Multi-omic analysis and validation reveal ZBP1 as a potential prognostic and immunotherapy-related biomarker in head and neck squamous cell carcinoma.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) exhibit unfavorable clinical outcomes, accompanied by high morbidity/mortality. In recent years, the management of HNSCC has encountered a significant obstacle. Z-DNA binding protein 1 (ZBP1) exerts crucial biological functions in chronic inflammatory disease and cancer. The aim of this research was to identify the possible function of ZBP1 in HNSCC. METHODS: The Cancer Genome Atlas (TCGA) database was used to collect the gene expression profile and corresponding clinical data. The gene expression, clinical prognosis, genetic alteration, immune characteristics, and subgroup analyses were performed. Meanwhile, an independent cohort (consisting of 66 tumor samples and 37 controls) was employed to validate the expression of ZBP1. RESULTS: Comparing to the normal controls, ZBP1 was upregulated in tumor samples. Low ZBP1 expression predicted undesirable clinical outcomes of HNSCC patients based on the survival analysis. Furthermore, the somatic mutations increased in low ZBP1 expression group. Immune characteristics analysis indicated a positive correlation of ZBP1 expression with the infiltration of immune cells, the expression of immunoregulatory genes and immune checkpoints. In the meantime, single-cell transcriptome analysis unveiled the expression of ZBP1 in tumor microenvironment (TME). In addition, differential gene expression analysis revealed that the expression of ZBP1 primarily contributes to the activation of T cells. Ultimately, ZBP1-associated prognostic and immune features in different subgroups of HNSCC patients were further investigated according to the subgroup analysis. CONCLUSION: Our study comprehensively disclosed that ZBP1 may have the potential to become a meaningful prognostic and immunotherapy-related biomarker for HNSCC.

Identification of the potential association between SARS-CoV-2 infection and acute kidney injury based on the shared gene signatures and regulatory network.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is identified as the cause of coronavirus disease 2019 (COVID-19) pandemic. Acute kidney injury (AKI), one of serious complications of COVID-19 infection, is the leading contributor to renal failure, associating with high mortality of the patients. This study aimed to identify the shared gene signatures and construct the gene regulatory network between COVID-19 and AKI, contributing to exploring the potential pathogenesis. METHODS: Utilizing the machine learning approach, the candidate gene signatures were derived from the common differentially expressed genes (DEGs) obtained from COVID-19 and AKI. Subsequently, receiver operating characteristic (ROC), consensus clustering and functional enrichment analyses were performed. Finally, protein-protein interaction (PPI) network, transcription factor (TF)-gene interaction, gene-miRNA interaction, and TF-miRNA coregulatory network were systematically undertaken. RESULTS: We successfully identified the shared 6 candidate gene signatures (RRM2, EGF, TMEM252, RARRES1, COL6A3, CUBN) between COVID-19 and AKI. ROC analysis showed that the model constructed by 6 gene signatures had a high predictive efficacy in COVID-19 (AUC = 0.965) and AKI (AUC = 0.962) cohorts, which had the potential to be the shared diagnostic biomarkers for COVID-19 and AKI. Additionally, the comprehensive gene regulatory networks, including PPI, TF-gene interaction, gene-miRNA interaction, and TF-miRNA coregulatory networks were displayed utilizing NetworkAnalyst platform. CONCLUSIONS: This study successfully identified the shared gene signatures and constructed the comprehensive gene regulatory network between COVID-19 and AKI, which contributed to predicting patients' prognosis and providing new ideas for developing therapeutic targets for COVID-19 and AKI.

ACT001 inhibited CD133 transcription by targeting and inducing Olig2 ubiquitination degradation.

Lung cancer is the most lethal malignancies with high aggressive and poor prognosis. Until now, the five-year survival rate has not been improved which brings serious challenge to human health. Lung cancer stem cells (LCSCs) serve as the root of cancer occurrence, progression, recurrence, and drug resistance. Therefore, effective anti-cancer agents and molecular mechanisms which could specifically eliminate LCSCs are urgently needed for drug design. In this article, we discovered Olig2 was overexpressed in clinical lung cancer tissues and acted as a transcription factor to regulate cancer stemness by regulating CD133 gene transcription. The results suggested Olig2 could be a promising target in anti-LCSCs therapy and new drugs targeted Olig2 may exhibit excellent clinical results. Furthermore, we verified ACT001, a guaianolide sesquiterpene lactone in phase II clinical trial with excellent glioma remission, inhibited cancer stemness by directly binding to Olig2 protein, inducing Olig2 ubiquitination degradation and inhibiting CD133 gene transcription. All these results suggested that Olig2 could be an excellent druggable target in anti-LCSCs therapy and lay a foundation for the further application of ACT001 in the treatment of lung cancer in clinical.

