Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis.

Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

Synthesis, preclinical evaluation and pilot clinical translation of [68Ga]Ga-PMD22, a novel nanobody PET probe targeting CLDN18.2 of gastrointestinal cancer.

PURPOSE: Claudin18.2 (CLDN18.2) is a novel target for diagnosis and therapy of gastrointestinal cancer. This study aimed to evaluate the safety and feasibility of a novel CLDN18.2-targeted nanobody, PMD22, labeled with gallium-68 ([68Ga]Ga), for detecting CLDN18.2 expression in patients with gastrointestinal cancer using PET/CT imaging. METHODS: [68Ga]Ga-PMD22 was synthesized based on the nanobody, and its cell binding properties were assayed. Preclinical pharmacokinetics were determined in CLDN18.2-positive xenografts using microPET/CT. Effective dosimetry of [68Ga]Ga-PMD22 was evaluated in 5 gastrointestinal cancer patients, and PET/CT imaging of [68Ga]Ga-PMD22 and [18F]FDG were performed head-to-head in 16 gastrointestinal cancer patients. Pathological tissues were obtained for CLDN18.2 immunohistochemical (IHC) staining and comparative analysis with PET/CT findings. RESULTS: Cell binding assay showed that [68Ga]Ga-PMD22 had a higher binding ability to AGSCLDN18.2 and BGC823CLDN18.2 cells than to AGS and BGC823 cells (p < 0.001). MicroPET/CT images showed that [68Ga]Ga-PMD22 rapidly accumulated in AGSCLDN18.2 and BGC823CLDN18.2 tumors, and high contrast tumor to background imaging was clearly observed. In the pilot study, the effective dose of [68Ga]Ga-PMD22 was 1.68E-02 ± 1.45E-02 mSv/MBq, and the CLDN18.2 IHC staining result was highly correlated with the SUVmax/BKGstomach of [68Ga]Ga-PMD22 (rs = 0.848, p < 0.01). CONCLUSION: A novel [68Ga]Ga-labeled nanobody probe targeting CLDN18.2, [68Ga]Ga-PMD22, was established and preliminarily proved to be safe and effective in revealing CLDN18.2-positive gastrointestinal cancer, providing a basis for the clinical translation of the agent. CLINICAL TRIAL REGISTRATION: This study was registered on the ClinicalTrials.gov (NCT05937919).

How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation.

Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI-H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic.

Wavefront measurement of a large aperture high image quality off-axis Fresnel lens.

Large aperture off-axis Fresnel lens will play an important role in the future 10 m scale aperture transmission space telescope system. Improving diffraction efficiency and wavefront image quality is always the goal of engineering applications. A 4-level off-axis fresnel lens with Ф350 mm effective aperture was fabricated through overlay etching technique by laser direct writing system. The wavefront aberration characteristics of the off-axis Fresnel lens at 632.8 nm wavelength are analyzed and discussed in detail, and the large aperture off-axis Fresnel lenses wavefront aberration measurement scheme, including a high-precision plane reflector, measured LAOFL, CGH, interferometer and laser tracker to compensate for certain low-order aberrations caused by LAOFL imperfect imaging, is proposed. Wavefront aberration of 0.020 λ(1/50 λ) RMS was achieved. This work presented the best results to our knowledge among the same field with similar aperture in open publications and provided a strong foundation for the future 10 m scale aperture transmission space telescope system.

The Effect of Metformin on Triple-Negative Breast Cancer Cells and Nude Mice.

Triple-negative breast cancer (TNBC) presents the most adverse prognosis due to its pronounced invasive and metastatic features. Existing research has highlighted that metformin, a prevalent diabetes medication, possesses strong anti-tumor properties, particularly in inhibiting tumor invasion and metastasis. This study delves deeper into the impact of metformin on TNBC by examining changes in proliferation, apoptosis, invasion, migration, and adhesion of TNBC cells, specifically MDA-MB-231, post-metformin exposure. The treatment of MDA-MB-231 with metformin in immunodeficient nude mice led to discernible changes in tumor metrics such as size, weight, lymph node engagement, and angiogenesis. Post-treatment, MDA-MB-231 cells exhibited a marked decline in proliferation, invasion, migration, and adhesion, alongside a significant rise in apoptosis. In the in vivo model with nude mice, tumors displayed notable reductions in size and weight post-metformin exposure. Furthermore, there was a pronounced decline in lymph node plasma cell proliferation and tumor angiogenesis. Through the use of both Enzyme-Linked Immunosorbent Assay and Real-Time Fluorescence Quantification, it was ascertained that the expression of Signal Transducer and Activator of Transcription 3 (STAT3) saw significant augmentation, while expressions of Matrix Metallopeptidase-2 (MMP-2), Matrix Metallopeptidase-9 (MMP-9), Interleukin-6 (IL-6), and Interleukin-7 (IL-7) decreased markedly. This suggests metformin's potential efficacy against TNBC, potentially mediated via the STAT3 signaling pathway and interleukins 6 and 7.

