A causal analysis of the relationship between exposure to sunlight and colorectal cancer risk: A Mendelian randomization study.

Several observational studies have found that exposure to sunlight reduces the risk of colorectal cancer (CRC). However, sun exposure remains ambiguous in its relationship to CRC. We carried out a Mendelian randomization (MR) study to explore the potential associations between them. We examined the exposure to sunlight summary statistics of the UK Biobank Consortium using a 2-sample MR analysis. Using data from the FinnGen consortium, we derived summary statistics for CRC. We conducted our analysis with various methods, incorporating inverse variance weighted (IVW) along with 4 other approaches. A Cochran Q statistic was used to measure the heterogeneity of instrumental variables (IVs). We screened 133 single nucleotide polymorphisms (SNPs) (time spent outdoors in summer), 41 SNPs (time spent outdoors in winter), and 35 SNPs (frequency of solarium/sunlamp use) representing sunlight exposure for MR analysis. All selected SNPs had an F-statistic >20, indicating that IVs did not weakly bias the results. The summer outdoor activity trait exhibited significant heterogeneity (Cochran Q statistic = 183.795, P = .002 < 0.05), but we found no horizontal polymorphisms or significant heterogeneity for the other exposure traits. According to IVW estimates, no causal association exists between time spent outdoors in summer and CRC (Odds Ratio, OR = 0.735, 95% confidence interval, CI = 0.494-1.017, P = .128 > 0.017). No causal relationship existed between time spent outdoors in winter and CRC, as indicated by Bonferroni-corrected adjusted p-values. The OR was 0.877 with a 95% CI of 0.334-2.299, and the P value was .789, more significant than the significance threshold of 0.017. The solarium/sunlamp use frequency was not associated with CRC (OR = 1.567, 95%CI = 0.243-10.119, P = .637 > .017). Also, an IVW with random effects was applied to determine the causal relationship between summer outdoor time and CRC. No causal association between summer outdoor time and CRC was found (OR = 0.735, 95% CI = 0.494-1.017, P = .128 > .017). Additionally, 4 additional analyses yielded similar results. The findings of our study suggest that exposure to sunlight may reduce CRC risk, but the causal relationship remains unsolved. There is no evidence to suggest that exposure to sunlight prevents CRC. Randomized, controlled trials are needed to determine whether sunlight exposure protects against CRC.

Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells.

Here, we present a gene regulation strategy enabling programmable control over eukaryotic translational initiation. By excising the natural poly-adenylation (poly-A) signal of target genes and replacing it with a synthetic control region harboring RNA-binding protein (RBP)-specific aptamers, cap-dependent translation is rendered exclusively dependent on synthetic translation initiation factors (STIFs) containing different RBPs engineered to conditionally associate with different eIF4F-binding proteins (eIFBPs). This modular design framework facilitates the engineering of various gene switches and intracellular sensors responding to many user-defined trigger signals of interest, demonstrating tightly controlled, rapid and reversible regulation of transgene expression in mammalian cells as well as compatibility with various clinically applicable delivery routes of in vivo gene therapy. Therapeutic efficacy was demonstrated in two animal models. To exemplify disease treatments that require on-demand drug secretion, we show that a custom-designed gene switch triggered by the FDA-approved drug grazoprevir can effectively control insulin expression and restore glucose homeostasis in diabetic mice. For diseases that require instantaneous sense-and-response treatment programs, we create highly specific sensors for various subcellularly (mis)localized protein markers (such as cancer-related fusion proteins) and show that translation-based protein sensors can be used either alone or in combination with other cell-state classification strategies to create therapeutic biocomputers driving self-sufficient elimination of tumor cells in mice. This design strategy demonstrates unprecedented flexibility for translational regulation and could form the basis for a novel class of programmable gene therapies in vivo.

Race and Gender Differences in Anterior Cruciate Ligament Femoral Footprint Location and Orientation: A 3D-MRI Study.

