Risk Factors for Radiographic Tibiofemoral Knee Osteoarthritis: The Wuchuan Osteoarthritis Study

Objective. To investigate the risk factors of radiographic tibiafemoral knee osteoarthritis (OA). Methods. A population-based cross-sectional survey was conducted in Wuchuan County. A questionnaire and bilateral weight-bearing posterior-anterior semi-flexed knee radiographs were completed and read for Kellgren and Lawrence (K/L) grade and joint space narrowing (JSN; 0–3 scale) in each compartment. An logistic regression analysis was performed for radiographic tibiafemoral, lateral compartment, and medial compartment knee OA, respectively. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated. Results. Age, sex, and knee injury were strongly associated with tibiafemoral, lateral and medial compartment knee OA. BMI also had a dose-response relationship with them. Physical activity level, and physical activity exposure at work, not significantly though, were associated with an elevated risk for this three kinds of knee OA. Conclusions. Physical activity exposure increased the risk of knee OA. It was likely to be the heavier physical activity in Wuchuan osteoarthritis study that counteracted the BMI gap compared with the Beijing and the Framingham OA study. We verified that Chinese had a more valgus alignment of the knee compared with Caucasian population, and this provide a possible explanation why Chinese have a higher prevalence of lateral compartment OA

Associations Between Genetic Variants in Mrna Splicing-Related Genes and Risk of Lung Cancer: a Pathway-Based Analysis from Published Gwass

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of thisprocess may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summarydata from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancerof the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The sixnovel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression inlymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shednew light on the role of mRNA splicing genes in the development of lung cancer

Marked disability and high use of nonsteroidal antiinflammatory drugs associated with knee osteoarthritis in rural China: a cross-sectional population-based survey

Introduction: The burden of disability, analgesia, and health services use associated with knee pain and osteoarthritis (OA) in developing countries is relatively unknown, despite a high proportion of these populations required to be engaged in heavy occupational physical activity throughout their life span. The aim of this survey was to estimate the burden of disability, analgesia, and health services use associated with knee pain in rural China. Methods: This was a population-based cross-sectional survey among residents, aged 50 years and older, of Wuchuan County, Inner Mongolia. Participants completed an interviewer-based questionnaire, evaluating knee pain and associated disability, analgesia, and health services use, and obtained bilateral standardized weight-bearing knee radiographs. Results: Of the 1,027 participants, 513 (50%) reported knee pain on most days of at least 1 month in the past year, with 109 (21%) also demonstrating radiographic OA (Kellgren-Lawrence grade >= 2) in the symptomatic knee. Adjusting for age, gender, body mass index (BMI), education, and back pain, the presence of knee pain was associated with significantly greater difficulty in walking, climbing 10 steps, stooping, completing cleaning chores, and preparing meals. Among the 513 subjects with knee pain, the additional presence of radiographic evidence of OA was significantly associated with more occasions of "unbearable" pain (59% versus 36%) and restricted activity (64% versus 39%), as well as increased use of nonsteroidal antiinflammatory drugs (NSAIDs) (88% versus 78%) and the reported number of doctor visits (59% versus 33%) in the past year. The use of paracetamol for knee pain was rare (6% versus 2%). Conclusions: Knee pain is highly prevalent in rural northern China. The associated significant disability and marked preferential use of NSAIDs as analgesia should be of concern in these communities reliant on heavy occupational physical activity for their livelihood. The findings will be useful to guide the distribution of future health care resources and preventive strategies. A similar article has been published in the Chinese language journal, National Medical Journal of China.RheumatologySCI(E)PubMed0ARTICLE6R2251

Personalized targeted therapy for esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial

SATB2 shows different profiles between appendiceal adenocarcinomas ex goblet cell carcinoids and appendiceal/colorectal conventional adenocarcinomas: An immunohistochemical study with comparison to CDX2