A High-Precision Real-Time Pose Measurement Method for the Primary Lens of Large Aperture Space Telescope Based on Laser Ranging.

The aperture of space telescopes increases with their required resolution, and the transmission optical systems with long focal length and diffractive primary lens are becoming increasingly popular. In space, the changes in the pose of the primary lens relative to the rear lens group have a significant impact on the imaging performance of the telescope system. The measurement of the pose of the primary lens in real-time and with high-precision is one of the important techniques for a space telescope. In this paper, a high-precision real-time pose measurement method for the primary lens of a space telescope in orbit based on laser ranging is proposed, and a verification system is established. The pose change of the telescope's primary lens can be easily calculated through six high-precision laser distance changes. The measurement system can be installed freely, which solves the problems of complex system structure and low measurement accuracy in traditional pose measurement techniques. Analysis and experiments show that this method can accurately obtain the pose of the primary lens in real-time. The rotation error of the measurement system is 2 × 10-5 degrees (0.072 arcsecs), and the translation error is 0.2 µm. This study will provide a scientific basis for high-quality imaging of a space telescope.

Large aperture high diffraction efficiency off-axis Fresnel lens fabrication and analysis.

Large aperture high diffraction efficiency off-axis Fresnel lens is one of the most important optical elements in future 10m scale aperture transmissive space telescope systems. Improving diffraction efficiency and effective aperture are long-term goals and bottlenecks for engineering applications. A 4-level off-axis fresnel lens with Ф350 mm effective aperture and 2 µm critical dimension was fabricated through overlay etching technique bylaser direct writing system. Average diffraction efficiency of 75.9% was achieved and certain distribution pattern was observed. Influence of alignment errors on diffraction efficiency distribution was analysed and discussed in detail. This work presented the best results to our knowledge among the same field with similar aperture and critical dimension in open publications, and layed a solid foundation for future large aperture diffractive telescope development.

Effects of bedside team-based learning on pediatric clinical practice in Chinese medical students.

BACKGROUND: Bedside teaching is a primary educational tool to improve the clinical practice of medical students. As a new medical pedagogical approach, team-based learning (TBL) is gradually being integrated into Chinese medical education programmes to promote clinical reasoning, knowledge application, teamwork and collaboration. The aim of this controlled study is to investigate the effects of TBL on pediatric bedside teaching in medical students. METHODS: Thirty medical students in pediatric clinical practice were randomly assigned to an intervention and a control group. Students in the intervention group exposed bedside teaching activity with TBL while students in the control group received traditional bedside teaching. Teaching for the two groups was conducted biweekly, and the same clinical cases were selected for both groups with the same instructors. After six months of clinical practice, the differences of learning outcomes between the two groups were compared through assessments by computer-based case simulations (CCS) and mini-Clinical Evaluation Exercise (mini-CEX). Student feedback following completion of bedside teaching was collected by questionnaire. RESULTS: The CCS scores in the intervention group were significantly higher than that in the control group (p < 0.05). The mini-CEX results showed that clinical judgment and counseling skills of the intervention group were higher than those in the control group (p < 0.01). Medical interviewing skills and overall clinical competence in the intervention group were better than those in the control group (p < 0.05). In the questionnaire survey, students in the intervention group believed that bedside teaching activity with TBL could promote active learning ability, improve counseling skills and strengthen teamwork. CONCLUSIONS: Application of TBL in bedside teaching not only enhanced clinical practice skills among medical students but also improved their clinical reasoning and counseling skills.

