CD276 enhances sunitinib resistance in clear cell renal cell carcinoma by promoting DNA damage repair and activation of FAK-MAPK signaling pathway.

OBJECTIVE: This study aimed to explore the effect of CD276 expression on the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cell and animal models and the potential mechanisms involved. METHODS: CD276 expression levels of ccRCC and normal samples were analyzed via online databases and real-time quantitative PCR (RT-qPCR). CD276 was knocked down in ccRCC cell models (sunitinib-resistant 786-O/R cells and sunitinib-sensitive 786-O cells) using shRNA transfection, and the cells were exposed to a sunitinib (2 µM) environment. Cells proliferation was then analyzed using MTT assay and colony formation experiment. Alkaline comet assay, immunofluorescent staining, and western blot experiments were conducted to assess the DNA damage repair ability of the cells. Western blot was also used to observe the activation of FAK-MAPK pathway within the cells. Finally, a nude mouse xenograft model was established and the nude mice were orally administered sunitinib (40 mg/kg/d) to evaluate the in vivo effects of CD276 knockdown on the therapeutic efficacy of sunitinib against ccRCC. RESULTS: CD276 was significantly upregulated in both ccRCC clinical tissue samples and cell models. In vitro experiments showed that knocking down CD276 reduced the survival rate, IC50 value, and colony-forming ability of ccRCC cells. Knocking down CD276 increased the comet tail moment (TM) values and γH2AX foci number, and reduced BRCA1 and RAD51 protein levels. Knocking down CD276 also decreased the levels of p-FAK, p-MEK, and p-ERK proteins. CONCLUSION: Knocking down CD276 effectively improved the sensitivity of ccRCC cell and animal models to sunitinib treatment.

Pro-cancer role of CD276 as a novel biomarker for clear cell renal cell carcinoma.

OBJECTIVE: Renal cell carcinoma (RCC) is a common malignant tumor with a high incidence in males and the elderly, and clear cell RCC (ccRCC) is the most common RCC subtype. ccRCC is highly metastatic with a poor prognosis. Therefore, it is crucial to obtain a detailed understanding of the molecular mechanism of ccRCC and to identify suitable biomarkers to realize early diagnosis and improve prognosis. METHODS: We analyzed data from the Cancer Genome Atlas, investigated the overall differential expression of CD276 in ccRCC, and evaluated the influence of CD276 on patient survival and prognosis. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis and investigated cell infiltration and drug responsiveness to further assess the regulatory effect of CD276 on ccRCC. Furthermore, we verified CD276 expression in RCC cell lines and control cell lines. RESULTS: The CD276 expression level in ccRCC samples was higher than that in corresponding samples adjacent to the tumors. Moreover, high CD276 expression levels were positively correlated with poor prognosis in patients with RCC. GSEA revealed that CD276 was significantly involved in immune-related pathways, and the level of CD276 expression was confirmed as associated with immune cell infiltration to some extent. Notably, some drugs were predicted to act on CD276, and this was confirmed by molecular docking. Furthermore, high levels of CD276 expression in RCC cell lines were verified. CONCLUSION: CD276 expression was significantly increased in ccRCC tissues and cells and positively correlated with patient prognosis. CD276 is a potential prognostic biomarker of ccRCC. Overall, this study provides a potential therapeutic strategy for ccRCC.

A multi-modal vision-language pipeline strategy for contour quality assurance and adaptive optimization.

Objective.Accurate delineation of organs-at-risk (OARs) is a critical step in radiotherapy. The deep learning generated segmentations usually need to be reviewed and corrected by oncologists manually, which is time-consuming and operator-dependent. Therefore, an automated quality assurance (QA) and adaptive optimization correction strategy was proposed to identify and optimize 'incorrect' auto-segmentations.Approach.A total of 586 CT images and labels from nine institutions were used. The OARs included the brainstem, parotid, and mandible. The deep learning generated contours were compared with the manual ground truth delineations. In this study, we proposed a novel contour quality assurance and adaptive optimization (CQA-AO) strategy, which consists of the following three main components: (1) the contour QA module classified the deep learning generated contours as either accepted or unaccepted; (2) the unacceptable contour categories analysis module provided the potential error reasons (five unacceptable category) and locations (attention heatmaps); (3) the adaptive correction of unacceptable contours module integrate vision-language representations and utilize convex optimization algorithms to achieve adaptive correction of 'incorrect' contours.Main results. In the contour QA tasks, the sensitivity (accuracy, precision) of CQA-AO strategy reached 0.940 (0.945, 0.948), 0.962 (0.937, 0.913), and 0.967 (0.962, 0.957) for brainstem, parotid and mandible, respectively. The unacceptable contour category analysis, the(FI,AccI,Fmicro,Fmacro)of CQA-AO strategy reached (0.901, 0.763, 0.862, 0.822), (0.855, 0.737, 0.837, 0.784), and (0.907, 0.762, 0.858, 0.821) for brainstem, parotid and mandible, respectively. After adaptive optimization correction, the DSC values of brainstem, parotid and mandible have been improved by 9.4%, 25.9%, and 13.5%, and Hausdorff distance values decreased by 62%, 70.6%, and 81.6%, respectively.Significance. The proposed CQA-AO strategy, which combines QA of contour and adaptive optimization correction for OARs contouring, demonstrated superior performance compare to conventional methods. This method can be implemented in the clinical contouring procedures and improve the efficiency of delineating and reviewing workflow.

