CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway.

Evidence from clinical trials suggests that CXCR4 antagonists enhance immunotherapy effectiveness in several cancers. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. Here, we employed single-cell transcriptomic analysis and identified CXCR4 as a marker gene in T cells, with CD8+PD-1high exhausted T (Tex) cells exhibiting high CXCR4 expression. By blocking CXCR4, the Tex phenotype was attenuated in vivo. Mechanistically, CXCR4-blocking T cells mitigated the Tex phenotype by regulating the JAK2-STAT3 pathway. Single-cell RNA/TCR/ATAC-seq confirmed that Cxcr4-deficient CD8+ T cells epigenetically mitigated the transition from functional to exhausted phenotypes. Notably, clinical sample analysis revealed that CXCR4+CD8+ T cells showed higher expression in patients with a non-complete pathological response. Collectively, these findings demonstrate the mechanism by which CXCR4 orchestrates CD8+ Tex cells and provide a rationale for combining CXCR4 antagonists with immunotherapy in clinical trials.

Erratum: Nuclear Charge Radii of Silicon Isotopes [Phys. Rev. Lett. 132, 162502 (2024)].

This corrects the article DOI: 10.1103/PhysRevLett.132.162502.

Spatial multi-omics: deciphering technological landscape of integration of multi-omics and its applications.

The emergence of spatial multi-omics has helped address the limitations of single-cell sequencing, which often leads to the loss of spatial context among cell populations. Integrated analysis of the genome, transcriptome, proteome, metabolome, and epigenome has enhanced our understanding of cell biology and the molecular basis of human diseases. Moreover, this approach offers profound insights into the interactions between intracellular and intercellular molecular mechanisms involved in the development, physiology, and pathogenesis of human diseases. In this comprehensive review, we examine current advancements in multi-omics technologies, focusing on their evolution and refinement over the past decade, including improvements in throughput and resolution, modality integration, and accuracy. We also discuss the pivotal contributions of spatial multi-omics in revealing spatial heterogeneity, constructing detailed spatial atlases, deciphering spatial crosstalk in tumor immunology, and advancing translational research and cancer therapy through precise spatial mapping.

[Oblique Lumbar Interbody Fusion Combined With 4-Screw Fixation for Treating Two-Level Degenerative Lumbar Diseases:A Finite Element Study].

Objective To demonstrate the feasibility of oblique lumbar interbody fusion (OLIF) combined with 4-screw fixation for treating two-level lumbar degenerative diseases.Methods An intact finite element model of L3-S1 (M0) was constructed and validated.Then,we constructed the M1 model by simulating OLIF surgery at L3/4 and L4/5 segments on the M0 model.By attachment of posterior 4-screw or 6-screw fixation to the M1 model,three 4-screw fixation models (M2-M4) and one 6-screw fixation model (M5) were established.The segmental and overall range of motion (ROM) and the peak von Mises stresses of superior endplate,cage,and posterior screw-rod were investigated under each implanted condition.Results Under the motion modes of forward flexion,backward extension,bilateral (left and right) flexion,and left and right rotation,the L3/4 ROM of M2 model and L4/5 ROM of M3 model increased,while the L3/4 and L4/5 ROM of M4 and M5 models significantly decreased compared with those of M1 model.Under all motion modes,the L4 superior endplate in M2 model and the L5 superior endplate in M3 model showed the maximum peak von Mises stress,and the peak von Mises stresses of L4 and L5 superior endplates in M4 and M5 models were close.The L3/4 cage in M2 model and the L4/5 cage in M3 model showcased the largest peak von Mises stress,and the peak von Mises stresses of cages in M4 and M5 models were close.The peak stresses of internal fixation in M2-M5 models were close.Conclusion Four-screw fixation can replace 6-screw fixation in the OLIF surgery for treating two-level degenerative lumbar diseases.

Nuclear Charge Radii of Silicon Isotopes.

The nuclear charge radius of ^{32}Si was determined using collinear laser spectroscopy. The experimental result was confronted with ab initio nuclear lattice effective field theory, valence-space in-medium similarity renormalization group, and mean field calculations, highlighting important achievements and challenges of modern many-body methods. The charge radius of ^{32}Si completes the radii of the mirror pair ^{32}Ar-^{32}Si, whose difference was correlated to the slope L of the symmetry energy in the nuclear equation of state. Our result suggests L≤60 MeV, which agrees with complementary observables.

