In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.     

Association between cranial asymmetry severity and chronic subdural hematoma laterality

Objectives:To analyze the association between cranial asymmetry severity and chronic subdural hematoma (CSDH) laterality.Methods:We retrospectively assessed 120 patients with surgically treated unilateral CSDH from January 2009 to December 2018. Preoperative computed tomography images were used to determine occipital vault angles, bilateral cranium areas, and cranial index of symmetry (CIS) ratios.Results:The male sex (70%) was the predominant factor promoting CSDH pathogenesis. In the overall study population (mean age, 71.3 years; left-sided CSDH, 58/120 [48%] patients; right-sided CSDH due to right-sided flat cranium, 38 patients; left-sided CSDH due to right-sided flat cranium, 37 patients). Flat cranial asymmetry was nonsignificantly associated with CSDH laterality (p- value=.689). However, most CSDH patients (86.7% of 120 patients) presented dominant-sided nonoverlapping areas on the left side. Thirteen (81.3%) patients presenting right-dominant nonoverlapping areas had right-sided CSDH, and 55 (52.9%) patients had left-dominant nonoverlapping area had left-sided CSDH (p- value=0.01). The CIS ratio was significantly higher in patients with right-dominant nonoverlapping areas than in those with left-dominant nonoverlapping areas (97.2% vs 95.9%, p- value<0.0001).Conclusion:Left-sided hematoma predominance is not associated with a flat cranium and laterality of unilateral CSDH. Moreover, more asymmetric crania with lower CIS ratios may predict left-sided CSDHs, whereas the right-sided CSDHs may be more common in symmetric crania with higher CIS ratios. The CSDH laterality is potentially attributable to cranial asymmetry severity.

Chronic subdural hematoma (CSDH), a common neurosurgical entity, is considered a delayed manifestation of head trauma, occurring mostly in older men.1 Although CSDHs can occur in unilateral or bilateral intracranial spaces, left-sided predominance has been previously reported.2,3 Few studies have reported that cranial morphology and gravity contribute to the laterality of CSDH.4–6 Cranial asymmetry is more common among crania flattened toward the right side, influencing the left-sided predominance of CSDH.6 The cranial index of symmetry (CIS) with a semiautomated method has been introduced to objectively determine the severity of cranial deformations including plagiocephaly.7 A preliminary study reported that the objective nonradiographic method potentially serves as an unbiased measurement of cranial asymmetry.7 The flat side has been simply defined by a smaller angle through a simple method considering angles among 3 lines.4–6 However, the angles may be manually affected by the points of the intersection of the manually selected lines, thus obstructing cranial asymmetry assessment. Therefore, here, we aimed to clarify the association between the severity of cranial asymmetry and the laterality of CSDH by using an objective semiautomated method.     

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High-grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell-cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox-treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral-mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X-ray repair cross-complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.