HyperTMO: a trusted multi-omics integration framework based on hypergraph convolutional network for patient classification.

MOTIVATION: The rapid development of high-throughput biomedical technologies can provide researchers with detailed multi-omics data. The multi-omics integrated analysis approach based on machine learning contributes a more comprehensive perspective to human disease research. However, there are still significant challenges in representing single-omics data and integrating multi-omics information. RESULTS: This article presents HyperTMO, a Trusted Multi-Omics integration framework based on Hypergraph convolutional network for patient classification. HyperTMO constructs hypergraph structures to represent the association between samples in single-omics data, then evidence extraction is performed by hypergraph convolutional network, and multi-omics information is integrated at an evidence level. Last, we experimentally demonstrate that HyperTMO outperforms other state-of-the-art methods in breast cancer subtype classification and Alzheimer's disease classification tasks using multi-omics data from TCGA (BRCA) and ROSMAP datasets. Importantly, HyperTMO is the first attempt to integrate hypergraph structure, evidence theory, and multi-omics integration for patient classification. Its accurate and robust properties bring great potential for applications in clinical diagnosis. AVAILABILITY AND IMPLEMENTATION: HyperTMO and datasets are publicly available at https://github.com/ippousyuga/HyperTMO.

Memory induced-mechanism of noise attenuator of myosin V molecular motors.

Depending on the chemical energy from ATP hydrolysis, myosin V can drive the multistep and continuous coupled cycling process to transport cellular cargo to targeted regions. However, it is still obscure how the molecular memory induced by the multistep coupled transported process could regulate the dynamic behavior of the motor state of myosin V. Here, we propose a novel non-Markovian polymorphic mechanochemical model to investigate the effect of the molecular memory on the mechanic of noise attenuation of myosin V system. We first define an effective transition rate for a multistep coupled reaction process which is the function of memory and system states to transform equivalently the non-Markovian process into the classical Markov process. By noise decomposition technology, it is observed that both the intrinsic and extrinsic noises of the ADP-myosin V bound state (AM ⋅ ADP) exhibit a monotonically decreasing trend with lengthening the molecular memory. Molecular memory as a regulation factor can amplify the contribution of intrinsic noise to the overall noise while reducing the influence of extrinsic noise on the AM ⋅ ADP. Moreover, the modulation of molecular memory could induce stochastic focusing. These results indicate that the role of molecular memory in the myosin V state transition can not only offer a handle to maintain the robustness of the motion system but also serve as a paradigm for studying more complex molecular motors.

Stochastic analysis and control for a delayed Hepatitis B epidemic model.

Considering the time delay originating from a certain incubation period or asymptomatic state, we propose a delayed epidemic system within the noisy environment of the hepatitis B virus to analyze the mechanism of disease transmission and elucidate how to control it by applying the strategy of vaccinating and treatment. Applying stochastic Lyapunov functional theory, we first construct an integral Lyapunov function coupling the time delay and stochastic fluctuation to investigate whether there exists a unique global solution to the model. Next, we yield the threshold condition for controlling disease extinction, and persistence, as well as its stationary distribution. Governed by these sufficient conditions, we study the existence of optimal control solutions in deterministic and stochastic scenarios to uncover how to accelerate disease extinction through vaccination and treatment. The results indicate that the time delay will prolong the duration of the disease for the original system but suppress the peak value of HBV in the controlled system. Finally, we verify the versatility of theoretical results by numerical simulations. These results will effectively decipher the importance of the time delay in the control of hepatitis B.

Magnetic anchor technique assisted laparoscopic cholecystectomy in swine.

