<abstract> <sec><title>Background</title><p>Bladder cancer (BLCA) has a high rate of morbidity and mortality, and is considered as one of the most malignant tumors of the urinary system. Tumor cells interact with surrounding interstitial cells, playing a key role in carcinogenesis and progression, which is partly mediated by chemokines. CXC chemokines exert anti-tumor biological roles in the tumor microenvironment and affect patient prognosis. Nevertheless, their expression and prognostic values patients with BLCA remain unclear.</p> </sec> <sec><title>Methods</title><p>We used online tools, including Oncomine, UALCAN, GEPIA, GEO databases, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRUST (version 2.0), LinkedOmics, TCGA, and TIMER2.0 to perform the relevant analysis.</p> </sec> <sec><title>Results</title><p>The mRNA levels of C-X-C motif chemokine ligand (<italic>CXCL)1</italic>, <italic>CXCL5</italic>, <italic>CXCL6</italic>, <italic>CXCL7</italic>, <italic>CXCL9</italic>, <italic>CXCL10</italic>, <italic>CXCL11</italic>, <italic>CXCL13</italic>, <italic>CXCL16</italic>, and <italic>CXCL17</italic> were increased significantly increased, and those of <italic>CXCL</italic>2, <italic>CXCL3</italic>, and <italic>CXCL12</italic> were decreased significantly in BLCA tissues as assessed using the Oncomine, TCGA, and GEO databases. GEO showed that high levels of <italic>CXCL1</italic>, <italic>CXCL6</italic>, <italic>CXCL10</italic>, <italic>CXCL1</italic>1, and <italic>CXCL13</italic> mRNA expression are associated significantly with the poor overall survival (all p &lt; 0.05), and similarly, those of <italic>CXCL2</italic> and <italic>CXCL12</italic> in the TCGA database (p &lt; 0.05). The predominant signaling pathways involving the differentially expressed CXC chemokines are cell cycle, chemokine, and cytokine-cytokine receptor interaction. Moreover, transcription factors such as Sp1 transcription factor (SP1), nuclear factor kappa B subunit 1 (NFKB1), and RELA proto-oncogene, NF-KB subunit (RELA) were likely play critical roles in regulating CXC chemokine expression. LYN proto-oncogene, src family tyrosine kinase (LYN) and LCK proto-oncogene, src family tyrosine kinase (LCK) were identified as the key targets of these CXC chemokines. MicroRNAs miR200 and miR30 were identified as the main microRNAs that interact with several CXC chemokines through an miRNA-target network. The expression of these chemokines is closely associated with the infiltration of six categories of immune cells.</p> </sec> <sec><title>Conclusion</title><p>We explored the CXC chemokines superfamily-based biomarkers associated with BLCA prognosis using public databases, and provided possible chemokine targets for patients with BLCA.</p> </sec> </abstract>

Background: In patients with squamous cell carcinoma of the cervix (SCCC), a squamous cell carcinoma (SqCC) in the lung represents either a second primary tumor or metastasis. This distinction between second primary tumors and lung metastases in patients with SCCC significantly influences patient prognosis and therapy. Here, we aimed to differentiate second primary tumors from lung metastases in patients with SCCC by exploring the HPV status in SqCCs involving the lung within a large cohort. Methods: P16 expression was assessed using immunohistochemistry on tissue microarrays including a total of 415 primary lung SqCCs and 21 lung SqCCs with prior SCCC. Following this, we performed HPV DNA typing and the sensitive RNAscope in situ method to screen all the cases for HPV E6/E7 expression, which is a more reliable indicator of transcriptively active HPV in tumor cells. Results: The p16 positive expression rate was 13.7% (57/415) in primary lung SqCCs, but HPV DNA was not detected in any of the 57 primary lung SqCC cases that positively expressed p16. In contrast, HPV DNA was detected in all cases (21/21) with prior SCCC. Consistently, all 21 lung SqCCs with prior SCCC (21/21) showed extensive HPV16 E6/E7 expression. In striking contrast, none of the primary lung SqCCs (0/415) had a detectable RNAscope signal. Conclusions: HPV does not seem to play a role in the development of primary lung SqCCs. HPV detection may be helpful in distinguishing second primary tumors from lung metastases in patients with SCCC.

