The learning curve for minimally invasive Achilles repair using the "lumbar puncture needle and oval forceps" technique.

INTRODUCTION: An acute Achilles tendon rupture represents a common tendon injury, and its operative methods have been developed over the years. This study aimed to quantify the learning curve for the minimally invasive acute Achilles tendon rupture repair. METHODS: From May 2020 to June 2022, sixty-seven patient cases who received minimally invasive tendon repair were reviewed. Baseline data and operative details were collected. The cumulative summation (CUSUM) control chart was used for the learning curve analyses. Achilles tendon rupture score (ATRS), American Orthopedic Foot and Ankle Society (AOFAS) ankle/hindfoot score, and visual analog scale (VAS) at 3/6/9/12 months were calculated to assess the clinical outcomes. RESULTS: Thirty-six cases underwent at least a year of follow up and were enrolled in this study. The gender ratio and average age were 80.5% and 32.5 years. The linear equation fitted well (R2 = 0.95), and CUSUM for operative time peaked in the 12th case, which was divided into the learning phase (n = 12) and master phase (n = 24). No significant difference was detected between the two groups in clinical variables, except for the operative time (71.1 ± 13.2 min vs 45.8 ± 7.2 min, p = 0.004). Moreover, we detected one case with a suture reaction and treated it properly. CONCLUSION: Minimally invasive Achilles repair provides an opportunity for early rehabilitation. Notably, the learning curve showed that the "lumbar puncture needle and oval forceps" technique was accessible to surgeons.

Comparison between screw fixation and plate fixation via sinus tarsi approach for displaced intra-articular calcaneal fractures: a systematic review and meta-analysis.

BACKGROUND: Optimal surgical fixation for displaced intra-articular calcaneal fractures (DIACF) remains a subject of debate, particularly regarding the superiority between screw fixation and plate fixation via the sinus tarsi approach (STA). This review aims to determine the preferred treatment for DIACF and compare the outcomes of minimally invasive surgery options. METHODS: Our study involved thorough searches across multiple electronic databases, including PubMed, Cochrane, Embase, and Web of Science, to identify all relevant publications on distal intra-articular fractures of the calcaneus (DIACFs) that were fixed using cannulated screws or plates via STA. Through a comprehensive meta-analysis, we evaluated several outcomes, including post-operative function, radiological measurements, and complications. RESULT: A total of 728 patients from 7 studies met the inclusion criteria. Among them, 435 patients underwent screw fixation via STA, and 373 patients underwent plate fixation via STA. The study found no statistically significant differences between the screw fixation and the plate fixation via sinus tarsi approach (STA) in terms of AOFAS scores, Bohler's angle, Gissane's angle, sural nerve injury, secondary subtalar arthrodesis and reoperation. Compared with screw fixation, plate fixation via STA can reduce reduction loss of Bohler's angle (WMD = - 1.64, 95% CI = [- 2.96, - 0.31], P = 0.06, I2 = 59%), lower the incidence of fixation failure (OR = 0.32, 95% CI = [0.13, 0.81], P = 0.78, I2 = 0%), and decrease intra-articular step-off (WMD = - 0.52, 95% CI = [- 0.87, - 0.17], P = 0.66, I2 = 0%). CONCLUSIONS: Plate fixation demonstrates superior capability in restoring calcaneal width, maintaining Bohler's angle, and minimizing intra-articular step-off, thereby maintaining better reduction of the subtalar articular surface. In addition, plate fixation exhibits the modest complication rate and a low incidence of fixation failure. Therefore, we recommend the use of plate fixation through the STA, especially for complex and comminuted intra-articular calcaneal fractures.

Comparison between anterior-to-posterior screw fixation versus posterolateral approach plate fixation for posterior malleous fracture: A systematic review and meta-analysis.