Magnetic anchor device based on the principle of magnet heteropolar attraction can assist laparoscopic surgery and reduce abdominal wall trauma. This study explored the feasibility of use of our self-designed magnetic anchor device for reduced-port laparoscopic cholecystectomy (LC) through animal experiments. Twelve experimental pigs (15-20 kg) were randomly divided into study group (magnetic anchor technique assisted 2-port LC, n = 6) and control group (conventional 3-port LC, n = 6). Operative time, intraoperative blood loss, and postoperative complications were compared between the two groups. LC was successfully performed in all 12 pigs. There was no significant between-group difference with respect to operative time (study group: 35.83 ± 5.12 min; control group: 34.50 ± 5.13 min, P = 0.662) or intraoperative blood loss (< 50 mL per animal in both groups). In the experimental group, there was no malfunction of the magnetic anchoring device, the use process was smooth, and the tissue traction and surgical field exposure were satisfactory. There were no perioperative complications such as bile duct injury, bile leakage, or bleeding in both groups. We demonstrated the feasibility of use of the self-designed magnetic anchor device in reduced-port LC. The device has important clinical application value.

Implementation of sodium alginate-Fe3O4 to localize undiagnosed small pulmonary nodules for surgical management in a preclinical rabbit model.

Many methods are used to locate preoperative small pulmonary nodules. However, deficiencies of complications and success rates exist. We introduce a novel magnetic gel for small pulmonary nodules localization in rabbit model, and furtherly evaluate its safety and feasibility. Rabbits were used as the experimental objects. A magnetic gel was used as a tracer magnet, mixed as sodium alginate-Fe3O4 magnetic fluid and calcium gluconate solution. In short-term localization, a coaxial double-cavity puncture needle was applied to inject the gel into the lung after thoracotomy, and a pursuit magnet made of Nd-Fe-B permanent magnetic materials was used to attract the gel representing location of the nodule. In long-term localization, the gel was injected under X-ray guidance. Imaging changes to the lung were observed under X-ray daily. Thoracotomy was performed to excise tissue containing the gel, and hematoxylin-eosin staining was used to observe the tissue on postoperative days 1, 3, 5, and 7. Observe tissues morphology of heart, liver, spleen, and kidney in the same way. The gel was formed after injection and drew lung tissue to form a protrusion from the lung surface under the applied magnetic field. No complication was observed. The shape and position of the gel had not changed when viewed under X-ray. Pathological analysis showed the gel had a clear boundary without diffusion of magnetic fluid. All tissues retained good histologic morphology and no magnetic fluid was observed. Our study preliminarily suggested that the technique using sodium alginate-Fe3O4 magnetic gel to locate small pulmonary nodules with guidance of X-ray, and to search for them under an applied magnetic field during the operation is safe and feasible.

Adhesive anastomosis for organ transplantation.

The recent development of tough tissue adhesives has stimulated intense interests among material scientists and medical doctors. However, these adhesives have seldom been tested in clinically demanding surgeries. Here we demonstrate adhesive anastomosis in organ transplantation. Anastomosis is commonly conducted by dense sutures and takes a long time, during which all the vessels are occluded. Prolonged occlusion may damage organs and even cause death. We formulate a tough, biocompatible, bioabsorbable adhesive that can sustain tissue tension and pressurized flow. We expose the endothelial surface of vessels onto a gasket, press two endothelial surfaces to the adhesive using a pair of magnetic rings, and reopen the bloodstream immediately. The time for adhesive anastomosis is shortened compared to the time for sutured anastomosis. We have achieved adhesive anastomosis of a great vein in transplanting the liver of a pig. After the surgery, the adhesive is absorbed, the vein heals, and the pig lives for over one month.

Coloured noise induces phenotypic diversity with energy dissipation.