Mesenchymal stem cells for repairing glaucomatous optic nerve.

Glaucoma is a common and complex neurodegenerative disease characterized by progressive loss of retinal ganglion cells (RGCs) and axons. Currently, there is no effective method to address the cause of RGCs degeneration. However, studies on neuroprotective strategies for optic neuropathy have increased in recent years. Cell replacement and neuroprotection are major strategies for treating glaucoma and optic neuropathy. Regenerative medicine research into the repair of optic nerve damage using stem cells has received considerable attention. Stem cells possess the potential for multidirectional differentiation abilities and are capable of producing RGC-friendly microenvironments through paracrine effects. This article reviews a thorough researches of recent advances and approaches in stem cell repair of optic nerve injury, raising the controversies and unresolved issues surrounding the future of stem cells.

Immune landscape and heterogeneity of cervical squamous cell carcinoma and adenocarcinoma.

Despite the differences in disease outcomes and pathological features between cervical squamous cell carcinoma (CSCC) and adenocarcinoma (ADC), the molecular characteristics in immune heterogeneity of the tumor microenvironment remain unclear. Here, we explored the immune landscape and heterogeneity between CSCC and ADC. Gene expression and clinical characteristics of cervical carcinoma from The Cancer Genome Atlas (TCGA) were downloaded. Differentially expressed genes (DEGs), immune cell infiltration, and pathway enrichment analyses were used to explore the immune landscape and heterogeneity between CSCC and ADC. Furthermore, distinct immune signatures between CSCC and ADC were validated based on clinical samples. In total, 4,132 upregulated DEGs and 2,307 down-regulated DEGs were identified between CSCC and ADC, with enrichments in immune related-pathways in CSCC. In addition, 54 hub DEGs correlated with patients' prognosis and immunocytes infiltration were identified. The CSCC patients had a higher ImmuneScore and more abundant immunocytes infiltration compared to ADC patients, as validated by immunohistochemistry (IHC) and multicolor immunofluorescence (mIF) analyses of collected samples. Furthermore, CSCC displayed higher inhibitory immune checkpoints expression, tumor mutation burden (TMB), and microsatellite instability (MSI) compared to ADC, which indicated CSCC patients were more likely to benefit from immunotherapy. In summary, our results revealed the huge immune heterogeneity between CSCC and ADC, and provided guidance for immunotherapy selection for different pathological types of cervical cancer.

A Promising New Model: Establishment of Patient-Derived Organoid Models Covering HPV-Related Cervical Pre-Cancerous Lesions and Their Cancers.

The lack of human-derived in vitro models that recapitulate cervical pre-cancerous lesions has been the bottleneck in researching human papillomavirus (HPV) infection-associated pre-cancerous lesions and cancers for a long time. Here, a long-term 3D organoid culture protocol for high-grade squamous intraepithelial lesions and cervical squamous cell carcinoma that stably recapitulates the two tissues of origin is described. Originating from human-derived samples, a small biobank of cervical pre-tumoroids and tumoroids that faithfully retains genomic and transcriptomic characteristics as well as the causative HPV genome is established. Cervical pre-tumoroids and tumoroids show differential responses to common chemotherapeutic agents and grow differently as xenografts in mice. By coculture organoid models with peripheral blood immune cells (PBMCs) stimulated by HPV antigenic peptides, it is illustrated that both organoid models respond differently to immunized PBMCs, supporting organoids as reliable and powerful tools for studying virus-specific T-cell responses and screening therapeutic HPV vaccines. In this study, a model of cervical pre-cancerous lesions containing HPV is established for the first time, overcoming the bottleneck of the current model of human cervical pre-cancerous lesions. This study establishes an experimental platform and biobanks for in vitro mechanistic research, therapeutic vaccine screening, and personalized treatment for HPV-related cervical diseases.

Efficacy of Multi-slice Spiral CT and Rapid On-site Evaluation in Diagnosis of Pulmonary Nodules.