PURPOSE: There are two main surgical fixation methods for the posterior malleolar fractures (PMFs), the anterior-to-posterior (AP) screws or via the posterolateral (PL) approach utilizing a buttress plate. This review aims to compare the clinical outcome between the AP screw fixation and the PL plate fixation for treating PMFs. METHODS: We searched all relevant publications about PMFs treated with AP screws or PL plates through electronic databases including the PubMed, the Cochrane Library, the Embase, the Wiley online library and the Web of Science. The meta-analysis was conducted to evaluated clinical outcomes including reduction quality, post-operative function and complications. RESULTS: Six studies (one single randomized controlled trial and five retrospective cohort studies) were enrolled. 172 patients underwent AP screw fixation and 214 patients underwent PL plate fixation with a total of 386 patients (169 males and 217 females). The PL plating group yielded better AOFAS scores(MD = 6.97, 95 % CI=[4.68, 9.27], P＜0.00001, I2 =0 %) and was more likely to achieve excellent anatomical reduction(OR=5.49, 95 % CI=[1.06, 28.42], P = 0.04, I2 =80 %). No differences were found in the bad reduction quality, incidences of complications (arthritis, neuralgia, superficial wound healing problems and implant failure), the walking VAS scores and the dorsiflexion restriction degrees. CONCLUSION: We suggest that the PL plate fixation method has the clinical benefit of achieving anatomical reduction and better AOFAS scores over the AP screw fixation for treating PMFs. No differences were found in the incidences of complications ( arthritis, neuralgia, superficial wound healing problems and implant failure), the walking VAS scores and the dorsiflexion restriction degrees. The posterior approach and the direct reduction are recommended for the treatment of the PMFs. LEVEL OF CONFIDENCE: Ⅱb.

Tumor specific methylome in Chinese high-grade serous ovarian cancer characterized by gene expression profile and tumor genotype.

OBJECTIVE: Extensive genetic and limited epigenetics have been characterized by the Cancer Genome Atlas (TCGA) among Western High-grade serous ovarian cancer (HGSOC). The present study aimed to characterize Chinese HGSOC at genome scale. METHODS: We used reduced representation bisulfite sequencing to investigate whole-genome and tumor-specific DNA methylation in 21 HGSOC tumors paired with their normal tissues, followed by a replication study involving additional 41 HGSOC patients. Altered methylation patterns in HGSOC were further characterized by gene expression profiles and whole-exome sequencing data. RESULTS: Comparing HGSOC tumors with normal tissues we observed global hypomethylation but with more specific hypermethylation in gene promoter. Totally, we revealed 159,881 differentially methylated regions (DMRs) and 4060 differentially expressed genes (DEGs). By integrating DNA methylation and mRNA expression data, we identified 153 negative (mainly in the upstream region) and 115 positive (mainly in the CDS regions) DMRs-DEGs correlated pairs, respectively. The negatively correlated DMRs-DEGs underlined Wnt and cell adhesion molecule binding as critical canonical pathways disrupted by DNA methylation. Eleven DMRs (in CAPS, FZD7, CDKN2A, PON3, KLF4, etc.), accompanied with a global DNA methylation marker, were validated in the replication samples. Whole-exome sequencing presented a relatively less dominated TP53 mutation in Chinese HGSOC compared to TCGA dataset. Unsupervised analysis of the three-level omics data identified differential methylation and expression subgroups based on tumor genetics, one of which presented increased DNA methylation and significantly associated with TP53 mutation. CONCLUSIONS: Our individual and integrated analyses contribute details about the tissue-specific genetic and DNA methylation landscape of Chinese HGSOC.

SNP rs2071095 in LincRNA H19 is associated with breast cancer risk.

PURPOSE: An increasing number of long intergenic non-coding RNAs (lincRNAs) appear to play critical roles in cancer development and progression. To assess the association between SNPs that reside in regions of lincRNAs and breast cancer risk, we performed a large case-control study in China. METHODS: We carried out a two-stage case-control study including 2881 breast cancer cases and 3220 controls. In stage I, we genotyped 17 independent (r2 < 0.5) SNPs located in 6 tumor-related lincRNAs by using the TaqMan platform. In stage II, SNPs potentially associated with breast cancer risk were replicated in an independent population. Quantitative real-time PCR was used to measure H19 levels in tissues from 228 breast cancer patients with different genotypes. RESULTS: We identified 2 SNPs significantly associated with breast cancer risk in stage I (P < 0.05), but not significantly replicated in stage II. We combined the data from stage I and stage II, and found that, compared with the rs2071095 CC genotype, AA and CA + AA genotypes were associated with significantly decreased risk of breast cancer (adjusted OR 0.83, 95% CI 0.69-0.99; adjusted OR 0.88, 95% CI 0.80-0.98, respectively). Stratified analyses showed that rs2071095 was associated with breast cancer risk in estrogen receptor (ER)-positive patients (P = 0.002), but not in ER-negative ones (P = 0.332). Expression levels of H19 in breast cancer cases with AA genotype were significantly lower than those with CC genotype. CONCLUSIONS: We identified that rs2071095 may contribute to the susceptibility of breast cancer in Chinese women via affecting H19 expression. The mechanisms underlying the association remain to be investigated.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Phagocytosis of Escherichia coli biofilm cells with different aspect ratios: a role of substratum material stiffness.