Genes integrate many different sources of noise to adapt their survival strategy with energy costs, but how this noise impacts gene phenotype switching is not fully understood. Here, we refine a mechanistic model with multiplicative and additive coloured noise and analyse the influence of noise strength (NS) and autocorrelation time (AT) on gene phenotypic diversity. Different from white noise, we found that in the autocorrelation time-scale plane, increasing the multiplicative noise will broaden the bimodal region of the gene product, and additive noise will induce bimodal region drift from the lower level to the higher level, while the AT will promote this transition. Specifically, the effect of AT on gene expression is similar to a feedback loop; that is, the AT of multiplicative noise will elongate the mean first passage time (MFPT) from the low stable state to the high stable state, but it will reduce the MFPT from the high stable state to the low stable state, and the opposite is true for additive noise. Moreover, these transitions will violate the detailed equilibrium and then consume energy. By effective topology network reconstruction, we found that when the NS is small, the more obvious the bimodality is, the lower the energy dissipation; however, when the NS is large, it will consume more energy with a tendency for bimodality. The overall analysis implies that living organisms will utilize noise strength and its autocorrelation time for better survival in complex and fluctuating environments.

Magnetic-assisted laparoscopic liver transplantation in swine.

BACKGROUND: Although laparoscopic technology has achieved rapid development in the surgical field, it has not been applied to liver transplantation, primarily because of difficulties associated with laparoscopic vascular anastomosis. In this study, we introduced a new magnetic-assisted vascular anastomosis technique and explored its application in laparoscopic liver transplantation in pigs. METHODS: Two sets of magnetic vascular anastomosis rings (MVARs) with different diameters were developed. One set was used for anastomosis of the suprahepatic vena cava (SHVC) and the other set was used for anastomosis of the infrahepatic vena cava (IHVC) and portal vein (PV). Six laparoscopic orthotopic liver transplantations were performed in pigs. Donor liver was obtained via open surgery. Hepatectomy was performed in the recipients through laparoscopic surgery. Anastomosis of the SHVC was performed using hand-assisted magnetic anastomosis, and the anastomosis of the IHVC and PV was performed by magnetic anastomosis with or without hand assistance. RESULTS: Liver transplants were successfully performed in five of the six cases. Postoperative ultrasonographic examination showed that the portal inflow was smooth. However, PV bending and blood flow obstruction occurred in one case because the MVARs were attached to each other. The durations of loading of MVAR in the laparoscope group and manual assistance group for IHVC and PV were 13 ± 5 vs. 5 ± 1 min (P < 0.01) and 10 ± 2 vs. 4 ± 1 min (P < 0.05), respectively. The durations of MVAR anastomosis in the laparoscope group and manual assistance group for IHVC and PV were 5 ± 1 vs. 1 ± 1 min (P < 0.01), and 5 ± 1 vs. 1 ± 1 min (P < 0.01), respectively. The anhepatic phase was 43 ± 4 min in the laparoscope group and 23 ± 2 min in the manual assistance group (P < 0.01). CONCLUSIONS: Our study showed that magnetic-assisted laparoscopic liver transplantation can be successfully carried out in pigs.

The role of magnetic anchoring and traction technique in thoracoscopic lymphadenectomy along the left recurrent laryngeal nerve.

BACKGROUND: Dissecting lymph nodes along the left recurrent laryngeal nerve (LRLN) is the most challenging step in thoracoscopic-assisted esophagectomy. To retract the proximal esophagus in the existing lymphadenectomy methods, either a special trocar is required to insert and take out endoscopic instruments or thoracic punctures are needed to externally retract the esophageal loop. Therefore, advanced skills for esophageal traction are important to facilitate the LRLN lymphadenectomy and to reduce the incidence of trauma to the chest wall. Herein, we present the magnetic anchoring and traction technique, a novel method for LRLN lymphadenectomy during thoracoscopic esophagectomy. METHODS: The magnetic anchoring traction system was successfully used to retract the upper thoracic esophagus and to help expose the upper mediastinum in 10 cases of thoracoscopic-assisted esophagectomy. When the external magnet was moved outside of body, the internal magnet was coupled with a magnetic force to pull the proximal esophagus to the appropriate direction, which helped to expose the LRLN and adjacent lymph nodes. The lymph nodes adjacent to the LRLN could then be dissected completely without any damage to the nerve. RESULTS: In all surgeries, the LRLN and adjacent lymph nodes were well visualized, and the number of trocars used to pass endoscopic instruments for retraction of the proximal esophagus or the number of thoracic punctures for external traction of the esophagus during the surgery were reduced. CONCLUSIONS: In thoracoscopic-assisted esophagectomy, the magnetic anchoring and traction technique can improve the exposure of the LRLN, facilitate LRLN lymphadenectomy, and reduce chest wall trauma.