Biomechanical Comparison of Anterior Cervical Corpectomy Decompression and Fusion, Anterior Cervical Discectomy and Fusion, and Anterior Controllable Antedisplacement and Fusion in the Surgical Treatment of Multilevel Cervical Spondylotic Myelopathy: A Finite Element Analysis.

PURPOSE: Multilevel cervical spondylotic myelopathy poses significant challenges in selecting optimal surgical approaches, warranting a comprehensive understanding of their biomechanical impacts. Given the lack of consensus regarding the most effective technique, this study aims to fill this critical knowledge gap by rigorously assessing and comparing the biomechanical properties of three distinct surgical interventions, including anterior controllable antedisplacement and fusion (ACAF), anterior cervical corpectomy decompression and fusion (ACCF), and anterior cervical discectomy and fusion (ACDF). The study offers pivotal insights to enhance treatment precision and patient outcomes. METHODS: The construction of the cervical spine model involved a detailed process using CT data, specialized software (Mimics, Geomagic Studio, and Hypermesh) and material properties obtained from prior studies. Surgical instruments were modeled (titanium mesh, anterior cervical plate, interbody cage, and self-tapping screws) to simulate three surgical approaches: ACAF, ACCF, and ACDF, each with specific procedures replicating clinical protocols. A 75-N follower load with 2 Nm was applied to simulate biomechanical effects. RESULTS: The range of motion decreased more after surgery for ACAF and ACDF than for ACCF, especially in flexion and lateral bending. ACCF have higher stress peaks in the fixation system than those of ACAF and ACDF, especially in flexion. The maximum von Mises stresses of the bone-screw interfaces at C3 of ACCF were higher than those of ACAF and ACDF. The maximum von Mises stresses of the bone-screw interfaces at C6 of ACDF were much higher than those of ACAF and ACCF. The maximum von Mises stresses of the grafts of ACCF and ACAF were much higher than those of ACDF. The maximum von Mises stresses of the endplate of ACCF were much higher than those of ACAF and ACDF. CONCLUSION: The ACAF and ACDF models demonstrated superior cervical reconstruction stability over the ACCF model. ACAF exhibited lower risks of internal fixation failure and cage subsidence compared to ACCF, making it a promising approach. However, while ACAF revealed improved stability over ACCF, higher rates of subsidence and internal fixation failure persisted compared to ACDF, suggesting the need for further exploration of ACAF's long-term efficacy and potential improvements in clinical outcomes.

Clinical effect and follow-up of laparoscopic radical proximal gastrectomy for upper gastric carcinoma.

Objective: To evaluate the safety and clinical effect of tubular esophagogastric anastomosis in laparoscopic radical proximal gastrectomy. Methods: A retrospective analysis was conducted involving 191 patients who underwent laparoscopic radical proximal gastrectomy in the Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University from January 2017 to October 2020. Patients were divided into tubular esophagogastric anastomosis group (TG group) and traditional esophagogastric anastomosis group (EG group) according to the digestive tract reconstruction. Their intraoperative conditions, perioperative recovery and postoperative follow-up were compared. Patients were also divided into indocyanine green group and non-indocyanine green group according to whether or not indocyanine green tracer technology was used during the operation. Their intraoperative condition and perioperative recovery were compared and analyzed after propensity score matching. Results: The operation was successfully completed in all patients. Compared with the EG group, the TG group had less volume of gastric tube drainage, shorter gastric tube drainage time and proton pump inhibitors application time, and lower reuse rate of proton pump inhibitors. However, the TG group had a higher anastomotic stenosis at three months after surgery, as measured using anastomotic width and dysphagia score. Nevertheless, the incidence of reflux esophagitis and postoperative quality of life score in the TG group were lower compared with the EG group at 1st and 2nd year after surgery. In the indocyanine green analysis, the indocyanine green group had significantly shorter total operation time and lymph node dissection time and less intraoperative blood loss compared with the non-indocyanine green group. However, compared with the non-indocyanine green group, more postoperative lymph nodes were obtained in the indocyanine green group. Conclusion: Laparoscopic radical proximal gastrectomy is safe and effective treatment option for upper gastric cancer. Tubular esophagogastric anastomosis has more advantages in restoring postoperative gastrointestinal function and reducing reflux, but it has a higher incidence of postoperative anastomotic stenosis compared with traditional esophagogastrostomy. The application of indocyanine green tracer technique in laparoscopic radical proximal gastrectomy has positive significance.

