (3) downregulated cell cycle-related genes (CDK6, MYC), and (4) downregulated cytokine receptors (IL4R). This study also analyzed the expression of monocytoid cell signature genes in various memory B-cell subsets. Atypical memory B-cells exhibited a gene expression pattern similar to that of monocytoid cells, but other memory B-cell subsets did not. Furthermore, monocytoid cells and marginal zone lymphomas differed in gene expression profiles. CONCLUSION: Spatial transcriptomic analyses indicated that monocytoid cells may be atypical memory B-cells.

Lymph Nodes With Increased IgG4-positive Plasma Cells and Patterns Suspicious for IgG4-related Disease: Can Lymph Nodes Be the Only Site of Disease?

Lymphadenopathy with increased immunoglobulin (Ig) G4 + plasma cells can be a nonspecific finding or a manifestation of immunoglobulin G4-related disease (IgG4-RD). It remains unclear whether there are characteristic pathologic features of IgG4-RD involving lymph nodes, or if IgG4-RD lymphadenopathy can occur without other manifestations of IgG4-RD. In this study, we assessed 55 lymph node biopsy specimens (44 men and 11 women with a mean age of 55 y) with increased IgG4 + plasma cells that had 1 of the 6 well-described pathologic patterns. We also correlated these findings with IgG4 serum levels and followed these patients for 7 to 108 months (mean, 34.9 mo) for the occurrence of extranodal IgG4-RD. We further compared lymphadenopathy in patients who developed other manifestations of IgG4-RD (RD + , n=20, 36%) versus those who did not (RD - , n=35, 64%). We found that there were only minor significant differences between 2 groups, including frequency of receiving treatment (RD + , 90% vs. RD - , 60%, P =0.021) and higher serum levels of C-reactive protein (>8 mg/L, RD + , 53% vs. RD - , 13%, P =0.007). Other differences were either borderline or not significant, including mean age (RD + , 59.8 y vs. RD - , 51.9 y, P =0.097), male-to-female ratio (RD + , 16:4 vs. RD - , 28:7, P =1), constitutional symptoms (RD + , 25% vs. RD - , 9%, P =0.096), multiple enlarged lymph nodes (RD + , 45% vs. RD - , 26%, P =0.143), good response to therapy (RD + , 94% vs. RD - , 94%, P =1); higher serum IgG4 levels (>280 mg/dL, RD + , 75% vs. RD - , 51%, P =0.086), anemia (RD + , 45% vs. RD - , 43%, P =0.877), leukopenia (RD + , 0% vs. RD - , 3%, P =0.446), thrombocytopenia (RD + , 10% vs. RD - , 6%, P =0.556), positivity for antinuclear antibody (RD + , 24% vs. RD - , 29%, P =0.688), elevated serum levels of lactate dehydrogenase (>225 U/L, RD + , 0% vs. RD - , 20%, P =0.064), elevated serum IgE level (>100 IU/mL, RD + , 75% vs. RD - , 92%, P =0.238), and hypergammaglobulinemia (RD + , 90% vs. RD - , 86%, P =0.754). There were also no differences in morphologic patterns ( P =0.466), IgG4 + cell location ( P =0.104), eosinophil counts (RD + , 10.3±11.3 vs. RD - , 13.4±17.5, P =0.496), Epstein-Barr virus positivity (RD + , 35% vs. RD - , 60%, P =0.074), and Epstein-Barr virus-positive cell location ( P =0.351). Our findings suggest that there are minimal differences between stringently defined IgG4-RD lymphadenopathy with versus without other manifestations of IgG4-RD. These findings also suggest the existence of IgG4-RD lymphadenopathy as the sole presentation of IgG4-RD.

The ADAM9/WISP-1 axis cooperates with osteoblasts to stimulate primary prostate tumor growth and metastasis.

Background: Metastatic prostate cancer (PCa) predicts a poor prognosis and lower likelihood of survival. Osteoblasts (OBs) are known to be responsible for the synthesis and mineralization of bone, although it is unclear as to whether PCa in the prostate gland cooperates with OBs in bone to promote PCa malignant transformation. We aimed to elucidate how primary PCa cells cooperate with distal OBs and contribute to the vicious cycle that leads to metastatic PCa. Methods: N-cadherin, E-cadherin, and Twist protein expression were measured by Western blot. Twist translocation into the nucleus was detected by the immunofluorescence (IF) assay. Enzyme-linked immunosorbent assay (ELISA) detected protein levels in human serum samples. Levels of candidate protein expression were examined by the human cytokine array. Prostate tumor growth and metastasis were analyzed by orthotopic and metastatic prostate cancer models, respectively. Immunohistochemistry (IHC) staining was used to observe ADAM metallopeptidase domain 9 (ADAM9) and WNT1 inducible signaling pathway protein 1 (WISP-1) expression in tissue. Results: Our in vitro and in vivo analyses have now discovered that primary PCa expressing ADAM9 protein enables the transformation of OBs into PCa-associated osteoblasts (PCa-OBs), inducing WISP-1 secretion from PCa-OBs in the bone microenvironment. The upregulation of WISP-1 in bone provided feedback to primary PCa and promoted PCa cell aggressiveness via epithelial-mesenchymal transition (EMT) activity. Elevated levels of WISP-1 expression were detected in the serum of patients with PCa. ADAM9 levels were overexpressed in tumor tissue from PCa patients; ADAM9 blockade interrupted OB-induced release of WISP-1 and also suppressed primary tumor growth and distal metastasis in orthotopic PCa mouse models. Conclusion: Our study suggests that the ADAM9/WISP-1 axis assists with metastatic PCa progression. Thus, targeting the ADAM9/WISP-1 axis may help to prevent the malignant phenotypes of PCa cells.

Apelin promotes osteosarcoma metastasis by upregulating PLOD2 expression via the Hippo signaling pathway and hsa_circ_0000004/miR-1303 axis.

Osteosarcoma is a highly mortal bone tumor, with a high metastatic potential, promoted in part by the enzyme procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2). Increasing level of PLOD2 in osteosarcoma tissue correlates with lymphatic and distant metastasis. The adipokine apelin (APLN) is also found in different cancers and APLN upregulation promotes angiogenesis and metastasis, but its effects on osteosarcoma metastasis are uncertain. We explored APLN functioning in metastatic osteosarcoma. An analysis of records from the Gene Expression Omnibus (GEO) database showed higher levels of APLN expression in osteosarcoma tissue than in normal tissue. Similarly, levels of APLN and PLOD2 mRNA synthesis were upregulated in osteosarcoma tissue. Levels of APLN and PLOD2 protein correlated positively with osteosarcoma clinical stages. APLN increased PLOD2 expression in human osteosarcoma cell lines and cell migration via the mammalian Sterile 20-like kinase 1 (MST1), monopolar spindle-one-binder protein (MOB)1, and YAP cascades, and through hsa_circ_0000004 functioning as a sponge of miR-1303. We also found that knockdown of APLN antagonized lung metastasis in mice with osteosarcoma. APLN may be a therapeutic target in osteosarcoma metastasis.