Mechanics-driven nuclear localization of YAP can be reversed by N-cadherin ligation in mesenchymal stem cells.

Mesenchymal stem cells adopt differentiation pathways based upon cumulative effects of mechanosensing. A cell's mechanical microenvironment changes substantially over the course of development, beginning from the early stages in which cells are typically surrounded by other cells and continuing through later stages in which cells are typically surrounded by extracellular matrix. How cells erase the memory of some of these mechanical microenvironments while locking in memory of others is unknown. Here, we develop a material and culture system for modifying and measuring the degree to which cells retain cumulative effects of mechanosensing. Using this system, we discover that effects of the RGD adhesive motif of fibronectin (representative of extracellular matrix), known to impart what is often termed "mechanical memory" in mesenchymal stem cells via nuclear YAP localization, are erased by the HAVDI adhesive motif of the N-cadherin (representative of cell-cell contacts). These effects can be explained by a motor clutch model that relates cellular traction force, nuclear deformation, and resulting nuclear YAP re-localization. Results demonstrate that controlled storage and removal of proteins associated with mechanical memory in mesenchymal stem cells is possible through defined and programmable material systems.

Plasma asprosin, CCDC80 and ANGPTL4 levels are associated with metabolic and cardiovascular risk in patients with inflammatory bowel disease.

Asprosin, coiled-coil domain-containing 80(CCDC80) and angiopoietin-like4(ANGPTL4) are newly discovered adipocytokine that affects glucose tolerance, insulin resistance and cardiovascular diseases. The goal of this study was to investigate if a relationship exists among asprosin, CCDC80 and ANGPTL4 and inflammatory bowel disease (IBD). Fifty subjects with newly diagnosed IBD and fifty healthy individuals were enrolled. Patients were treated with standard therapies for 3 months. Plasma asprosin, CCDC80 and ANGPTL4 levels were measured with enzyme-linked immunosorbent assay. High resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia (flow-mediated dilation, FMD) and after sublingual glyceryltrinitrate.Compare with healthy individuals, plasma CCDC80,erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and homeostasis modelassessment of insulin resistance (HOMA-IR) were significantly higher (p < 0.05, respectively), whereas plasma asprosin,ANGPTL4 levels and FMD were significantly lower inboth UC and CD patients(p <0.05). Plasma CCDC80 levels were significantly higher in patients with CD (p<0.05), while plasma asprosin and ANGPTL4 levels were lower (p<0.05) as compared with those in patients with UC. Standard therapies increased plasma asprosin, ANGPTL4 levels and FMD in both UC and CD (p<0.05),UC and CD patientswhile decreased plasma CCDC80, ESR, CRP levels and HOMA-IR (p<0.05). The changes in HOMA-IR and FMD were correlated with the changes in plasma asprosin, CCDC80 and ANGPTL4 levels over the study period (p<0.05). Plasma asprosin, CCDC80 and ANGPTL4 levels may be applied as a significant marker for early stage of insulin resistance and atherosclerosis in IBD, especially of CD.

Prevalence and impact of comorbid obstructive sleep apnoea in diffuse parenchymal lung diseases.