Association between IL8RB C1208T mutation and risk of cancer: A pooled analysis based on 5299 cases and 6899 controls.

INTRODUCTION: The CXC chemokines are unique cytokines that play a vital role in the progression of many cancers. Association between chemokine (C-X-C motif) receptor 2 (IL8RB) C1208T mutation and cancer risk remains incomprehensive. METHODS: We therefore utilized odds ratios and in silico analysis to explore the relationship of IL8RB polymorphism on risk to cancer. Furthermore, we adopted gene set enrichment analysis to investigate the IL8RB expression in prostate adenocarcinoma. RESULTS: A total of 14 case-control studies combined with 5299 cases and 6899 controls were included in our analysis. We revealed that individuals carrying TT genotype had an 14% increased cancer risk compared with those with TC + colon cancer (CC) genotype (odds ratio [OR] = 1.14, 95% CI = 1.05-1.25, P = .003, I2 = 35.6). Stratification analysis by race showed that East Asians with TT + TC genotype may have a 25% decreased cancer risk compared with control. Stratification analysis by cancer type revealed that individuals with TT genotype were associated with elevated risk of urinary cancer than control. The expression of IL8RB was attenuated in prostate adenocarcinoma. CONCLUSIONS: IL8RB C1208T may be correlated with the risk of cancer, especially prostate adenocarcinoma.

Anatomical Evaluation of Spinal Nerve and Cervical Intervertebral Foramina in Anterior Controllable Antedisplacement and Fusion Surgery: A Cadaveric and Radiologic Study.

OBJECTIVE: To achieve the anatomical evaluation of spinal nerve and cervical intervertebral foramina in anterior controllable antedisplacement and fusion (ACAF) surgery, a novel surgical technique with the wider decompression, through a cadaveric and radiologic study. METHODS: Radiographic data of consecutive 47 patients (21 by ACAF and 26 by anterior cervical corpectomy and fusion [ACCF]) who have accepted surgery for treatment of cervical ossification of the posterior longitudinal ligament(OPLL) and stenosis from March 2017 to March 2018 were retrospectively reviewed and compared between an ACAF group and ACCF group. Three postoperative radiographic parameters were evaluated: the decompression width and the satisfaction rate of decompression at the entrance zone of intervertebral foramina on computed tomography (CT), and the transverse diameter of spinal cord in the decompression levels on magnetic resonance imaging (MRI). In the anatomic study, three fresh cadaveric spines (death within 3 months) undergoing ACAF surgery were also studied. Four anatomic parameters were evaluated: the width of groove, the distance between the bilateral origins of ventral rootlets, the length of ventral rootlet from their origin to the intervertebral foramina, the descending angle of ventral rootlet. RESULTS: The groove created in ACAF surgery included the bilateral origins of ventral rootlets. The rootlets tended to be vertical from the rostral to the caudal direction as their takeoff points from the central thecal sac became higher and farther away from their corresponding intervertebral foramina gradually. No differences were identified between left and right in terms of the length of ventral rootlet from the origin to the intervertebral foramina and the descending angle of ventral rootlet. The decompression width was significantly greater in ACAF group (19.2 ± 1.2 vs 14.7 ± 1.2, 21.3 ± 2.2 vs 15.4 ± 0.9, 21.5 ± 2.1 vs 15.7 ± 1.0, 21.9 ± 1.6 vs 15.9 ± 0.8, from C3 to C6 ). The satisfactory rate of decompression at the entrance zone of intervertebral foramina tended to be better in the left side in ACAF group (significant differences were identified in the left side at C3/4 , C4/5 , C6/7 level, and in the right side at C4/5 level when compared with ACCF). And decompression width was significantly greater than the transverse diameter of spinal cord in ACAF group. Comparatively, there existed no significant difference in the ACCF group besides the C5 level. CONCLUSION: ACAF can decompress the entrance zone of intervertebral foramina effectively and its decompression width includes the origins and massive running part of bilateral ventral rootlets. Due to its wider decompression range, ACAF can be used as a revision strategy for the patients with failed ACCF.