Objective: This study aims to explore the efficacy of multi-slice spiral computed tomography (MSCT) and rapid on-site evaluation (ROSE) in diagnosing pulmonary nodules, thereby providing more diagnostic information for clinical diagnosis, and improving the diagnostic efficiency of pulmonary nodules. Methods: With the means of a retrospective study, 103 patients with pulmonary nodules in our hospital from January 2019 to December 2021 were analyzed. The included patients had no history of lung surgery, and had no cognitive, audio-visual, language communication and physical activity disorders, with visual lesions in bronchoscopy. All patients underwent MSCT scans and ROSE. In the process of cell puncture or tissue biopsy, cell fluid smears or tissue prints were directly used to make cytological specimens. In the operation site, real-time production, staining and real-time cell analysis were carried out to determine whether the material was qualified. The diagnostic efficacy of MSCT, ROSE, and the combination of the two for pulmonary nodules was analyzed. Results: Of the 103 patients, there were finally 68 cases diagnosed with solitary nodules (66.02%) and 35 cases with multiple nodules (33.98%), with 196 pulmonary nodules in total; 25 of them were peripheral lung cancer (24.27%) and 78 were benign nodules (75.73%); and based on the results of clinical diagnosis, they were divided into the malignant group and the benign group separately. Diagnosis of MSCT showed that the probabilities of calcification, spicular sign, lobulation sign, vacuolar sign, and spinous process in the malignant group were significantly higher than those in the benign group (P = .000). 30 positive cases and 73 negative cases were detected by MSCT, including 13 false positives and 8 false negatives. ROSE detected 29 positive cases and 74 negative cases, of which 5 positives were diagnosed as negatives, and the 9 negatives were diagnosed as positives. There were 28 positive cases and 75 negative cases detected by the combination of MSCT and ROSE, including 5 false positives and 2 false negatives. The combined diagnosis of MSCT and ROSE demonstrated an accuracy of 93.20%, sensitivity of 92.00%, specificity of 93.59%, positive predictive value of 82.14%, and negative predictive value of 97.33%. The accuracy, sensitivity, specificity, positive and negative predictive values of MSCT diagnosis were 79.61%, 68.00%, 83.33%, 56.67% and 89.04%, respectively. In ROSE diagnosis, the accuracy, sensitivity, specificity, positive and negative predictive values were 86.41%, 80.00%, 88.46%, 68.97% and 93.24%. The combined diagnosis of MSCT and ROSE had a significantly higher diagnosis rate than the single diagnosis of MSCT and ROSE (P = .000). Through ROC analysis, the area under the curve (AUC) of combined diagnosis was overtly larger than that of single diagnosis of MSCT and ROSE (P = .000). The AUC of MSCT diagnosis and ROSE diagnosis were 0.757 (95%CI: 0.639-0.875) and 0.842 (95%CI: 0.742-0.943) respectively, and the AUC of the combined diagnosis of MSCT and ROSE was 0.928 (95%CI: 0.859-0.997). Conclusion: The combination of MSCT and ROSE contributes to the advances in the diagnostic efficacy for pulmonary nodules in order to reduce the damage caused by ineffective biopsy, which is of great clinically instructional value to the early diagnosis of this disease. This method is convenient to provide reasonable reference materials for the formulation of scientific clinical treatment plan and accurate judgment of prognosis, thereby promoting the good prognosis of patients.

[Unilateral interlaminar approach 270° circular spinal canal decompression under the iLESSYS Delta for the treatment of lumbar spinal stenosis in the elderly].

OBJECTIVE: To investigate the clinical effect of unilateral interlaminar approach 270° circular spinal canal decompression under the Interlaminar Endoscopic Surgical System(iLESSYS) Delta for the treatment of lumbar spinal stenosis (LSS) in the elderly. METHODS: Total of 29 patients with LSS treated with the iLESSYS Delta from December 2018 to January 2021 were retrospectively analyzed, including 12 males and 17 females with an average age of (71.52±10.82) years old ranging from 63 to 83 years old. All patients had definite intermittent claudication, mainly neurogenic symptoms of both lower limbs. All patients had single-level spinal stenosis, including L3,4 5 cases, L4,5 21 cases, and L5S1 3 cases. Visual analogue scale (VAS), Oswestry Disability Index (ODI) and modified Macnab assessment criteria were used to evaluate pain, low back pain dysfunction index and clinical efficacy, respectively. RESULTS: All 29 cases were successfully completed. The operation time was (73.45±5.89) min, the intraoperative blood loss was (9.93±0.83) ml, the hospital stay was (4.03±0.41) days, and the follow-up was more than 12 months. The VAS scores of low back pain before surgery and 1 day, 1 month, 3 months, 1 year after surgery were 2.31±0.88, 1.45±0.62, 1.21±0.61, 1.10±0.55, 1.03±0.49;VAS of leg pain were 6.48±0.49 0.56, 1.97±0.61, 1.31±0.59, 1.17±0.59, 1.10±0.55;ODI scores were 38.41±2.74, 18.14±1.17, 5.17±0.53, 5.07±0.45, 4.90±0.48;low back and leg pain VAS score and ODI score have statistically significant differences between preoperative and postoperative follow-up time points (P<0.05). The MacNab efficacy evaluation at 1-year follow-up:excellent in 22 cases, good in 5 cases and fair in 2 cases. CONCLUSION: The clinical effect of unilateral interlaminar approach 270° circular spinal canal decompression under the iLESSYS Delta for the treatment of lumbar spinal stenosis in the elderly is satisfactory, with the advantages of less trauma and less bleeding, large microscopic operation space, sufficient decompression, and ideal post-operative recovery, and at the same time, it can minimize the damage to the stable structure of the lumbar spine, which is an ideal surgical method for the treatment of elderly lumbar spinal stenosis.