OBJECTIVE: The femoral tunnel position is crucial to anatomic single-bundle anterior cruciate ligament (ACL) reconstruction, but the ideal femoral footprint position are mostly based on small-sized cadaveric studies and elderly patients with a single ethnic background. This study aimed to identify potential race- or gender-specific differences in the ACL femoral footprint location and ACL orientation, determine the correlation between the ACL orientation and the femoral footprint location. METHODS: Magnetic resonance images (MRIs) of 90 Caucasian participants and 90 matched Chinese subjects were used for reconstruction of three-dimensional (3D) femur and tibial models. ACL footprints were sketched by several experienced orthopedic surgeons on the MRI photographs. The anatomical coordinate system was applied to reflect the ACL footprint location and orientation of scanned samples. The femoral ACL footprint locations were represented by their distance from the origin in the anteroposterior (A/P) and distal-proximal (D/P) directions. The orientation of the ACL was described with the sagittal, coronal and transverse deviation angles. The ACL orientation and femoral footprint position were compared by the two-sided t-test. Multiple regression analysis was used to study the correlation between the orientation and femoral footprint position. RESULTS: The average femur footprint A/P position was -6.6 ± 1.6 mm in the Chinese group and -5.1 ± 2.3 mm in the Caucasian group, (p < 0.001). The average femur footprint D/P position was -2.8 ± 2.4 mm in Chinese and - 3.9 ± 2.0 mm in Caucasians, (p = 0.001). The Chinese group had a mean difference of a 1.5 mm (6.1%) more posterior and 1.1 mm (5.3%) more proximal in the position from the flexion-extension axis (FEA). And the males have a sagittal plane elevation about 4-5° higher than females in both racial groups. Furthermore, for every 1% (0.40 mm) increase in A/P and D/P values, the sagittal angle decreased by about 0.12° and 0.24°, respectively; the coronal angle decreased by about 0.10° and 0.30°, respectively. For every 1% (0.40 mm) increase in D/P value, the transverse angle increased by about 0.14°. CONCLUSION: The significant race- and gender-specific differences in the femoral footprint and orientation of the ACL should be taken in consideration during anatomic single-bundle ACL reconstruction. Furthermore, the quantitative relationship between the ACL orientation and the footprint location might provide some reference for surgeons to develop a surgical strategy in ACL single-bundle reconstruction and revision.

Relationships between position of patellar ridge high point and morphology of resected surface for patellar resurfacing in total knee arthroplasty.

Background: Reproducing the native patellar ridge high point while maximizing osseous coverage is important for the success of patellar replacement, but it cannot always be achieved simultaneously. This study aimed to thoroughly investigate the relationships and their influencing factors between the positions of the high point of patellar ridge (HPPR) and the morphology of the patellar resected surface. Methods: Four hundred seventy-three patients (265 men, 208 women) aged 18 to 50 years with knee injuries before arthroscopy were retrospectively collected for this cross-sectional study. Computed tomography (CT) and magnetic resonance imaging (MRI) were used to construct 3D computer models of the patella and patellar cartilage. The morphometric characteristics of the patellar cut after virtual resection and the HPPR position relative to the patellar cut centre were measured and analyzed. Results: The medial displacements of the HPPR were positively correlated with Wiberg's classification and index (all P<0.001). The mean values of HPPR's medial displacements were 0.15 of the medial width of patellar cut, and 93.2% of all patella ranged from 0 to 0.3. When the implant's apex were placed at 0.15 of the medial width of patellar cut medialized, the proportion of implant placement errors within 1 mm of the native high point was 12% more in female patella (P=0.01), and 7% more in all patella (P=0.03) than 3 mm medialized. Conclusions: Wiberg's system can roughly predicted the medial-lateral position of the HPPR. The HPPR was mainly medially located at the 0.15 of the medial patellar width approximately, and 15% medialized of the implant's apex can better reproduce the native patellar high point than 3 mm medialized. The current results provide basic data for patellar implant selection, preoperative planning, and implant design to reproduce the native patellar high point better while maximizing osseous coverage for patellar resurfacing.

Overexpression of hsa_circ_0006470 inhibits the malignant behavior of gastric cancer cells via regulation of miR-1234/TP53I11 axis.

Gastric cancer (GC) is a subtype of a common malignant tumor found in the digestive system. Hsa_circ_0006470 is known to be closely associated with the development of GC. Nevertheless, the mechanism by which hsa_circ_0006470 regulates the tumorigenesis of GC has not been fully elucidated. To investigate the role of hsa_circ_0006470 in GC, its expression levels were assessed in GES-1, AGS, MKN45, and SNU5 cells by reverse transcription-quantitative PCR. Fluorescence in situ hybridization was used to evaluate the localization of hsa_circ_0006470 in AGS and MKN45 cells. In addition, cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays were performed to evaluate the viability and proliferation of GC cells, respectively. The dual-luciferase reporter assay was used to explore the interaction among hsa_circ_0006470, microRNA (miR)-1234, and TP53I11. The expression levels of TP53I11, Akt, p-Akt, forkhead box O1, and cyclin dependent kinase 2 in AGS cells were analyzed by Western blotting. The data indicated that hsa_circ_0006470 expression was downregulated in AGS cells. In addition, overexpression (OE) of hsa_circ_0006470 could inhibit the viability and proliferation of GC cells. Moreover, OE of hsa_circ_0006470 inhibited the migration of GC cells and induced G1 cell cycle phase arrest. Moreover, miR-1234 was bound to hsa_circ_0006470 and TP53I11 was targeted by miR-1234. Furthermore, OE of hsa_circ_0006470 inhibited the tumorigenesis of GC via the regulation of the miR-1234/TP53I11 axis. In summary, the present study demonstrated that OE of hsa_circ_0006470 notably inhibited the tumorigenesis of GC by regulating the miR-1234/TP53I11 axis. Therefore, the present study may provide a theoretical basis for exploring novel therapeutic strategies for the treatment of GC.