Communication Skills (CS) training of physicians in China and its role in actual challenges of patient-physician relationship: a cross-sectional survey.

BACKGROUND: The Chinese healthcare system is affected by frequent disputes between physicians and patients. Although recent reforms have contributed towards improving the patient-physician relationship, distrust in physicians is still high. Communication skills (CS) training of physicians holds the key to improving patient confidence and diffusing stressful situations. This survey reports on the status of CS training in medical education in China, and the experiences and attitudes of physicians towards CS training. METHODS: A cross-sectional survey was conducted at medical institutions across China. A questionnaire developed for this study included the status of CS training, current aspects of patient-physician relationships, perceived own CS and patient-centeredness with Likert-scaled items from 1 (most negative) to 6 (most positive). Physicians' attitude towards CS training was measured with the Communication Skills Attitude Scale (CSAS) and its subscales PAS (Positive Attitude Scale) and NAS (Negative Attitude Scale). Data were analyzed descriptively and for group differences between the hospital level and operating vs. non-operating physicians. Binary logistic regression analysis was done to find associations explaining the occurrence of verbal and physical attacks and the role of CS attitudes. RESULTS: Out of 1080 questionnaires, 772 physicians met inclusion criteria. A total of 466/772 participants (60.4%) had received at least one CS training during their career. The participants rated the current situation related to patient-physician relationship in China as highly stressful (mean = 4.52, SD = 1.26, 95% CI: 4.43-4.60), experiencing verbal attacks in the past three years once a year in 372/772 cases (48.2%) and physical attacks 111/772 times (14.4%). The mean PAS was 62.96 (SD = 7.63, 95% CI: 62.41-63.47). Being female was associated with increased risk of verbal attacks (OR = 1.51, 95% CI: 1.01-2.25) while working in a tertiary hospital and showing high levels of PAS decreased this risk (OR = 0.62, 95% CI: 0.43-0.89, and OR = 0.95, 95% CI: 0.93-0.98). Having received a previous CS training decreased the odds of physical attacks (OR = 0.54, 95% CI: 0.35-0.83). CONCLUSIONS: A majority of Chinese physicians showed a high positive attitude towards CS training, were trained in CS and would value further training. Our results highlight that CS training is likely to promote patient-centered communication and reduce attacks against physicians. Both of these effects are to improve the patient-physician-relationship in the long run. More CS training should be offered to Chinese physicians, especially at secondary- and primary-care hospitals, where such practices remain infrequent.

Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib ameliorates influenza-virus-induced pneumonia in mice.

Treatments against influenza A viruses (IAV) have to be updated regularly due to antigenic drift and drug resistance. Poly (ADP-ribose) polymerases (PARPs) are considered effective therapeutic targets of acute lung inflammatory injury. This study aimed to explore the effects of PARP-1 inhibitor olaparib on IAV-induced lung injury and the underlying mechanisms. Male wild-type C57BL/6 mice were intranasally infected with IAV strain H1N1 to mimic pneumonia experimentally. Olaparib at different doses was intraperitoneally injected 2 days before and 5 consecutive days after virus stimulation. On day 6 post-infection, lung tissues as well as bronchoalveolar lavage fluid (BALF) were sampled for histological and biochemical analyses. Olaparib increased the survival rate of IAV mice dose-dependently. Olaparib remarkably reduced IAV mRNA expression, myeloperoxidase (MPO) level, and inflammatory cell infiltration in IAV lungs. Moreover, olaparib significantly reduced the level of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-6, and IL-4 and increased IL-10 in IAV lungs. Also, olaparib efficiently reduced IL-6, monocyte chemotactic protein (MCP)-1, granulocyte colony-stimulating factor (G-CSF), TNF-α, chemokine (C-X-C motif) ligand (CXCL)1, CXCL10, chemokine (C-C motif) ligand (CCL)3, and regulated on activation, normal T cell expressed and secreted (RANTES) release in IAV BALF. Olaparib decreased PARylated protein content and p65, IκBα phosphorylation in IAV lung tissues. This study successfully constructed the pneumonia murine model using IAV. Olaparib decreased IAV-induced mortality in mice, lung injury, and cytokine production possibly via modulation of PARP-1/NF-κB axis.