Single-nucleus RNA sequencing reveals heterogenous microenvironments and specific drug response between cervical squamous cell carcinoma and adenocarcinoma.

BACKGROUND: Cervical squamous cell carcinoma (CSCC) and adenocarcinoma (CAde) are two major pathological types of cervical cancer (CC), but their high-resolution heterogeneity of tumor and immune microenvironment remains elusive. METHODS: Here, we performed single-nucleus RNA sequencing (snRNA-seq) from five CSCC and three CAde samples, and systematically outlined their specific transcriptome atlas. FINDINGS: We found CD8+ T cells in CSCC were more cytotoxic but lower exhausted compared to those in CAde, and phagocytic MRC1+ macrophages were specifically enriched in CSCC. Interestingly, we discovered that pro-tumoral cancer-associated myofibroblasts (myoCAFs) and cancer-associated vascular-fibroblasts (vCAFs) were more abundant in CSCC, and further verified their pro-metastatic roles in vitro. Furthermore, we also identified some specific chemotherapy drugs for CSCC (Dasatinib and Doramapimod) and CAde (Pyrimethamine and Lapatinib) by revealing their heterogeneity in transcriptomic profiles of malignant epithelial cells, and further verified their specific sensitivity in cell lines and constructed CC-derived organoids. Cell-cell communication networks revealed that the pathways of NRG1-ERBB2, and FN1-ITAG3 were specific for CAde and CSCC, respectively, which may partly explain the specificities of identified chemotherapy drugs. INTERPRETATION: Our study described the immune heterogeneity and specific cellular interactions between CSCC and CAde, which could provide insights for uncovering pathogenesis and designing personalized treatment. FUNDINGS: National Key R&D Program of China (2021YFC2701201), National Natural Science Foundation of China (82072895, 82141106, 82103134, 81903114).

Surgical approach for complete resection of giant retroperitoneal liposarcoma with diaphragmatic hernia via ninth rib thoracotomy.

Background: Resection of a giant retroperitoneal liposarcoma is difficult and technically demanding, especially for large retroperitoneal tumors accompanied by a diaphragmatic hernia. Technically, the open abdominal approach can be time-consuming and difficult to perform, with possible intraoperative complications and other factors bringing psychological and physical difficulties to the patient. This study reports a safe and feasible approach for the complete resection of a large retroperitoneal tumor complicated by a diaphragmatic hernia. Methods: A 58-year-old male patient with persistent upper abdominal pain and distension was treated at a local hospital on 4 July 2022. Computed tomography showed a mixed-density mass on the right retroperitoneum, and liposarcoma was considered. On 6 July 2022, the patient was transferred to our hospital for further treatment. Computed tomography showed a mass with low-density fatty shadow in the right adrenal region. The boundary with the right adrenal gland was unclear. The mass was 102 mm × 74 mm, and the right lobe of the liver was compressed. Insufficiency of the right middle lobe of the liver was seen due to a right diaphragmatic hernia and left mediastinal deviation. We considered the traditional approach for tumor resection via laparotomy, but we opted to perform a comprehensive evaluation first. The tumor was close to the back of the right kidney and liver, causing the diaphragm to rise because of its proximity to these organs. Exposing the tumor through laparotomy would be difficult, making it challenging to remove. The patient had a diaphragmatic hernia and moderate pulmonary dysfunction; therefore, we decided to enter the abdomen through a thoracotomy of the ninth rib. Results: Using our technique, the tumor was easily visualized and completely removed in approximately 30 min. The intraoperative blood loss was 100 ml, and no postoperative bleeding, pneumothorax, intestinal fistula, infection, or other complications occurred. Conclusion: The transthoracic approach may be a safer and more feasible resection method than the traditional open approach for patients with giant retroperitoneal liposarcoma with a diaphragmatic hernia.