Bacterial biofilms play an important role in chronic infections due to high-level tolerance to antibiotics. Thus, it is important to eradicate bacterial cells that are attached to implanted medical devices of different materials. Phagocytosis is a key process of the innate immunity to eliminate invading pathogens. Previous research demonstrated that the efficiency of phagocytosis is affected by the aspect ratio of polymer beads. Recently, we reported that the stiffness of polydimethylsiloxane (PDMS) influences Escherichia coli biofilm formation and the biofilm cells on stiff (5:1) PDMS are 46.2% shorter than those on soft (40:1) PDMS. Based on these findings, we hypothesized that E. coli cells attached on stiff PDMS can be more effectively removed via phagocytosis. This hypothesis was tested in the present study using viability assays, flow cytometry, and cell tracking. The results revealed that shorter E. coli cells detached from stiff PDMS were easier to be phagocytized than the longer cells from soft PDMS surfaces. Furthermore, macrophage cells were found to be more motile on stiff PDMS surfaces and more effective at phagocytosis of E. coli cells attached on these surfaces. These results may help the design of better biomaterials to reduce fouling and associated infections.

Regulatory MiR-148a-ACVR1/BMP circuit defines a cancer stem cell-like aggressive subtype of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cancer in Asia. HCC has heterogeneous etiologic and molecular profiles and a varied response to therapeutics. The high recurrence rate and curtailed survival in this cancer are attributed to its resistance to therapy. The ultimate goal is to develop a more effective personalized therapeutic strategy for HCC, but the first step is to develop a system for classifying the disease on the basis of molecular biomarkers. To that end, we performed mRNA and microRNA (miRNA) expression profiling in 100 HCC tissues. Clustering analysis of informative genes identified two robust subtypes, which were validated by an independent dataset. The subtype characterized by a cancer stem cell-like signature was clinically aggressive and associated with poor survival. Integrated analysis of miRNA and mRNA expression in this subtype showed that miR-148a was expressed at a significantly lower level in these tumors than in the other subtype. MiR-148a has been shown to directly suppress the expression of activin A receptor type 1 (ACVR1), a key receptor in the signaling pathway of the bone morphogenetic proteins (BMPs), which regulate many stem cell markers as well as the clinically important cytokine interleukin-8 (IL-8). Increased expression of ACVR1 and its downstream genes EPCAM, CD24, CD90, and IL-8 was associated with shorter survival in a larger cohort of 227 HCC cases. Introduction of miR-148a resulted in suppressed tumor phenotypes both in vitro and in vivo. CONCLUSION: We identified a clinically aggressive stem cell-like subtype of HCC that is characterized by an miR-148a-ACVR1-BMP-Wnt circuit. We propose that miR-148a may serve as a prognostic biomarker and therapeutic target for this subtype of HCC.

Low dose of lipopolysaccharide pretreatment can alleviate the in?ammatory response in wound infection mouse model.

PURPOSE: To assess the effects of lipopolysaccharide (LPS) pretreatment on wound infection mouse model and evaluate the biological safety of the optimal pretreatment dose in vivo. METHODS: Mice were pretreated with LPS of different doses at 48 and 24 h before femoral medial lon- gitudinal incision was made and infected with different bacteria. RESULTS: It is showed that 0.5 mg/kg/time of LPS pretreatment can significantly alleviate the inflammation in mouse model infected with methicillin-resistances Staphylococcus aureus, methicillin-sensitive S. aureus, Pseudomonas aeruginosa,or Escherichia coli compared with doses of 0.25 mg/kg/time, 1 mg/ kg/time, and 1.5 mg/kg/time. CONCLUSIONS: LPS pretreatment can alleviate the inflammation in mouse model and the optimal dose is 0.5 mg/kg/time, and meanwhile it does not damage organs' function.