OBJECTIVE: Obstructive sleep apnea (OSA) are increasingly recognized as important features in diffuse parenchymal lung diseases (DPLDs) with differed prevalence and impact reported. The aim of this study is to systematically review the prevalence of comorbid OSA and characterize its impact on clinical and outcome measurements in adults with DPLDs. METHODS: Publications addressing the prevalence of OSA in DPLDs and its impacts on DPLDs were selected from electronic databases. A random-effect model was used to estimate the pooled prevalence of OSA. Odds ratios (ORs) or mean differences (MDs) were used to assess the associations of OSA with clinical and outcome measurements. Heterogeneity was quantified by I2 with 95% confidence interval (95% CI). RESULTS: 4 studies comprising 643 participants were included. Overall, the pooled prevalence of OSA among DPLDs was 72% (95% CI: 65-79%; I2 = 75.4%). Moderate-severe OSA was observed in 40% patients (95% CI: 28-52%; I2 = 90.8%). The prevalence was higher as 76% in idiopathic pulmonary fibrosis (IPF) patients than in connective tissue associated-ILD or sarcoidosis (60%). Although oxygen desaturation during sleep was greater in OSA group compared with non-OSA patients, there was no difference in lung function or systematic comorbidities between the two groups. The associations between OSA and the mortality or disease progression of DPLDs were also systematically reviewed. CONCLUSION: In conclusion, OSA is a common comorbidity in DPLD patients, affecting approximately three in four patients, which may exacerbate the nocturnal desaturation and have negative influence on the outcomes. Larger studies with more homogeneous samples are warranted.

Application of a novel magnetic anchoring and traction technique in thoracoscopic esophagectomy: a swine experiment.

BACKGROUND: Effective traction and dissection of the esophagus are key steps during thoracoscopic esophagectomy. In traditional methods, a separate trocar for the traction instruments or thoracic punctures are adopted to externally retract the esophageal loop. However, both methods bring about chest wall damage that is associated with increased morbidity and mortality. The magnetic anchoring and traction system can not only achieve exposure and pulling multi-directional flexible but also reduce the number of transthoracic ports and trocars used, and then avoid the chopstick effect in surgery. We aimed to verify the feasibility and safety of a self-designed magnetic anchoring and traction system in assisted thoracoscopic esophagectomy. METHODS: Ten healthy pigs were used as the experimental objects. A magnetic anchoring and traction system composed of an external unit and internal unit was designed, then the requirements and stress characteristics of esophageal pulling and exposure during thoracoscopic esophagectomy were analyzed. The internal unit was introduced through the 5th intercostal space port and was secured to the right wall of the esophagus, the external unit was placed on the surface of the chest wall to allow pairing with the internal unit. The external unit was moved on the chest wall to help exposing operative field. RESULTS: Ten pigs underwent a 3-port thoracoscopic esophagectomy using a magnetic anchoring and traction technique, and all operations were successful. The system provided adequate traction force to pull the esophagus. The external unit could move freely outside the chest wall, enabling suitable positioning of the esophagus for dissection. CONCLUSIONS: The novel magnetic anchoring and traction system in thoracoscopic esophagectomy is safe and feasible, and has the potential for clinical application.

Subcutaneous injection of IFN alpha-2b for COVID-19: an observational study.

BACKGROUND: The global pandemic of coronavirus disease 2019 (COVID-19) infection is ongoing and associated with high mortality. The aim of this study was to investigate the efficacy and safety of subcutaneous injection of interferon alpha-2b (IFN alpha-2b) combined with lopinavir/ritonavir (LPV/r) in the treatment of COVID-19 infection, compared with that of using LPV/r alone. METHODS: Patients diagnosed with laboratory-confirmed COVID-19 infection in Wuhan Red Cross hospital during the period from January 23, 2020 to March 19, 2020 were included. The length of stay, the time to viral clearance and adverse reactions during hospitalization were compared between patients using oral LPV/r and combined therapy of LPV/r and subcutaneous injection of IFN alpha-2b. RESULTS: A total of 22 patients were treated with LPV/r alone and 19 with combined therapy with subcutaneous injection of IFN alpha-2b. The average length of hospitalization in the combination group was shorter than that of LPV/r group (16 ± 9.7 vs 23 ± 10.5 days; P = 0.028). Moreover, the days of hospitalization in early intervention group decreased from 25 ± 8.5 days to 10 ± 2.9 days compared with delayed intervention group (P = 0.001). Combined therapy with IFN alpha-2b also significantly reduced the duration of detectable virus in the upper respiratory tract. No patient in each group was transferred to intensive care unit (ICU) or died during the treatment. There was no significant difference in the adverse effect composition between two groups. CONCLUSIONS: Subcutaneous injection of IFN alpha-2b combined with LPV/r shortened the length of hospitalization and accelerated viral clearance in COVID-19 patients, which deserves further investigation in clinical practice.