Comprehensive analysis identifies ARHGEF6 as a potential prognostic and immunological biomarker in lung adenocarcinoma.

Lung adenocarcinoma (LUAD), the most common histological type in lung cancer, is one of leading cancers with considerable morbidity/mortality worldwide. Treating LUAD remains an outstanding challenge due to the lack of early diagnosis and the poor therapeutic effects. Rac/Cdc42 guanine nucleotide exchange factor 6 (ARHGEF6), one of cytoskeletal regulators, exerts crucial biological functions in T cell migration. The potential biological role of ARHGEF6 in LUAD has yet to be established. Using multiple bioinformatics tools and statistical methods, we discovered that the mRNA and protein expression level of ARHGEF6 was significantly downregulated in tumor tissues comparing to normal controls. Moreover, ARHGEF6 presented high diagnostic value in LUAD patients (AUC = 0.949), and the patients with low ARHGEF6 expression had more somatic mutations and poor T stage, N stage, clinical prognosis. Experimental validation indicated that ARHGEF6 was low expressed in A549 and PC-9 cells comparing to the normal lung epithelial cells. The overexpression of ARHGEF6 remarkably attenuated the abilities of cell proliferation and colony formation. Furthermore, the immune landscape analysis in TME revealed that ARHGEF6 expression was positively associated with immune cell infiltration and immune checkpoints. Single-cell transcriptome analysis indicated that ARHGEF6 expression was also distributed in immune cell types in TME based on TISCH database. Additionally, differentially expressed genes (DEGs) and functional enrichment analyses uncovered that ARHGEF6 was involved in T cell activation. Finally, LUAD samples were classified two clusters based on DEGs for subgroups analysis. In summary, this study comprehensively uncovered that ARHGEF6 could be identified as a potential prognostic and immunological biomarker in lung adenocarcinoma.

A New Parameter of Hip Instability in Developmental Dysplasia of the Hip (DDH): Teardrop Distance.

Background: Hip instability is one of the etiologies of accelerated onset of osteoarthritis in developmental dysplasia of the hip (DDH). There are some radiological parameters for hip instability in hip dysplasia like broken shenton's line, elevated acetabular index, reduced lateral center edge angle (LCEA), upsloping lateral sourcil. We have discovered a new index of teardrop distance (TD) for assessing instability. Herein, we hypothesized that increased TD could be used as evidence of hip instability in DDH patients, which we verified using TD as an auxiliary diagnostic parameter for DDH, from supine to standing position. Methods: Female DDH patients undergoing Bernese periacetabular osteotomy (PAO) were enrolled in the DDH group, and normal female volunteers were in the control group. Anteroposterior radiographs of the pelvis in the supine and standing positions were taken, and LCEA, Tönnis angle (TA), sharp angle (SA), and TD were tested using Stata software to analyze the changes between supine and standing anteroposterior pelvic radiographs. Results: There were 26 female volunteers with 52 hips in the control group: supine TD 6.80 ± 0.98 mm, standing TD 6.65 ± 1.3 mm (P > 0.05). A total of 78 patients with 135 hips were included in the DDH group: supine TD 10.51 ± 3.50 mm, standing TD 10.93 ± 4.23 mm (P < 0.05). In either supine or standing position, TD in the DDH group was significantly wider than that in the control group (P < 0.05). In the DDH group, TD was correlated with TA and LCEA (rp 0.494-0.588, P < 0.05); TD was not correlated with SA, weight, or BMI (P > 0.05). There was a weak correlation between TD difference and standing LCEA (rp -0.276, P < 0.05). Conclusion: TD > 10 mm was a common imaging feature of DDH. It increased from supine to standing position, thus indicating hip instability in DDH patients. The hip parameters of both positions should be compared, fully considering the factors of hip stability.

Meta-analysis on the association between knee extensor strength and structural changes of knee osteoarthritis.