Augmentation of intramedullary nail in unstable intertrochanteric fractures with plate or cable.

Backgrounds: This study aims to evaluate the clinical outcome of intramedullary nail supplemented by buttress plate or cable in the treatment of intertrochanteric fracture with broken lateral wall. Methods: From May 2015 to January 2022, patients with unstable intertrochanteric femoral fractures underwent intramedullary fixations strengthened with buttress plates or cables, which depended on the lateral femur wall fragment type. The clinical and radiographic results were compared between the two groups. The hip function was evaluated according to the Harris Hip Scoring (HHS) system. Results: Forty-one patients who sustained intertrochanteric fracture + broken lateral wall were enrolled. Of these, thirty-four received a minimum of twelve months of follow-ups. No statistically significant differences in baseline and operative data were proved between these groups (p > 0.05). Three patients were observed fat liquefaction after surgery (plate group: 2 cases, cable group: 1 case). All patients could sustain partial/full weight-bearing and no case underwent subsequent operation. The HHS of the last follow-up presented 83.6 ± 4.9 points in the plate group and 83.8 ± 3.7 points in the cable group. Conclusions: Intertrochanteric femoral fracture with broken lateral wall is an unstable injury type, the operative treatments of which have been challenging and controversial over the years. Augmentation of intramedullary nailing system using plate/cable contributes to reconstructing the lateral femur wall.

Three-Dimensional Heat Map: The OTA/AO Type 43C Pilon Fracture Lines Distribution.

Background: This study aimed to create three-dimensional heat map and study the characteristic of fracture lines and represented fragments of OTA/AO type 43C pilon fractures. Methods: CT scan was performed in105 fractures diagnosed with OTA/AO type 43C pilon fractures between January 2017 and December 2022. Three-dimensional pilon fracture maps were created and converted into fracture heat maps. CT scan graphic parameters including the fracture line height, α angle, ß angle, the ratio of the area and size of bone fragment represented by the fracture line to the total articular surface were measured. Results: The study included 105 patients with 91 males and 14 females. The fractures included C1 (n=16), C2 (n=23), and C3 (n=66). There was no statistically different among the most parameters except in the fracture-line height of the anterior fracture line (p=0.03) and the sagittal fracture line (p=0.02) between C2 and C3 pilon fractures. The average size of the anterolateral fragment, occupied approximately 13.5% of the articular surface area, was (11.5±2.8) mm × (20.5±6.3) mm with the average height of 29.8 mm. The average size of the posterolateral fragment, occupied approximately 13.0% of the articular surface area, was (15.7±4.6) mm × (19.3±4.0) mm with the average height of 19.1 mm. Conclusion: This study demonstrates that the articular surface fracture lines in the C type pilon fracture are formed by fixed main fracture lines. The understand of morphological and distribution characteristics of the fracture lines and size of fragments in OTA/AO type 43C pilon fractures would help the surgeons take suitable approach and fixation.

Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer.

Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. A genome-wide association study (GWAS) identified a novel variant on chromosome 9q22.33 as a susceptibility locus for epithelial ovarian cancer (EOC) in the Han Chinese population. However, the underlying mechanism of this genomic region remained unknown. In this study, we conducted a fine-mapping analysis of 130 kb regions, including 1,039 variants in 200 healthy women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants that were significantly associated with ovarian cancer risk (rs7027650, P = 1.91 × 10-7; rs1889268, P = 3.71 × 10-2). Expression quantitative trait locus (eQTL) analysis found that rs7027650 was significantly correlated with COL15A1 gene expression (P = 0.009). The Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1, reducing its activity. An electrophoretic mobility shift assay (EMSA) showed the allele-specific binding capacity of rs7027650. These findings revealed that rs7027650 could be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study offered insight into the molecular mechanism behind a potential causal variant that affects the risk of ovarian cancer.

Comparison of arthroscopic and open Brostrom-Gould surgery for chronic ankle instability: a systematic review and meta-analysis.