MicroRNA-155-5p inhibits the invasion and migration of prostate cancer cells by targeting SPOCK1.

The aim of the present study was to determine the effect of microRNA (miR)-155-5p on the expression of testican-1 (SPOCK1) and the invasion and migration of prostate cancer cells in vitro. Bioinformatics analysis and molecular biology assays revealed that SPOCK1 may be a direct target gene of miR-155-5p. In addition, a negative correlation was identified between SPCOK1 and miR-155-5p expression in prostate tumor tissues and cell lines. miR-155-5p mimic transfection inhibited SPOCK1 expression in PC3 cells and decreased cell migration and invasion abilities, while the expression of vimentin, N-cadherin, E-cadherin, ß-catenin, matrix metalloproteinase (MMP)3 and MMP9 was upregulated. In summary, SPOCK1 was found to be a target gene of miR155-5p in prostate cancer, and miR-155-5p acts as a tumor-suppressor gene and may inhibit SPOCK1-mediated prostate cancer progression.

Cyclin-Dependent Kinase 14 Promotes Cell Proliferation, Migration and Invasion in Ovarian Cancer by Inhibiting Wnt Signaling Pathway.

OBJECTIVE: The study aimed to investigate cyclin-dependent kinase 14 (CDK14) and its co-function with Wnt signaling pathway on cell proliferation, migration and invasion in ovarian cancer. METHODS: CDK14 expressions were detected by quantitative real-time polymerase chain reaction. The expressions c-Myc, cyclinD1, PFTK1, ki67 and OGT were examined by Western blot. MTT assay was applied to observe cell proliferation after transfection of pEGFP-N1/CDK14-siRNA and pEGFP-N1 into SKOV3 cells, and scratch test and Transwell assay to observe invasion and migration ability. Transfected tumor model in nude mice was established. RESULTS: CDK14 was upregulated in the ovarian cancer tissues and cell lines (both p < 0.05). Expressions of downstream molecules in Wnt signaling pathway as well as the proliferation, invasion and migration ability of the SKOV3 cells were reduced when CDK14 was inhibited (all p < 0.05). The expression of ß-catenin in the nucleus was also decreased when CDK14 was inhibited (p < 0.05). In the transfected tumor model of nude mice, the results showed, compared with the pEGFP-N1 group and blank control group, that the expressions of c-Myc, cyclinD1, PFTK1, ki67 and OGT in the pEGFP-N1/CDK14-siRNA group in the transplantation tumor tissues decreased significantly (all p < 0.05). CONCLUSION: CDK14 suppression-mediated Wnt signaling pathway can inhibit cell proliferation, invasion and migration in ovarian cancer.

Evaluation of reported prostate cancer risk-associated SNPs from genome-wide association studies of various racial populations in Chinese men.

BACKGROUND: Several genome-wide association studies (GWAS) of prostate cancer (PCa) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with PCa risk in various racial groups. The objective of this study is to evaluate which of these SNPs are associated with PCa risk in Chinese men and estimate their strength of association. METHODS: All SNPs that were reported to be associated with PCa risk in GWAS from populations of European, African American, Japanese, and Chinese descent were evaluated in 1,922 PCa cases and 2,175 controls selected from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). A logistic regression analysis was used to estimate allelic odds ratios (ORs) of these SNPs for PCa. RESULTS: Among the 53 SNPs, 50 were polymorphic in the Chinese population. Of which, 10 and 24 SNPs were significantly associated with PCa risk in Chinese men at P < 0.001 and <0.05, respectively. These 24 significant SNPs included 17, 5, and 2 SNPs that were originally discovered in European, Japanese, and Chinese descent, respectively. The estimated ORs ranged from 1.10 to 1.49 and the direction of association was consistent with previous studies. When ORs were estimated separately for PCa with Gleason score ≤7 and ≥8, a marginally significant difference in ORs was found only for two of the 24 SNPs (P = 0.02 and 0.04). CONCLUSION: About half of PCa risk-associated SNPs identified in GWAS of various populations are associated with PCa risk in Chinese men. Information on PCa risk-associated SNPs and their ORs may facilitate risk assessment of PCa risk in Chinese men.