An xception model based on residual attention mechanism for the classification of benign and malignant gastric ulcers.

To explore the application value of convolutional neural network combined with residual attention mechanism and Xception model for automatic classification of benign and malignant gastric ulcer lesions in common digestive endoscopy images under the condition of insufficient data. For the problems of uneven illumination and low resolution of endoscopic images, the original image is preprocessed by Sobel operator, etc. The algorithm model is implemented by Pytorch, and the preprocessed image is used as input data. The model is based on convolutional neural network for automatic classification and diagnosis of benign and malignant gastric ulcer lesions in small number of digestive endoscopy images. The accuracy, F1 score, sensitivity, specificity and precision of the Xception model improved by the residual attention module for the diagnosis of benign and malignant gastric ulcer lesions were 81.411%, 81.815%, 83.751%, 76.827% and 80.111%, respectively. The superposition of residual attention modules can effectively improve the feature learning ability of the model. The pretreatment of digestive endoscopy can remove the interference information on the digestive endoscopic image data extracted from the database, which is beneficial to the training of the model. The residual attention mechanism can effectively improve the classification effect of Xception convolutional neural network on benign and malignant lesions of gastric ulcer on common digestive endoscopic images.

A New Reference Axis for Tibial Component Rotation in Total Knee Arthroplasty: A Three-dimensional Computed Tomography Analysis.

The purpose of this study was to introduce a new reference axis for tibial rotation in total knee arthroplasty (TKA) and verify its reliability. A consecutive series of 80 knees that underwent TKA from 2018 to 2020 as well as 80 healthy knees were analyzed using a three-dimensional tibial model. A coordinate system was established based on the standard TKA tibial cut. The line connecting the lateral-tibial eminence and the medial 1/3rd of the tibial tubercle or the medial border of the tibial tubercle was identified as the lateral eminence line (LE line) and the medial lateral eminence line (MLE line), respectively. To evaluate the reliability of the new reference axis, Akagi's line, the medial third of the tibial tubercle (1/3 line) was compared with the LE and MLE lines by measuring the angle between the lines and the Z-axis. In the coronal view, the intersection angle (TPA), which is composed of the line connecting the center of the medial and lateral tibial plateau with the Z-axis, was measured. The mean angle between Akagi's line and the Z-axis in the healthy group and the osteoarthritis (OA) group was 87.57 ± 3.48° and 87.61 ± 3.47°, respectively. The mean angle between the LE line and Z-axis in the healthy and OA groups was 87.15 ± 4.13° and 86.78 ± 3.95°, respectively. A weak correlation was found between the TPA and Akagi's line and the 1/3 line. A moderate correlation was observed between the TPA and LE lines. There were no significant differences between the healthy and OA groups (P > 0.05) in any of the four reference axes. The LE line showed excellent intra- and inter-observer reliability and reproducibility. The novel and easily drawn LE line is a preferable option for tibial component rotational alignment in TKA.

Effects of Gentiana delavayi Flower Extract on APP Processing in APP/PS1 CHO Cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Gentiana delavayi Franch. (Gentianaceae) as an ethnomedicinal plant contains a variety of effective active ingredients and exhibits diverse pharmacological actions, such as hepatoprotective, anti-inflammatory and central nervous system effects. In this study we investigated the influence of G. delavayi flower extract on amyloid precursor protein (APP) processing at molecular and cellular levels. APP/PS1 Chinese hamster ovary (CHO) cells were treated with chloroform extract of G. delavayi flower in different concentrations for 24 h. Concentrations of amyloid ß (Aß) 40 and Aß42 in the cell supernatant and activity of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), BACE2, and cathepsin D were determined. The expression of APP and neprilysin (NEP) within the cell were further determined. Compared with the control group, the levels of Aß40 and Aß42 declined notably and the activity of BACE1 was inhibited significantly in the APP/PS1 CHO cells after treatment with the chloroform extract of G. delavayi flower. Although the activities of BACE2 and cathepsin D were not changed, the expression of Aß degrading enzyme NEP increased remarkably. Our experiments have clearly showed that the chloroform extract of G. delavayi flower inhibits the generation of ß-amyloid by specifically inhibiting ß-secretase and increases the expression of NEP which fastens the degradation of Aß, exhibiting the effect of decreasing Aß accumulation in APP/PS1 CHO cells. These results suggest that the active components from the chloroform extract of G. delavayi flower have a further prospect to be developed as potential anti-Aß drug.