Correlation in gene expression between the aggravation of chronic obstructive pulmonary disease and the occurrence of complications.

Aggravation of the chronic obstructive pulmonary disease (COPD) often leads to a slew of complications, but the correlation between COPD aggravation and the complications on the basis of molecular level remains unclear. In this study, gene expression profiles of COPD in patients at early and aggravation stages were collected and differentially-expressed genes were selected. Meanwhile, gene expression data implicated in COPD complications were analyzed to establish a regulatory network of COPD aggravation and COPD related complications. In addition, the gene enrichment function of DAVID6.7 was utilized to evaluate the similarities between COPD aggravation and COPD complications in term of biological process. By analyzing the genes of COPD aggravation and the COPD complications, we found 18 genes highly related to COPD aggravation, among which haptoglobin (HP) was correlated with 14 complications, followed by ADRB2, LCK and CA1, which were related to 13, 11 and 11 complications, respectively. As far as the complications concerned, obesity was regulated by 17 of the 18 genes, which indicated that there was a close correlation between COPD aggravation and obesity. Meanwhile, lung cancer, diabetes and heart failure were regulated by 15, 15 and 14 genes, respectively, among the 18 selected genes. This study suggested the driver genes of COPD aggravation were capable of extensively regulating COPD complications, which would provide a theoretical basis for development of cures for COPD and its complications.

Fast and Effective Nonsuture Anastomosis of Magnetic Artificial Blood Vessel Transplantation for Caval Reconstruction in Canines.

BACKGROUND: The resection and reconstruction of the vena cava is frequently needed in tumor resection. The goal of this study was to evaluate the performance of the magnetic compression anastomosis (MCA) device for fast nonsuture anastomosis of caval reconstruction with artificial blood vessel transplantation after resection in canines. METHODS: The MCA device consisted of paired neodymium-ferrum-boron (Nd-Fe-B) magnetic rings that were coated with titanium nitride and embedded in a polypropylene shell. Artificial blood vessel transplantation procedure was performed in sixteen canines and then they were divided into 2 groups: MCA group (n = 8), in which the novel magnetic pinned-ring device was used, and the traditional manual suture group (n = 8). In situ artificial blood vessel anastomoses were performed in the inferior vena cava (IVC). The anastomosis time and anastomotic patency and quality were investigated through ultrasonographic scans, angiographic, gross observation, histological staining, and scanning electron microscopy at 24 weeks postoperatively. RESULTS: The IVC anastomoses were reconstructed successfully in all canines and all animals survived. In the MCA group, the operation time for IVC anastomosis with artificial blood vessel was significantly shorter than that in the tradition manual suture group (P < 0.05). Vena cava angiography and ultrasound showed good blood patency. The scanning electron microscope showed the re-endothelialization was smooth and endothelial cells were arranged regularly at the anastomotic site. Histological examination confirmed that the MCA group was associated with infiltration of inflammatory cells compared with the manual suture group. CONCLUSIONS: The MCA device combined with artificial blood vessels is applicable in reconstruction of large vessels after resection. The magnetic pinned-ring device offers a simple, fast, reliable, and effective technique for nonsuture artificial blood vessel anastomosis of caval reconstruction in canines, and the anastomosis is functionally better than the traditional sutured anastomosis.

miR-146a regulates inflammation and development in patients with abdominal aortic aneurysms by targeting CARD10.