A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men.

BACKGROUND: A rare mutation G84E in HOXB13 was recently identified to be associated with prostate cancer (PCa) in Caucasians. The goal of this study is to test association between HOXB13 genetic variants and PCa risk in Chinese men. METHODS: All study subjects were part of the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). In the first stage, we screened for mutations by sequencing the HOXB13 coding region in 96 unrelated PCa patients. In stage 2, G84E and novel mutations found in stage 1 were genotyped in 671 PCa patients and 1,536 controls. In stage 3, mutation status in 751 additional PCa patients was imputed via haplotype. RESULTS: The G84E mutation was not detected in this study. However, a novel mutation, G135E, was identified among 96 patients in stage 1. It was also observed twice in 575 additional PCa patients but not in 1,536 control subjects of stage 2. The frequency of G135E was significantly different between cases and controls, with a P-value of 0.027, based on Fisher's exact test. Haplotype estimation showed that G135E mutation carriers shared a unique haplotype that was not observed in other subjects. In stage 3, two more PCa patients were predicted to carry the G135E mutation. CONCLUSIONS: We identified a novel rare mutation in the HOXB13 gene, G135E, which appears to be a founder mutation. This mutation is associated with increased PCa risk in Chinese men. Consistent with a previous report, our findings provide further evidence that rare mutations in HOXB13 contribute to PCa risk.

Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4.

Prostate cancer risk-associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk-associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10(-14)) and 19q13.4 (rs103294, P = 5.34 × 10(-16)) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10(-4)). These findings may advance the understanding of genetic susceptibility to prostate cancer.

[In vitro biocompatibility of novel absorbable hydroxyapatite and AO artificial bone beta-tricalcium phosphate with rhesus bone marrow stromal cells].

OBJECTIVE: To study the in vitro biocompatibility of novel hydroxyapatite (HA) and AO artificial bone beta-tricalcium phosphate (beta-TCP) with rhesus bone marrow stromal cells (rBMSCs) . METHODS: The third passage of rBMSCs were cultured with HA and beta-TCP respectively, with the cells cultured without the materials as the control. The morphology and proliferation of cells were observed by inverted phase-contrast microscope and scanning electron microscope (SEM). MTT assay was used to semiquantitatively evaluate the cell proliferation. RESULTS: The rBMSC cocultured with HA exhibited good growth as observed under inverted phase-contrast microscope, without significant difference from the cells in the control group. Some small particles were seen pealing off from beta-TCP, and some of the cells died. Under SEM, rBMSCs showed good adhesion to HA with obvious proliferation, but the ratio of adhesive cells was not as high as that in beta-TCP group. MTT assay showed no significant difference in the cell number between HA and the control groups, but the cell number in beta-TCP group was notably less than that of control group. CONCLUSION: Novel HA has good biocompatibility with rBMSCs for bone tissue engineering, and AO artificial bone still needs improvement to serve as scaffold material for BMSCs.

[Surgical treatment and function rehabilitation of Monteggia fracture in children].

OBJECTIVE: To establish better treatment for Monteggia fracture by evaluating the operative effect and function rehabilitation in children. METHODS: From 1994 to 2001, 78 children with Monteggia fracture (30 cases of new fracture, 48 cases of old fracture) were treated with open reduction and internal fixation. The patients were randomly divided into two groups. In the first group (45 cases, 16 new and 29 old), radius-humeral joint was fixed with a Kirschner wire after reduction and without fixation of ulna fracture; in the second group(33 cases, 14 new and 19 old), both radiohumeral joint and ulna fracture were fixed with Kirschner wire. Two groups were treated with plaster-splint after operation. The effect of operation was evaluated according to the function criteria for bending elbow and rotation of forearm. RESULTS: All patients were followed up 6 months to 7 years (4.6 years on average). All wound healed well without bone nonunion, delayed union and infection after operation. In the first group, 37 cases were rated as excellent, 5 good and 3 poor. The effective rate was 93.3%. In the second group, 22 cases were rated as excellent, 7 good and 4 poor. The effective rate was 87.9%. There was no significant difference between two groups (P > 0.05). CONCLUSION: Surgical treatment is the choice for Monteggia fracture in children. It should be treated with single Kirschner wire fixing after open reduction of radiohumeral and plaster-splint. This method is simple, safe and has satisfactory results in fracture healing and function rehabilitation after operation.