Immunodiagnosis - the promise of personalized immunotherapy.

Immunotherapy showed remarkable efficacy in several cancer types. However, the majority of patients do not benefit from immunotherapy. Evaluating tumor heterogeneity and immune status before treatment is key to identifying patients that are more likely to respond to immunotherapy. Demographic characteristics (such as sex, age, and race), immune status, and specific biomarkers all contribute to response to immunotherapy. A comprehensive immunodiagnostic model integrating all these three dimensions by artificial intelligence would provide valuable information for predicting treatment response. Here, we coined the term "immunodiagnosis" to describe the blueprint of the immunodiagnostic model. We illustrated the features that should be included in immunodiagnostic model and the strategy of constructing the immunodiagnostic model. Lastly, we discussed the incorporation of this immunodiagnosis model in clinical practice in hopes of improving the prognosis of tumor immunotherapy.

Olfactory ensheathing cells and neuropathic pain.

Damage to the nervous system can lead to functional impairment, including sensory and motor functions. Importantly, neuropathic pain (NPP) can be induced after nerve injury, which seriously affects the quality of life of patients. Therefore, the repair of nerve damage and the treatment of pain are particularly important. However, the current treatment of NPP is very weak, which promotes researchers to find new methods and directions for treatment. Recently, cell transplantation technology has received great attention and has become a hot spot for the treatment of nerve injury and pain. Olfactory ensheathing cells (OECs) are a kind of glial cells with the characteristics of lifelong survival in the nervous system and continuous division and renewal. They also secrete a variety of neurotrophic factors, bridge the fibers at both ends of the injured nerve, change the local injury microenvironment, and promote axon regeneration and other biological functions. Different studies have revealed that the transplantation of OECs can repair damaged nerves and exert analgesic effect. Some progress has been made in the effect of OECs transplantation in inhibiting NPP. Therefore, in this paper, we provided a comprehensive overview of the biology of OECs, described the possible pathogenesis of NPP. Moreover, we discussed on the therapeutic effect of OECs transplantation on central nervous system injury and NPP, and prospected some possible problems of OECs transplantation as pain treatment. To provide some valuable information for the treatment of pain by OECs transplantation in the future.

Prospects for fertility preservation: the ovarian organ function reconstruction techniques for oogenesis, growth and maturation in vitro.

Today, fertility preservation is receiving more attention than ever. Cryopreservation, which preserves ovarian tissue to preserve fertility in young women and reduce the risk of infertility, is currently the most widely practiced. Transplantation, however, is less feasible for women with blood-borne leukemia or cancers with a high risk of ovarian metastasis because of the risk of cancer recurrence. In addition to cryopreservation and re-implantation of embryos, in vitro ovarian organ reconstruction techniques have been considered as an alternative strategy for fertility preservation. In vitro culture of oocytes in vitro Culture, female germ cells induction from pluripotent stem cells (PSC) in vitro, artificial ovary construction, and ovaria-related organoids construction have provided new solutions for fertility preservation, which will therefore maximize the potential for all patients undergoing fertility preservation. In this review, we discussed and thought about the latest ovarian organ function reconstruction techniques in vitro to provide new ideas for future ovarian disease research and fertility preservation of patients with cancer and premature ovarian failure.

Prognostic significance of the preoperative hemoglobin to albumin ratio for the short-term survival of gastric cancer patients.