Background: Special AT-rich sequence-binding protein 2 (SATB2) is a novel marker for colorectal adenocarcinomas but little is known about its expression in appendiceal adenocarcinomas. We aim to investigate SATB2 in these tumors and colorectal adenocarcinomas with comparison to CDX2. Methods: Immunohistochemical stains for SATB2 and CDX2 were performed in 49 appendiceal adenocarcinomas (23 conventional, 26 adenocarcinoma ex goblet cell carcinoids (AdexGCCs)) and 57 colorectal adenocarcinomas. Their expression was correlated with tumor differentiation and growth patterns. Results: SATB2 staining was positive in 26/26 (100%) appendiceal AdexGCCs and 15/23 (65%) appendiceal conventional adenocarcinomas (P = 0.001). Their mean percentage of SATB2-positive cells was 93% and 34%, respectively (P \u3c 0.0001). CDX2 staining was seen in 26/26 (100%) AdexGCCs and 22/23 (96%) appendiceal conventional adenocarcinomas (P = 0.4694). SATB2 and CDX2 showed similar staining in AdexGCCs but CDX2 labeled more tumor cells than SATB2 in conventional adenocarcinomas (mean 84% vs. 34%, P \u3c 0.0001). SATB2 and CDX2 staining was seen in 82% (47/57) and 96% (55/57) colorectal adenocarcinomas, respectively (P = 0.01). The mean percentage of cells positive for SATB2 and CDX2 was 48% and 91%, respectively (P \u3c 0.00001). Decreased SATB2 immunoreactivity was associated with non-glandular differentiation particularly signet ring cells in colorectal (P = 0.001) and appendiceal conventional adenocarcinomas (P = 0.04) but not in appendiceal AdexGCCs. Conclusions: SATB2 is a highly sensitive marker for appendiceal AdexGCCs with similar sensitivity as CDX2. In colorectal and appendiceal conventional adenocarcinomas, SATB2 is not as sensitive as CDX2 and its immunoreactivity is dependent on tumor differentiation

Comparative genomic analysis of esophageal squamous cell carcinoma among different geographic regions

IntroductionEsophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence, survival, and risk factors. Although the genomic characteristics of ESCC have been extensively characterized, the genomic differences between different geographic regions remain unclear.MethodsIn this study, we sequenced 111 patients with ESCC from northern (NC) and southern (SC) China, combined their data with those of 1081 cases from previous reports, and performed a comparative analysis among different regions. In total, 644 ESCC cases were collected from six geographic regions (NC, SC, Xinjiang, China [XJC], Japan [JP], Vietnam [VN], and Europe & America [EA]) as the discovery cohort. Validation cohort 1 included 437 patients with ESCC from the NC region. Validation cohort 2 included 54 and 57 patients from the NC and SC regions, respectively.ResultsPatients with ESCC in different regions had different genomic characteristics, including DNA signatures, tumor mutation burdens, significantly mutated genes (SMGs), altered signaling pathways, and genes associated with clinical features. Based on both the DNA mutation signature and the mutation profile of the most common genes, the NC and SC groups were clustered close together, followed by the JP, XJC, EA, and VN groups. Compared to patients with ESCC from SC, SMGs, including KMT2D, FAT1, and NOTCH1 were more frequently identified in patients with ESCC from NC. Furthermore, some genes (TDG and DNAH8) correlated with overall survival in completely opposite ways in patients with ESCC from different geographical regions.ConclusionsOur study provides insights into genomic differences in ESCC among different regions. These differences may be related to differences in environmental carcinogens, incidence, and survival

Structural analysis reveals features of the spindle checkpoint kinase Bub1–kinetochore subunit Knl1 interaction

The function of the essential checkpoint kinases Bub1 and BubR1 requires their recruitment to mitotic kinetochores. Kinetochore recruitment of Bub1 and BubR1 is proposed to rely on the interaction of the tetratricopeptide repeats (TPRs) of Bub1 and BubR1 with two KI motifs in the outer kinetochore protein Knl1. We determined the crystal structure of the Bub1 TPRs in complex with the cognate Knl1 KI motif and compared it with the structure of the equivalent BubR1TPR–KI motif complex. The interaction developed along the convex surface of the TPR assembly. Point mutations on this surface impaired the interaction of Bub1 and BubR1 with Knl1 in vitro and in vivo but did not cause significant displacement of Bub1 and BubR1 from kinetochores. Conversely, a 62-residue segment of Bub1 that includes a binding domain for the checkpoint protein Bub3 and is C terminal to the TPRs was necessary and largely sufficient for kinetochore recruitment of Bub1. These results shed light on the determinants of kinetochore recruitment of Bub1

Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer