Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.

The phosphoinositide 3-kinase (PI3K)-Akt axis is one of the most frequently activated pathways and is demonstrated as a therapeutic target in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated colorectal cancer (CRC). Targeting the PI3K-Akt pathway has been a challenging undertaking through the decades. Here we unveiled an essential role of E3 ligase SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated phosphoinositide-dependent protein kinase 1 (PDK1) neddylation in PI3K-Akt signaling and tumorigenesis. Upon growth factor stimulation, Smurf1 immediately triggers PDK1 neddylation and the poly-neural precursor cell expressed developmentally downregulated protein 8 (poly-Nedd8) chains recruit methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1). The cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) consisting of PDK1, Smurf1 and SETDB1 directs Akt membrane attachment and T308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1-Akt blockade and potent tumor suppression alone or combined with PDK1 inhibitor in KRAS-mutated CRC. The findings presented here unveil previously unrecognized roles of PDK1 neddylation and offer a potential strategy for targeting the PI3K-Akt pathway and KRAS mutant cancer therapy.

PSCAT: a lightweight transformer for simultaneous denoising and super-resolution of OCT images.

Optical coherence tomography (OCT), owing to its non-invasive nature, has demonstrated tremendous potential in clinical practice and has become a prevalent diagnostic method. Nevertheless, the inherent speckle noise and low sampling rate in OCT imaging often limit the quality of OCT images. In this paper, we propose a lightweight Transformer to efficiently reconstruct high-quality images from noisy and low-resolution OCT images acquired by short scans. Our method, PSCAT, parallelly employs spatial window self-attention and channel attention in the Transformer block to aggregate features from both spatial and channel dimensions. It explores the potential of the Transformer in denoising and super-resolution for OCT, reducing computational costs and enhancing the speed of image processing. To effectively assist in restoring high-frequency details, we introduce a hybrid loss function in both spatial and frequency domains. Extensive experiments demonstrate that our PSCAT has fewer network parameters and lower computational costs compared to state-of-the-art methods while delivering a competitive performance both qualitatively and quantitatively.

Analysis of factors impacting postoperative pain and quality of life in patients with mixed hemorrhoids: A retrospective study.

BACKGROUND: Hemorrhoids are among the most common and frequently encountered chronic anorectal diseases in anorectal surgery. They are venous clusters formed by congestion, expansion, and flexion of the venous plexus in the lower part of the rectum. Mixed hemorrhoids bleed easily and recurrently, and this can result in severe anemia. Hence, they may have a negative effect on the health of the patient and surgical treatment is required. Milligan-Morgan hemorrhoidectomy has been widely used since 1937 for the treatment of grade III and IV hemorrhoids. However, most patients experience different degrees of postoperative pain that may cause anxiety. AIM: To assess the factors influencing pain scores and quality of life (QoL) in patients with mixed hemorrhoids post-surgery. METHODS: The clinical data of patients with mixed hemorrhoids who underwent Milligan-Morgan hemorrhoidectomy were collected retrospectively. The basic characteristics of the enrolled patients with mixed hemorrhoids were recorded, and based on the Goligher clinical grading system, the hemorrhoids were classified as grades III or IV. The endpoint of this study was the disappearance of pain in all patients. Quantitative data were presented as mean ± SD, such as age, pain score, and QoL score. Student's t-test was used to compare the groups. RESULTS: A total of 164 patients were enrolled. The distribution of the visual analog scale pain scores of all patients at 3, 7, 14 and 28 d after surgery showed that post-surgery pain was significantly reduced with the passage of time. Fourteen days after the operation, the pain had completely disappeared in some patients. Twenty-eight days after the surgery, none of the patients experienced any pain. Comparing the World Health Organization Quality of Life - BREF self-reporting questionnaire scores of patients between 14 and 28 d after surgery, we observed that the quality-of-life scores of the patients post-surgery had significantly improved. There were six items that were compared at 14- and 28-d post-surgery. The mean QoL score 28 d after surgery (4.79 ± 0.46) was higher than that at 14 d post-surgery (3.79 ± 0.57). The mean health condition score 28 d after surgery (4.80 ± 0.41) was also higher than that at 14 d post-surgery (4.01 ± 0.62). The mean physical health score 28 d after surgery (32.10 ± 2.96) was significantly higher than that at 14 d post-surgery (23.41 ± 2.85). The mean psychological health score 28 d after surgery (27.22 ± 1.62) was significantly higher than that at 14 d post-surgery (21.37 ± 1.70). The mean social relations score 28 d after surgery (12.21 ± 1.59) was significantly higher than that at 14 d post-surgery (6.32 ± 1.66). The mean surrounding environment score 28 d after surgery (37.13 ± 2.88) was significantly higher than that at 14 d post-surgery (28.42 ± 2.86). The differences in quality-of-life scores at day 14 and day 28 post-surgery were observed to be statistically significant (P < 0.001). CONCLUSION: Milligan-Morgan hemorrhoidectomy can significantly improve the postoperative QoL of patients. Age, sex, and the number of surgical resections were important factors influencing Milligan-Morgan hemorrhoidectomy.

Identification of the shared gene signature and biological mechanism between type 2 diabetes and colorectal cancer.

Background: The correlation of type 2 diabetes mellitus (T2DM) with colorectal cancer (CRC) has garnered considerable attention in the scientific community. Despite this, the molecular mechanisms underlying the interaction between these two diseases are yet to be elucidated. Hence, the present investigation aims to explore the shared gene signatures, immune profiles, and drug sensitivity patterns that exist between CRC and T2DM. Methods: RNA sequences and characteristics of patients with CRC and T2DM were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. These were investigated using weighted gene co-expression network analysis (WGCNA) to determine the co-expression networks linked to the conditions. Genes shared between CRC and T2DM were analyzed by univariate regression, followed by risk prognosis assessment using the LASSO regression model. Various parameters were assessed through different software such as the ESTIMATE, CIBERSORT, AND SSGSEA utilized for tumor immune infiltration assessment in the high- and low-risk groups. Additionally, pRRophetic was utilized to assess the sensitivity to chemotherapeutic agents in both groups. This was followed by diagnostic modeling using logistic modeling and clinical prediction modeling using the nomogram. Results: WGCNA recognized four and five modules that displayed a high correlation with T2DM and CRC, respectively. In total, 868 genes were shared between CRC and T2DM, with 14 key shared genes being identified in the follow-up analysis. The overall survival (OS) of patients in the low-risk group was better than that of patients in the high-risk group. In contrast, the high-risk group exhibited higher expression levels of immune checkpoints The Cox regression analyses established that the risk-score model possessed independent prognostic value in predicting OS. To facilitate the prediction of OS and cause-specific survival, the nomogram was established utilizing the Cox regression model. Conclusion: The T2DM + CRC risk-score model enabled independent prediction of OS in individuals with CRC. Moreover, these findings revealed novel genes that hold promise as therapeutic targets or biomarkers in clinical settings.

Management of esophagogastric fistula caused by adjustable gastric band erosion: A case report and literature review.

Laparoscopic adjustable gastric banding (LAGB) is commonly used in the treatment of morbid obesity. However, with clinical application and long-term follow-up, the shortcomings of this procedure were also exposed, bringing about surgery-related complications include dysphagia, intragastric band migration, slippage, and gastric band erosion. Lower esophageal and gastric fistula is a rare but dangerous complication after LAGB. We describe a case of esophagogastric fistula occurring twelve years after a laparoscopic band procedure and its successful management in a multidisciplinary and staged manner, followed by a short review of the literature.

Background-Aware Classification Activation Map for Weakly Supervised Object Localization.

Weakly supervised object localization (WSOL) relaxes the requirement of dense annotations for object localization by using image-level annotation to supervise the learning process. However, most WSOL methods only focus on forcing the object classifier to produce high activation score on object parts without considering the influence of background locations, causing excessive background activations and ill-pose background score searching. Based on this point, our work proposes a novel mechanism called the background-aware classification activation map (B-CAM) to add background awareness for WSOL training. Besides aggregating an object image-level feature for supervision, our B-CAM produces an additional background image-level feature to represent the pure-background sample. This additional feature can provide background cues for the object classifier to suppress the background activations on object localization maps. Moreover, our B-CAM also trained a background classifier with image-level annotation to produce adaptive background scores when determining the binary localization mask. Experiments indicate the effectiveness of the proposed B-CAM on four different types of WSOL benchmarks, including CUB-200, ILSVRC, OpenImages, and VOC2012 datasets.

The risk factors of postoperative nausea and vomiting in patients undergoing laparoscopic sleeve gastrectomy and laparoscopic distal gastrectomy: a propensity score matching analysis.

Postoperative nausea and vomiting (PONV) is a common side effect after laparoscopic surgery. The aim of the study is to investigate the variables that could predict PONV in patients who underwent laparoscopic gastrectomy. We divided patients who underwent laparoscopic gastrectomy into PONV and No-PONV groups. Propensity score matching (PSM) was applied to adjust confounding factors for further validation, and ordinal logistic regression analysis was used to identify predictors for PONV. In the ordinal logistic regression analysis, the preoperative neutrophil-to-lymphocyte ratio (NLR) (odds ratio [OR]: 3.19, 95% confidence interval [CI]: 1.38-7.38; p < 0.01) was identified as an independent risk factor for the presence of PONV and a predictor of the severity of PONV (OR: 3.44, 95% CI: 1.67-5.20; p < 0.01) in 94 PSM patients. Besides, NLR was positively correlated with the PONV score (r = 0.534, p < 0.001). In the receiver-operating characteristic (ROC) curve analysis, an NLR with an optimal cutoff value of 1.59 predicted severe PONV with a sensitivity of 72% and specificity of 81%. The NLR was an independent risk factor for the presence of PONV, and a high NLR tends to be positively associated with the severity of PONV after laparoscopic gastrectomy.

The association between the body roundness index and the risk of colorectal cancer: a cross-sectional study.

BACKGROUND: Colorectal cancer (CRC), has a link between obesity, especially visceral fat. The body roundness index (BRI) can more accurately assess body fat and visceral fat levels. It is, however, unknown whether BRI is associated with CRC risk. METHODS: 53,766 participants were enrolled from the National Health and Nutrition Examination Survey (NHANES). Analysing the corelation between BRI and CRC risk was performed using logistic regression. Stratified analyses revealed the association based on the population type. Receiver operating characteristic curve (ROC) was performed for predicting CRC risk using different anthropometric indices. RESULTS: The risk of CRC mounting apparently with elevated BRI for participants with CRC compared to normal participants (P-trend < 0.001). The association persisted even after adjusting for all covariates (P-trend = 0.017). In stratified analyses, CRC risk increased with increasing BRI, especially among those who were inactive (OR (95% CI): Q3 3.761 (2.139, 6.610), P < 0.05, Q4 5.972 (3.347, 8.470), P < 0.01), overweight (OR (95% CI): Q3 2.573 (1.012, 7.431), P < 0.05, Q4 3.318 (1.221, 9.020), P < 0.05) or obese (OR (95% CI): Q3 3.889 (1.829, 8.266), P < 0.001, Q4 4.920 (2.349, 10.308), P < 0.001). ROC curve showed that BRI had a better ability in forecasting the risk of CRC than other anthropometric indices such as body weight etc. (all P < 0.05). CONCLUSIONS: CRC risk and BRI have a positive and significant relationship, particularly in inactive participants with BMI ≥ 25 kg/m2. It is hoped that these results will raise awareness of the importance of reducing visceral fat deposition.

Murine neonatal dermal fibroblast acquires a lymphoid tissue organizer cell-like activity upon synergistic activation of TNF-α receptor and LTß receptor.

Tertiary lymphoid organs (TLOs) are ectopic aggregates of immune cells. As accumulating studies demonstrate TLOs as a predictor of better prognosis in certain cancers, targeting TLO formation, which is tightly regulated by the lymphoid tissue organizer cells (LTOs), has become intriguing in cancer treatment. However, the clinical outcome of these attempts is limited, because the approaches for activating tumor adjacent LTO is lack and little is known about what type of self-cell can be used as LTO to initiate TLO formation. Here we demonstrate that co-stimulation with membrane-bound ligand LTα1ß2 and soluble TNF-α could induced an LTO-like activity in murine neonatal dermal fibroblast, featured by high expression of cell migration-associated chemokines and adhesion molecules that resemble typical LTO gene signature. Furthermore, the LTO-phenotypic dermal fibroblast could enhance the attachment and survival of T and B cell and proliferation of T cell. These findings suggest dermal fibroblast as a promising target for TLO induction to improve cancer immunotherapy.

Comprehensive analysis of the prognostic and immunotherapeutic implications of STAT family members in human colorectal cancer.

Background: Colorectal cancer (CRC) is the third most prevalent cancer worldwide and the second leading cause of cancer mortality. Signal transducer and activator of transcription (STAT) proteins are a group of transcription factors implicated in cell signal transduction and gene transcription in several cancer types. However, the level of expression, genetic alterations, and biological function of different STATs, as well as their prognostic and immunotherapeutic value in CRC remain unclear. Methods: The mRNA and protein expression levels, genetic alterations, prognostic value, gene-gene and protein-protein interaction networks, and biological function of STATs in CRC were studied using the GEPIA, HPA, cBioPortal, PrognoScan, Kaplan-Meier plotter, GeneMANIA, STRING, and Metascape databases. The expression of STATs in CRC was confirmed using immunohistochemistry (IHC). Finally, the relationship between STAT expression and immune infiltration as well as immunotherapy-associated indicators was also investigated. Results: The expression levels of STAT2/5A/5B are downregulated in CRC, and the STAT1/3/4/5B expressions were significantly associated with the tumor stage of patients with CRC. The abnormal expression of STAT2/4/5B in patients with CRC is related to the prognosis of patients with CRC. The STATs and their neighboring proteins are primarily associated with lymphocyte activation, cytokine-mediated signaling pathways, positive regulation of immune response, regulation of cytokine production, and growth hormone receptor signaling pathways in cancer. The expression of STATs was significantly associated with immune infiltration and immunotherapy response-associated indicators. Conclusion: This study may help further understand the molecular mechanism of CRC and provide new prognostic biomarkers and immunotherapy targets in patients with CRC.

Boosting medical image segmentation via conditional-synergistic convolution and lesion decoupling.

Medical image segmentation is a critical step in pathology assessment and monitoring. Extensive methods tend to utilize a deep convolutional neural network for various medical segmentation tasks, such as polyp segmentation, skin lesion segmentation, etc. However, due to the inherent difficulty of medical images and tremendous data variations, they usually perform poorly in some intractable cases. In this paper, we propose an input-specific network called conditional-synergistic convolution and lesion decoupling network (CCLDNet) to solve these issues. First, in contrast to existing CNN-based methods with stationary convolutions, we propose the conditional synergistic convolution (CSConv) that aims to generate a specialist convolution kernel for each lesion. CSConv has the ability of dynamic modeling and could be leveraged as a basic block to construct other networks in a broad range of vision tasks. Second, we devise a lesion decoupling strategy (LDS) to decouple the original lesion segmentation map into two soft labels, i.e., lesion center label and lesion boundary label, for reducing the segmentation difficulty. Besides, we use a transformer network as the backbone, further erasing the fixed structure of the standard CNN and empowering dynamic modeling capability of the whole framework. Our CCLDNet outperforms state-of-the-art approaches by a large margin on a variety of benchmarks, including polyp segmentation (89.22% dice score on EndoScene) and skin lesion segmentation (91.15% dice score on ISIC2018). Our code is available at https://github.com/QianChen98/CCLD-Net.

Colorectal cancer immunotherapy-Recent progress and future directions.

Compared with conventional chemotherapy and targeted therapy, immunotherapy has changed the treatment prospects of various solid tumors and has recently become the main treatment method for metastatic or recurrent solid tumors, including malignant melanoma, non-small-cell lung cancer, and renal cell carcinoma. The application of immune checkpoint inhibitor (ICI)-based immunotherapy in patients with colorectal cancer (CRC) has yielded satisfactory results in terms of safety and efficacy, and several immunotherapeutic agents, including pembrolizumab, nivolumab, and ipilimumab, have been approved for the treatment of advanced CRC. The advent of other immunotherapies, such as chimeric antigen receptor-modified T (CAR-T) cells or cancer vaccines, have also contributed to the development of immunotherapy for CRC. Here, we summarize the findings of recent clinical trials on the efficacy of immunotherapy in CRC and briefly describe the mechanisms associated with tumor-intrinsic resistance to ICIs. We then discuss potential biomarkers for predicting the efficacy of immunotherapy.

The Significance of Neutrophil Extracellular Traps in Colorectal Cancer and Beyond: From Bench to Bedside.

Neutrophil extracellular traps (NETs), products of neutrophil death when exposed to certain stimuli, were first proposed as a type of response to bacterial infection in infectious diseases. Since then, extensive studies have discovered its involvement in other non-infectious inflammatory diseases including thromboembolism, autoimmune diseases, and cancer. Colorectal cancer (CRC) is one of the most common malignancies in the world. NET formation is closely associated with tumorigenesis, progression, and metastasis in CRC. Therefore, the application of NETs in clinical practice as diagnostic biomarkers, therapeutic targets, and prognostic predictors has a promising prospect. In addition, therapeutics targeting NETs are significantly efficient in halting tumor progression in preclinical cancer models, which further indicates its potential clinical utility in cancer treatment. This review focuses on the stimuli of NETosis, its pro-tumorigenic activity, and prospective clinical utility primarily in but not limited to CRC.

Evaluating the impact of different positron emitters on the performance of a clinical PET/MR system.

PURPOSE: The positron range and prompt gamma emission are distinctive with different positron emitters. The performance assessment of an integrated PET/MR scanner with these positron emitters is required for related applications, as the magnetic field interferes with the positron propagation. Such an assessment is to be performed on the United Imaging uPMR 790-integrated PET/MR system. METHODS: The performance measurement methods were modified based on NEMA NU 2-2012, involving 18 F, 64 Cu, 68 Ga, 89 Zr, and 124 I as positron emitters. The NEMA IEC phantom was used for evaluations of image qualities. An agarose cap was wrapped around the point source for tissue-simulating spatial resolution measurement. The count rate performance was assessed with selected positron emitters. Images of a 3D-printed Derenzo phantom and representative patients were also acquired. RESULTS: The image quality measurement showed that all five positron emitters were suitable for the PET/MR system studied. However, due to the magnetic field, the image of the point source showed an elongated comet-tail feature, which could be eliminated by a tissue-simulating cap. This effect is more obvious in 124 I and 68 Ga, due to their long positron ranges. The imaging ability with various positron emitters was further validated with the count rate assessment, the Derenzo phantom, and the clinical images. CONCLUSIONS: Different positron emitters could be effectively imaged by the PET/MR system tested. The resolution measurement strategy proposed could be applied to measure PET spatial resolution in the magnetic field.

Content-Noise Complementary Learning for Medical Image Denoising.

Medical imaging denoising faces great challenges, yet is in great demand. With its distinctive characteristics, medical imaging denoising in the image domain requires innovative deep learning strategies. In this study, we propose a simple yet effective strategy, the content-noise complementary learning (CNCL) strategy, in which two deep learning predictors are used to learn the respective content and noise of the image dataset complementarily. A medical image denoising pipeline based on the CNCL strategy is presented, and is implemented as a generative adversarial network, where various representative networks (including U-Net, DnCNN, and SRDenseNet) are investigated as the predictors. The performance of these implemented models has been validated on medical imaging datasets including CT, MR, and PET. The results show that this strategy outperforms state-of-the-art denoising algorithms in terms of visual quality and quantitative metrics, and the strategy demonstrates a robust generalization capability. These findings validate that this simple yet effective strategy demonstrates promising potential for medical image denoising tasks, which could exert a clinical impact in the future. Code is available at: https://github.com/gengmufeng/CNCL-denoising.

Comparison between high-frequency irreversible electroporation and irreversible electroporation ablation of small swine liver: follow-up of DCE-MRI and pathological observations.

BACKGROUND: High-frequency irreversible electroporation (H-FIRE) is a novel, next-generation nanoknife technology with the advantage of relieving irreversible electroporation (IRE)-induced muscle contractions. However, the difference between IRE and H-FIRE with distinct ablation parameters was not clearly defined. This study aimed to compare the efficacy of the two treatments in vivo. METHODS: Ten Bama miniature swine were divided into two group: five in the 1-day group and five in the 7-day group. The efficacy of IRE and H-FIRE ablation was compared by volume transfer constant (Krans), rate constant (Kep) and extravascular extracellular volume fraction (Ve) value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), size of the ablation zone, and histologic analysis. Each animal underwent the IRE and H-FIRE. Temperatures of the electrodes were measured during ablation. DCE-MRI images were obtained 1, 4, and 7 days after ablation in the 7-day group. All animals in the two groups were euthanized 1 day or 7 days after ablation, and subsequently, IRE and H-FIRE treated liver tissues were collected for histological examination. Student's t test or Mann-Whitney U test was applied for comparing any two groups. One-way analysis of variance (ANOVA) test and Welch's ANOVA test followed by Holm-Sidak's multiple comparisons test, one-way ANOVA with repeated measures followed by Bonferroni test, or Kruskal-Wallis H test followed by Dunn's multiple comparison test was used for multiple group comparisons and post hoc analyses. Pearson correlation coefficient test was conducted to analyze the relationship between two variables. RESULTS: Higher Ve was seen in IRE zone than in H-FIRE zone (0.14 ±â€Š0.02 vs. 0.08 ±â€Š0.05, t = 2.408, P = 0.043) on day 4, but no significant difference was seen in Ktrans or Kep between IRE and H-FIRE zones at all time points (all P > 0.05). For IRE zone, the greatest Ktrans was seen on day 7, which was significantly higher than that on day 1 (P = 0.033). The ablation zone size of H-FIRE was significantly larger than IRE 1 day (4.74 ±â€Š0.88 cm2vs. 3.20 ±â€Š0.77 cm2, t = 3.241, P = 0.009) and 4 days (2.22 ±â€Š0.83 cm2vs. 1.30 ±â€Š0.50 cm2, t = 2.343, P = 0.041) after treatment. Apoptotic index (0.05 ±â€Š0.02 vs. 0.73 ±â€Š0.06 vs. 0.68 ±â€Š0.07, F = 241.300, P < 0.001) and heat shock protein 70 (HSP70) (0.03 ±â€Š0.01 vs. 0.46 ±â€Š0.09 vs. and 0.42 ±â€Š0.07, F = 64.490, P < 0.001) were significantly different between the untreated, IRE and H-FIRE zones, but no significant difference was seen in apoptotic index or HSP70 between IRE and H-FIRE zone (both P > 0.05). Electrode temperature variations were not significantly different between the two zones (18.00 ±â€Š3.77°C vs. 16.20 ±â€Š7.45°C, t = 0.682, P = 0.504). The Ktrans value (r = 0.940, P = 0.017) and the Kep value (r = 0.895, P = 0.040) of the H-FIRE zone were positively correlated with the number of hepatocytes in the ablation zone. CONCLUSIONS: H-FIRE showed a comparable ablation effect to IRE. DCE-MRI has the potential to monitor the changes of H-FIRE ablation zone.