BACKGROUND: We present the expression of miR-146a in abdominal aortic aneurysms (AAA) patients, and its mechanism for regulating inflammation and development in AAA patients. METHODS: The expression of miR-146a in serum, PBMC, and abdominal aorta tissues was measured in AAA patients. RESULTS: We found that level of miR-146a in the serum and its expression in AAA tissues were significantly higher than that in healthy people or normal abdominal aorta tissues. Pearson's method analysis showed that miRNA-146a in the serum of AAA patients was negatively correlated with serum TNF-α, IFN-γ and CRP, and was positively correlated with serum IL-10. The luciferase reporter gene system confirmed that miR-146a targeted inhibition of CARD10 expression in THP-1 and human umbilical vein endothelial cells (HUVECs), and miR-146a was negatively correlated with the expression of CARD10 in the tissues/PBMC of AAA patients. In PBMC of healthy people, over-expression of miR-146a by transferring miR-146a-mimic could increase the expression of SIRT1 but decreased the expression of p65 and the level of TNF-α secretion. Moreover, HUVECs cellular activity change by TNF-α in a dose-dependent manner. CONCLUSIONS: These results suggested that miR-146a suppressed the inflammation of peripheral blood in AAA patients by targeting CARD10, and miR-146a blocked the progression of AAA through CARD10/SIRT1/p65 pathway.

Immune cell concentrations among the primary tumor microenvironment in colorectal cancer patients predicted by clinicopathologic characteristics and blood indexes.

BACKGROUND: Immune cells play a key role in cancer progression and treatment. It is unclear whether the clinicopathologic characteristics and blood indexes of colorectal cancer (CRC) patients could predict immune cell concentrations in the tumor microenvironment. METHODS: CRC patients with detailed data and tumor tissue who visited Sun Yat-sen University Cancer Center between April 1, 2004, and September 1, 2017, were enrolled. The densities of CD3+ and CD8+ T cells examined by immunohistochemistry in both the core of the tumor (CT) and the invasive margin (IM) were summed as the Immunoscore. The relationships between the Immunoscore and clinicopathologic characteristics and blood indexes, including tumor biomarkers (carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9)), inflammatory markers (lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin (ALB), neutrophils, lymphocytes, monocytes, platelets, NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and LMR (lymphocyte-to-monocyte ratio)) and lipid metabolism markers (cholesterol (CHO), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB)), were analyzed using SPSS. RESULTS: Older patients had lower CD3+ and CD8+ T cell expression in the IM and a lower Immunoscore than did younger patients. CD8+ T cell expression in the IM and the Immunoscore were lower in right-side tumors than in left-sided tumors. High CD8+ T cell expression in the CT was found in the T4 stage group. The higher the CEA level in the blood, the fewer CD8+ T cells were in the CT. Either fewer monocytes or a higher LMR in the blood, the larger number of CD3+ T cells in the CT. The more ApoA1 was in the blood, the more CD3+ T cells were in both the CT and the IM. CONCLUSION: Age, T stage, tumor location, CEA, monocytes, LMR and ApoA1 could reflect immune cells infiltrating the tumor microenvironment of CRC.

Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data.

BACKGROUND: Colorectal cancer (CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC (ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic. AIM: To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS. METHODS: ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005, to October 1, 2015, were studied. Expression of autophagy-related proteins [Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed. RESULTS: In CACO-2 cells exposed to cetuximab, LC3 and 4E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients, immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3 (0.657, P < 0.001) and 4E-BP1 (0.211, P = 0.042) in ACRC tissues. LC3 was significantly overexpressed in tumor tissues compared to normal tissues (P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1 (P = 0.010) and 4E-BP1 (P = 0.005), pathological grade (P = 0.002), and T stage (P = 0.004) were independent prognostic factors for overall survival (OS). CONCLUSION: The effect of cetuximab on colon cancer cells might be improved by autophagy. LC3 is overexpressed in tumor tissues, and Beclin1 and 4E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.