BACKGROUND: Approximately 20% of acute ankle sprains progress to chronic lateral ankle instability (CLAI) requiring surgical intervention. There has been growing interest among surgeons regarding whether arthroscopic techniques can replace open Brostrom-Gould surgery in treating CLAI. The purpose of this study was to pool the results of multiple studies comparing the treatment effects of these two fixation approaches. METHODS: Our study involved thorough searches across multiple electronic databases, including PubMed, Cochrane, Embase, and Web of Science, to identify all relevant publications on CLAI that were repaired using the arthroscopic or open Broström-Gould technique. Through a comprehensive meta-analysis, we evaluated several outcomes, including post-operative function, radiological measurements, complications, and time efficiency. RESULT: A total of 686 patients from 11 studies were included in the analysis. Among them, 351 patients underwent open repair, and 335 underwent arthroscopic Brostrom-Gould surgery. The present study revealed that arthroscopic and open Brostrom-Gould techniques demonstrated no significant differences in talar tilt, talar anterior translation, complication rate, and time to return to previous level of activity. Furthermore, no significant differences were observed in AOFAS, K-P, VAS, and Tegner scores at the 2-year follow-up. However, significant differences were noted between the two surgical approaches in terms of early weight-bearing (WMD = - 1.33 weeks, 95% CI = [- 1.91, - 0.76], P = 0.17, I2 = 40%), as well as AOFAS scores (WMD = 1.00, 95% CI = [0.05, 1.95], P = 0.73, I2 = 0%), K-P scores (WMD = 1.57, 95% CI = [0.49, 2.64], P = 0.15, I2 = 47%), and VAS scores (WMD = - 0.15, 95% CI = [- 0.60, 0.29], P < 0.08, I2 = 61%) within the first postoperative year. CONCLUSIONS: Our findings support that arthroscopic repair yields comparable outcomes to open surgery. Consequently, we advocate for adopting arthroscopic repair as a preferred alternative to the conventional open Broström-Gould procedure for treating chronic lateral ankle instability.

Comparisons of clinical characteristics, prognosis, epidemiological factors, and genetic susceptibility between HER2-low and HER2-zero breast cancer among Chinese females.

BACKGROUND: Traditional human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) is recommended to be divided into HER2-low and HER2-zero subtypes due to different prognosis. However, few studies investigated their differences in clinical characteristics and prognosis among Chinese HER2-negative BC and their stratified differences by hormone receptor (HR), while fewer studies investigated their differences in epidemiological factors and genetic susceptibility. METHODS: A total of 11,911 HER2-negative BC were included to compare the clinical characteristics and prognosis between HER2-zero and HER2-low BC, and 4227 of the 11,911 HER2-negative BC were further compared to 5653 controls to investigate subtype-specific epidemiological factors and single nucleotide polymorphisms(SNPs). RESULTS: Overall, 64.2% of HER2-negative BC were HER2-low BC, and the stratified proportions of HER2-low BC were 61.9% and 75.2% for HR-positive and HR-negative BC, respectively. Compared to HER2-zero BC, HER2-low BC among HR-positive BC showed younger age at diagnosis, later stage, poorer differentiation, and higher Ki-67, while elder age at diagnosis and lower mortality were observed for HER2-low BC among HR-negative BC (all p values <0.05). Compared to healthy controls, both HER2-low and HER2-zero BC are associated with similar epidemiological factors and SNPs. However, stronger interaction between epidemiological factors and polygenic risk scores were observed for HER2-zero BC than HER2-low BC among either HR-positive [odds ratios: 10.71 (7.55-15.17) and 8.84 (6.19-12.62) for the highest risk group compared to the lowest risk group] or HR-negative BC [7.00 (3.14-15.63) and 5.70 (3.26-9.98)]. CONCLUSIONS: HER2-low BC should deserve more attention than HER2-zero BC, especially in HR-negative BC, due to larger proportion, less clinical heterogeneity, better prognosis, and less susceptibility to risk factors.

Elbow dislocation approach for complex elbow fractures: a cadaveric study.