Background:The objective of this study was to determine the cutoff value of PD-L1 expression that can predict response to immune checkpoint inhibitor (ICI) immunotherapy for upper tract urothelial carcinoma (UTUC). Methods:The concordance of PD-L1 expression between paired surgical resection specimens (SRSs) and urine cell blocks (UCBs) (cohort 1) was studied in a retrospective set of 58 UTUC patients to determine its suitability as a predictor of ICI immunotherapy efficacy. PD-L1 expression in UCBs obtained before neoadjuvant ICI immunotherapy was verified in a prospective set of 12 UTUC patients (cohort 2). PD-L1 (SP263 clone) expression was assessed for percentage (tumor proportional score) of tumor cell (TC) showing PD-L1 staining. Results:The authors found an overall agreement of 94.4% (51 of 54) between UCBs and SRSs in cohort 1 (positive percent agreement = 100%, negative percent agreement = 93.8%, r value = 0.63). PD-L1 expression in <10% and ≥10% of tumor cells (TCs) of UCBs were the best predictors of negative (<25%) and positive (≥25%) expression in TCs of SRSs, respectively (concordance = 98.1%, r value = 0.93). These findings were verified in cohort 2: at the 10% cutoff for PD-L1 expression, the best response predictive value was 83.3% (5 of 6) in PD-L1-positive patients, and the nonresponse predictive value was 50% (3 of 6) in PD-L1-negative patients. The sensitivity, specificity, and area under the receiver operating characteristic curve values for predicting ICI immunotherapy efficacy based on PD-L1expressing TCs in UCBs were 62.5%, 75%, and 0.688, respectively.Conclusions: Immunocytochemistry of UCBs is reliable for determining PD-L1 expression, which can predict the efficacy of ICI immunotherapy at a cutoff of 10%.

Background: The level of ferritin has been shown to be associated with the prognosis of various tumors.In this study, we proposed prognostic indicator, named ferritin/globulin ratio (FGR), and to evaluate the important value in hepatocellular carcinoma (HCC).Methods: A total of 472 HCC patients and 219 healthy controls were concluded in our retrospective study. The clinical characteristics were analyzed in these patients. The optimal cutoff value of the prognostic factors (α-fetoprotein, alanine aminotransferase, aspartate aminotransferase, ferritin, globulin and FGR) were determined by using receiver operating characteristic curve analysis, and then analyzed by univariate and multivariate Cox hazard models to evaluate the prognostic significance.Results: Serum ferritin, globulin and FGR levels were significantly higher in HCC patients than in healthy controls. Multivariate analysis showed that FGR was a significant and independent risk factor OS (HR =1.575; 95% CI: 1.122-2.212; P=0.009) and DFS (HR =1.569; 95% CI: 1.117-2.204; P=0.009) in whole patients. Furthermore, we also classified the data according to α-fetoprotein (AFP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), highly significant differences of FGR were observed between the two groups in OS and DFS. High FGR levels were associated with poor OS and DFS in HCC patients. Conclusions:The serum FGR levels may serve as a significant predictor of prognosis in HCC patients.

Bladder cancer (BLCA) has a high rate of morbidity and mortality, and is considered as one of the most malignant tumors of the urinary system. Tumor cells interact with surrounding interstitial cells, playing a key role in carcinogenesis and progression, which is partly mediated by chemokines. CXC chemokines exert anti‑tumor biological roles in the tumor microenvironment and affect patient prognosis. Nevertheless, their expression and prognostic values patients with BLCA remain unclear. We used online tools, including Oncomine, UALCAN, GEPIA, GEO databases, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRUST (version 2.0), LinkedOmics, TCGA, and TIMER2.0 to perform the relevant analysis. The mRNA levels of C-X-C motif chemokine ligand (CXCL)1, CXCL5, CXCL6, CXCL7, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, and CXCL17 were increased significantly increased, and those of CXCL2, CXCL3, and CXCL12 were decreased significantly in BLCA tissues as assessed using the Oncomine, TCGA, and GEO databases. GEO showed that high levels of CXCL1, CXCL6, CXCL10, CXCL11, and CXCL13 mRNA expression are associated significantly with the poor overall survival (all p < 0.05), and similarly, those of CXCL2 and CXCL12 in the TCGA database (p < 0.05). The predominant signaling pathways involving the differentially expressed CXC chemokines are cell cycle, chemokine, and cytokine-cytokine receptor interaction. Moreover, transcription factors such as Sp1 transcription factor (SP1), nuclear factor kappa B subunit 1 (NFKB1), and RELA proto-oncogene, NF-KB subunit (RELA) were likely play critical roles in regulating CXC chemokine expression. LYN proto-oncogene, src family tyrosine kinase (LYN) and LCK proto-oncogene, src family tyrosine kinase (LCK) were identified as the key targets of these CXC chemokines. MicroRNAs miR200 and miR30 were identified as the main microRNAs that interact with several CXC chemokines through an miRNA-target network. The expression of these chemokines is closely associated with the infiltration of six categories of immune cells. We explored the CXC chemokines superfamily-based biomarkers associated with BLCA prognosis using public databases, and provided possible chemokine targets for patients with BLCA.