This study aimed to perform a meta-analysis to evaluate whether knee extensor (KE) strength weakness was associated with increased structural worsening in knee osteoarthritis (KOA) including joint space narrowing (JSN) and cartilage loss. PubMed, Embase, Scopus, ScienceDirect, Web of Science, and Cochrane library were searched from their inception to May 2020, to identify eligible studies. Odds ratios (ORs) accompanied by 95% confidence intervals (CIs) were calculated for the relationship between KE strength and outcomes. Totally eleven longitudinal studies were included. The pooled crude OR indicated no significant association between KE strength weakness and KOA progression of JSN (OR: 1.13, 95% CI: 0.90, 1.42), and this result duplicated after confounders were adjusted (OR: 1.10, 95% CI: 0.87, 1.39). Subgroup analysis showed the association remained non-significant in sex-specific outcomes and subsets of neutral and malaligned knees, but there was a trend toward increased risk of JSN progression in female knees with low strength (OR: 1.24, 95% CI: 0.87, 1.76, I2 = 82%). The pooled crude OR showed that KE strength weakness was associated with increased risk of cartilage loss (OR:1.43, 95% CI: 1.05, 1.95). After adjustment, we found a non-significant trend that low KE strength could increase the risk of cartilage loss (OR: 1.25, 95% CI: 0.95, 1.64), and this trend was separately observed in tibiofemoral or patellofemoral compartments. This meta-analysis suggested that KE strength weakness was not significantly associated with an increased risk of radiographic structural KOA progression in patients with KOA or known risk factors for KOA. However, there was a trend that women with weaker KE strength displayed a higher risk of JSN worsening and that KE strength weakness had an association with an increased risk of cartilage damage. Key points • Knee extensor strength weakness is not significantly associated with an increased risk of radiographic structural KOA progression in patients with or at risk of knee osteoarthritis. • There is a non-significant trend toward an increased risk of JSN progression in female knees with low knee extensor strength. • There is a trend that low KE strength can increase the risk of cartilage loss no matter in tibiofemoral or patellofemoral compartments, but it's not significant.

Differences of Anteroposterior Pelvic Radiographs Between Supine Position and Standing Position in Patients with Developmental Dysplasia of the Hip.

OBJECTIVE: To explore the difference in pelvic tilt and hip joint parameters with developmental dysplasia of the hip (DDH) comparing the anteroposterior (AP) pelvic radiographs taken in supine and standing positions. METHODS: A prospective study of DDH patients undergoing Bernese periacetabular osteotomy (PAO) was conducted. AP pelvic radiographs were taken in supine and standing positions before surgery The pelvic tilt and hip joint parameters from the two radiographs were compared. Contrast parameters included the distance between the pubic symphysis to sacrococcygeal distance (PSSC), lateral center-edge angle (LCEA), Tönnis angle (TA), and angle of sharp (SA). RESULTS: A total of 110 young DDH patients were enrolled, including 32 men and 78 women, aged 18-49 years. The male PSSC was 45.63 ± 13.69 mm in supine position and 36.91 ± 12.33 mm in standing position (P < 0.05). The female PSSC was 56.76 ± 13.54 mm in supine position and 48.62 ± 15.44 mm in standing position (P < 0.05). In this study, LCEA <20° in AP pelvic radiographs in the supine position was found in 52 men and 135 women. For male patients, in supine position and standing position, LCEA were 5.51° ± 11.88° and 4.45° ± 12.22°, respectively (P < 0.05); TA were 20.20° ± 9.63° and 21.30° ± 9.97°, respectively (P < 0.05), and SA comparison showed no significant differences. For female patients, in supine position and standing position, LCEA were 3.07° ± 12.07° and 1.69° ± 12.11°, respectively (P < 0.05), TA were 22.62° ± 9.31° and 23.82° ± 9.45°, respectively (P < 0.05), and SA were 48.01° ± 4.68° and 48.49° ± 4.74°, respectively (P < 0.05). CONCLUSION: Compared with the supine position, the young DDH patients have pelvic tilt backward and a decrease in hip coverage in the standing position.

The Influence of Pelvic Tilt on the Anteversion Angle of the Acetabular Prosthesis.

The concept of the "safe area" of the acetabular prosthesis has a long history and has been recognized by many scholars. It is generally believed that postoperative hip dislocation rate is low, when the acetabular anteversion angle is placed in the range of 15° ± 10°. Despite this, hip dislocation is a common complication after total hip arthroplasty. In recent years, more and more scholars have paid attention to the influence of pelvic tilt on the acetabular anteversion angle. The concept of acetabular anteversion changes as the pelvic tilt changes, and is challenging the traditional acetabular prosthesis "safe area." This study summarized the potential influencing factors of pelvic tilt and discussed the influence of the phenomenon on the anteversion angle of total hip arthroplasty (THA) acetabular prosthesis based on the literature review. We conclude that from the supine position to standing, followed by sitting, the pelvis tends to move backward. Pelvic sagittal activity, lumbar disease (ankylosing spondylitis), lumbar fusion (lumbar fusion, spine-pelvic fusion), and other factors related to the tilt are THA risk factors for postoperative dislocation and revision. With the change of body position, the degree of acetabular anteversion is directly related to the degree of pelvic tilt. The acetabular anteversion varies greatly, which leads to increased hip prosthesis wear and even hip dislocation. The lateral X-ray of the spine and pelvis is recommended in supine, standing, and sitting positions before THA. In addition, the pelvic tilt should be regarded as a reference of the acetabular prosthesis in the preoperative planning of THA.