BACKGROUND: Approach need to be considered when surgeons dealt with complex elbow injuries and the choice of the approach is a challenge for surgeons due to the complex anatomy. On the basis of releasing the lateral collateral ligament, we modified the dislocation technique to pursue the superior exposure including not only the distal humeral surface but also the anterior facet of the coronoid process. METHODS: A total of 4 cadaver specimens and 8 elbows were included in the study. Each cadaver provided one elbow for either the elbow dislocation approach or the posterior olecranon approach. The exposed distal articular surface of humerus, humeral capitulum, humeral trochlea, anterior trochlea of distal humerus, posterior trochlea of distal humerus and the ulnar coronoid process surface were marked by image J software and calculated for a comparison for each surgical approach. RESULTS: The total distal humeral surface was exposed as a median of 98.2 (97.6, 99.6)% and 62.0 (58.3, 64.5)% for the elbow dislocation approach and the olecranon osteotomy approach (P < 0.001), the capitulum 100% and 32.4 (28.0, 39.2)% (P < 0.001), the trochlea 93.2(90.1, 96.9)% and 72.5 (65.2, 78.8)% (P < 0.001), the anterior trochlear articular surface 96.0(93.0, 97.4)% and 50.3 (43.6, 59.1)% (P < 0.001), the posterior trochlear articular surface 95.4 (93, 100)% and 100% (P = 0.76) and the articular surface of the coronoid process of ulna 71.3 (66.0, 74.2)% and 0% (P < 0.001). CONCLUSION: For complex elbow fractures, the technique of elbow dislocation provides complete exposure of the distal humerus surface and a significant portion of the coronoid process surface, facilitating direct visualization for reduction and fixation. Level of evidence Anatomy Study; Cadaver Dissection.

ABO blood groups and expression of blood group antigens of epithelial ovarian cancer in Chinese women.

BACKGROUND: ABO blood groups has been associated with risk of several cancers; however, the results for an association with ovarian cancer are inconsistent and little is known about the expression of histo-blood group (ABH) antigens and ABO gene in ovarian tumor tissues. METHODS: To assess the impact of genotype-derived ABO blood types on the risk of EOC, we conducted a case-control study in 1,870 EOC and 4,829 controls. Expression of A and B antigen in 70 pairs of ovarian tumor tissues and adjacent normal tissues were detected by immunohistochemistry. Gene expression and DNA methylation profiling was conducted in ovarian tumor tissues. RESULTS: We identified that blood group A was associated with increased risk for EOC compared to blood group O (OR = 1.18, 95% CI = 1.03-1.36, p = 0.019). Increased frequency of aberrant expression of histo-blood group antigens was observed in patients with blood group A (76.5%) compared to patients with blood group O (21.1%) and B (5.0%) by immunohistochemistry (p < 0.001). ABO gene expression was down-regulated in ovarian tumor tissues compared with paired adjacent normal tissues (p = 0.027). In addition, ABO gene expression was positively correlated with NFYB (r = 0.38, p < 0.001) and inversely correlated with DNA methylation level of four CpG sites on ABO gene (cg11879188, r = - 0.3, p = 0.002; cg22535403, r = - 0.30, p = 0.002; cg13506600, r = - 0.22, p = 0.025; cg07241568, r = - 0.21, p = 0.049) in ovarian tumor tissues. CONCLUSION: We identified blood group A was associated with increased EOC risk in Chinese women and provided the clues of the possible molecular mechanisms of blood group A related to ovarian cancer risk.

[SNP rs16917496 within SET8 3'UTR is associated with the age of onset of breast cancer].

OBJECTIVE: We have identified a SNP within the seed-binding region for miR-502 in the 3'-UTR of the SET8 gene that codes for a methyltransferase for histone H4. SET8 methylates TP53 and thus regulates cell proliferation and genome stability. This study is to investigate the role for this SNP and its interaction with the TP53 codon 72 SNP in the age of onset of breast cancer. METHODS: We conducted a case-only study of 1, 110 breast cancer cases. PCR-RFLP was used for SNP genotyping. Ages of onset of breast cancer among different genotypes were analyzed using SAS software. RESULTS: Our analysis revealed that the SET8 CC and TP53 GG genotypes were independently associated with earlier age of onset of breast cancer in an allele-dose dependent manner. Moreover, individuals with both SET8 CC and p53 GG genotypes developed cancer at age of 47.74 years, compared with 54.55 years for individuals with both SET8 TT and TP53 CC genotypes. CONCLUSIONS: miR-502-binding SNP in SET8 may modulate SET8 expression and contribute to early development of breast cancer either independently or together with the TP53 codon 72 SNP.