BACKGROUND: Hemoglobin and albumin are associated with the prognosis of gastric cancer (GC) patients. However, the prognostic value of the hemoglobin to albumin ratio (HAR) for the short-term survival of GC patients with D2 radical resection has not been studied. AIM: To investigate the significance of the HAR in evaluating the short-term survival of GC patients after D2 radical resection and to construct a nomogram to predict the prognosis in GC patients after surgery, thus providing a reference for the development of postoperative individualized treatment and follow-up plans. METHODS: Cox regression and Kaplan-Meier analysis was used for prognostic analysis. Logistic regression was used to analyze the relationships between HAR and the clinicopathological characteristics of the GC patients. A prognostic nomogram model for the short-term survival of GC patients was constructed by R software. RESULTS: HAR was an independent risk factor for the short-term survival of GC patients. GC patients with a low HAR had a poor prognosis (P < 0.001). Low HAR was markedly related to high stage [odds ratio (OR) = 0.45 for II vs I; OR = 0.48 for III vs I], T classification (OR = 0.52 for T4 vs T1) and large tumor size (OR = 0.51 for ≥ 4 cm vs < 4 cm) (all P < 0.05). The nomogram model was based on HAR, age, CA19-9, CA125 and stage, and the C-index was 0.820. CONCLUSION: Preoperative low HAR was associated with short-term survival in GC patients. The prognostic nomogram model can accurately predict the short-term survival of GC patients with D2 radical resection.

Immunopathogenesis of patients with COVID-19: from the perspective of immune system 'evolution' and 'revolution'.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 is sweeping the world, threatening millions of lives and drastically altering our ways of living. According to current studies, failure to either activate or eliminate inflammatory responses timely and properly at certain stages could result in the progression of the disease. In other words, robust immune responses to coronavirus disease 2019 (COVID-19) are critical. However, they do not theoretically present in some special groups of people, including the young, the aged, patients with autoimmunity or cancer. Differences also do occur between men and women. Our immune system evolves to ensure delicate coordination at different stages of life. The innate immune cells mainly consisted of myeloid lineage cells, including neutrophils, basophils, eosinophils, dendritic cells and mast cells; they possess phagocytic capacity to different degrees at different stages of life. They are firstly recruited upon infection and may activate the adaptive immunity when needed. The adaptive immune cells, on the other way, are comprised mainly of lymphoid lineages. As one grows up, the adaptive immunity matures and expands its memory repertoire, accompanied by an adjustment in quantity and quality. In this review, we would summarise and analyse the immunological characteristics of these groups from the perspective of the immune system 'evolution' as well as 'revolution' that has been studied and speculated so far, which would aid the comprehensive understanding of COVID-19 and personalised-treatment strategy.

Implication of IGF1R signaling in the protective effect of Astragaloside IV on ischemia and reperfusion-induced cardiac microvascular endothelial hyperpermeability.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) causes damage to coronary capillary endothelial barrier and microvascular leakage (MVL), aggravating tissue injury and heart dysfunction. However, the effective strategy for protecting endothelium barrier of cardiac vasculature remains limited. PURPOSE: This study aimed to explore the effect of Astragaloside IV (ASIV) on coronary MVL after cardiac I/R and the underlying mechanism. STUDY DESIGN: Sprague-Dawley (SD) rats were used for assessment of the efficacy of Astragaloside IV in protection of myocardial I/R injury, while human cardiac microvascular endothelial cells were applied to gain more insight into the underlying mechanism. METHODS: Sprague-Dawley rats with or without pretreatment by ASIV at 10 mg/kg were subjected to occlusion of left coronary anterior descending artery followed by reperfusion. Endothelial cells were exposed to hypoxia and re-oxygenation (H/R). The distribution of junction proteins was detected by immunofluorescence staining and confocal microscope, the content of junction proteins was detected by Western blot, the level of adenosine triphosphate (ATP) was detected by ELISA, and the signal pathway related to permeability was detected by siRNA infection. The fluorescence intensity of FITC-albumin and FITC-Dextran was measured to evaluate the permeability of endothelial cells. RESULTS: ASIV exhibited protective effects on capillary damage, myocardium edema, albumin leakage, leucocyte infiltration, and the downregulated expression of endothelial junction proteins after I/R. Moreover, ASIV displayed ability to protect ATP from depletion after I/R or H/R, and the effect of ASIV on regulating vascular permeability and junction proteins was abolished once ATP synthase was inhibited. Notably, ASIV activated the insulin-like growth factor 1 receptor (IGF1R) and downstream signaling after reoxygenation. Knocking IGF1R down abolished the effect of ASIV on restoration of ATP, junction proteins and endothelial barrier after H/R. CONCLUSION: ASIV was potential to prevent MVL after I/R in heart. Moreover, the study for the first time demonstrated that the beneficial role of ASIV depended on promoting production of ATP through activating IGF1R signaling pathway. This result provided novel insight for better understanding the mechanism underlying the potential of ASIV to cope with cardiac I/R injury.

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways.

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.