Intra- and inter-observer reliability assessment of widely used classifications and the "Ten-segment classification" of tibial plateau fractures.

BACKGROUND: Ten-segment classification provides a different approach to the evaluation of tibial plateau fractures. The purpose of this study was to assess the intra- and inter-observer reliability of three widely used classification systems (Schatzker, Arbeitsgemeinschaft für Osteosynthesefragen (AO/OTA), and the updated three-column concept (uTCC)) with ten-segment classification in two-dimensional computed tomography (2D-CT) and three-dimensional computed tomography (3D-CT). METHOD: Ninety 2D-CT and 3D-CT scans of patients with tibial plateau fractures were included in this retrospective cohort study. The included data were independently classified by six observers of different years of seniority and were independently observed and classified again after eight weeks. Inter-observer and intra-observer reliability of the four fracture classifications made by the six observers was analyzed using the kappa statistic. Kappa values were interpreted according to the categorical rating by Landis and Koch. RESULTS: When the inter-observer reliability was based on 2D-CT/3D-CT analysis, the mean Kappa values for the Schatzker, AO/OTA, uTCC, and ten-segment classification were 0.64/0.66, 0.56/0.59, 0.53/0.65, and 0.60/0.73, respectively. When intra-observer reliability was based on 2D-CT/3D-CT, the mean Kappa values for the Schatzker, AO/OTA, uTCC, and ten-segment classification were 0.68/0.83, 0.69/0.83, 0.74/0.85, and 0.80/0.91, respectively. CONCLUSIONS: The use of 3D-CT is important for the reliable diagnosis and recognition of tibial plateau fracture features compared to 2D-CT. When using 3D-CT, ten-segment classification showed high intra- and inter-observer agreement.

Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci.

Identifying causal regulatory variants and their target genes from the majority of non-coding disease-associated genetic loci is the main challenge in post-Genome-Wide Association Studies (GWAS) functional studies. Although chromosome conformation capture (3C) and its derivative technologies have been successfully applied to nominate putative causal genes for non-coding variants, many GWAS target genes have not been identified yet. This study generated a high-resolution contact map from epithelial ovarian cancer (EOC) cells with two H3K27ac-HiChIP libraries and analyzed the underlying gene networks for 15 risk loci identified from the largest EOC GWAS. By combinatory analysis of 4,021 fine-mapped credible variants of EOC GWAS and high-resolution contact map, we obtained 162 target genes that mainly enriched in cancer related pathways. Compared with GTEx eQTL genes in ovarian tissue and annotated proximal genes, 132 HiChIP targets were first identified for EOC causal variants. More than half of the credible variants (CVs) involved interactions that were over 185 kb in distance, indicating that long-range transcriptional regulation is an important mechanism for the function of GWAS variants in EOC. We also found that many HiChIP gene targets showed significantly differential expressions between normal ovarian and EOC tumor samples. We validated one of these targets by manipulating the rs9303542 located region with CRISPR-Cas9 deletion and dCas9-VP64 activation experiments and found altered expression of HOXB7 and HOXB8 at 17q21.32. This study presents a systematic analysis to identify putative target genes for causal variants of EOC, providing an in-depth investigation of the mechanisms of non-coding regulatory variants in the etiology and pathogenesis of ovarian cancer.

Genome-wide association and functional interrogation identified a variant at 3p26.1 modulating ovarian cancer survival among Chinese women.

Ovarian cancer survival varies considerably among patients, to which germline variation may also contribute in addition to mutational signatures. To identify genetic markers modulating ovarian cancer outcome, we performed a genome-wide association study in 2130 Chinese ovarian cancer patients and found a hitherto unrecognized locus at 3p26.1 to be associated with the overall survival (Pcombined = 8.90 × 10-10). Subsequent statistical fine-mapping, functional annotation, and eQTL mapping prioritized a likely casual SNP rs9311399 in the non-coding regulatory region. Mechanistically, rs9311399 altered its enhancer activity through an allele-specific transcription factor binding and a long-range interaction with the promoter of a lncRNA BHLHE40-AS1. Deletion of the rs9311399-associated enhancer resulted in expression changes in several oncogenic signaling pathway genes and a decrease in tumor growth. Thus, we have identified a novel genetic locus that is associated with ovarian cancer survival possibly through a long-range gene regulation of oncogenic pathways.