Mental Health Among Medical Professionals During the COVID-19 Pandemic in Eight European Countries: Cross-sectional Survey Study.

BACKGROUND: The death toll of COVID-19 topped 170,000 in Europe by the end of May 2020. COVID-19 has caused an immense psychological burden on the population, especially among doctors and nurses who are faced with high infection risks and increased workload. OBJECTIVE: The aim of this study was to compare the mental health of medical professionals with nonmedical professionals in different European countries during the COVID-19 pandemic. We hypothesized that medical professionals, particularly those exposed to COVID-19 at work, would have higher levels of depression, anxiety, and stress. We also aimed to determine their main stressors and most frequently used coping strategies during the crisis. METHODS: A cross-sectional online survey was conducted during peak COVID-19 months in 8 European countries. The questionnaire included demographic data and inquired whether the participants were exposed to COVID-19 at work or not. Mental health was assessed via the Depression Anxiety Stress Scales32 (23.53)-21 (DASS-21). A 12-item checklist on preferred coping strategies and another 23-item questionnaire on major stressors were completed by medical professionals. RESULTS: The sample (N=609) consisted of 189 doctors, 165 nurses, and 255 nonmedical professionals. Participants from France and the United Kingdom reported experiencing severe/extremely severe depression, anxiety, and stress more often compared to those from the other countries. Nonmedical professionals had significantly higher scores for depression and anxiety. Among medical professionals, no significant link was reported between direct contact with patients with COVID-19 at work and anxiety, depression, or stress. "Uncertainty about when the epidemic will be under control" caused the most amount of stress for health care professionals while "taking protective measures" was the most frequently used coping strategy among all participants. CONCLUSIONS: COVID-19 poses a major challenge to the mental health of working professionals as a considerable proportion of our participants showed high values for depression, anxiety, and stress. Even though medical professionals exhibited less mental stress than nonmedical professionals, sufficient help should be offered to all occupational groups with an emphasis on effective coping strategies.

Mental Health Burden in Different Professions During the Final Stage of the COVID-19 Lockdown in China: Cross-sectional Survey Study.

BACKGROUND: COVID-19 resulted in considerable mental health burden in the Chinese general population and among health care workers at the beginning and peak of the pandemic. However, little is known about potentially vulnerable groups during the final stage of the lockdown. OBJECTIVE: The aim of this survey study was to assess the mental health burden of different professions in China in order to find vulnerable groups, possible influencing factors, and successful ways of coping during the last 4 weeks of the lockdown in Hubei Province. METHODS: A cross-sectional online survey asked participants about current residence, daily working hours, exposure to COVID-19 at work, and media preferences. We used a shortened version of the Depression, Anxiety and Stress Scale (DASS-21) to assess mental health. Further assessments included perceived stress (Simplified Chinese version of the 14-item Perceived Stress Scale), coping strategies for all participants, and specific stressors for health care workers. We followed the reporting guidelines of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement for observational studies. RESULTS: The sample (N=687) consisted of 158 doctors, 221 nurses, 24 other medical staff, 43 students, 60 teachers/government staff, 135 economy staff, 26 workers/farmers, and 20 professions designated under the "other" category. We found increased depression (n=123, 17.9%), anxiety (n=208, 30.3%), and stress (n=94, 13.7%) in our sample. Professions that were vulnerable to depression were other medical staff and students. Doctors, nurses, and students were vulnerable to anxiety; and other medical staff, students, and economy staff were vulnerable to stress. Coping strategies were reduced to three factors: active, mental, and emotional. Being female and emotional coping were independently associated with depression, anxiety, or stress. Applying active coping strategies showed lower odds for anxiety while mental coping strategies showed lower odds for depression, anxiety, and stress. Age, being inside a lockdown area, exposure to COVID-19 at work, and having a high workload (8-12 hours per day) were not associated with depression, anxiety, or stress. WeChat was the preferred way of staying informed across all groups. CONCLUSIONS: By the end of the lockdown, a considerable part of the Chinese population showed increased levels of depression and anxiety. Students and other medical staff were the most affected, while economy staff were highly stressed. Doctors and nurses need support regarding potential anxiety disorders. Future work should focus on longitudinal results of the pandemic and develop targeted preventive measures.

The origins and homeostasis of monocytes and tissue-resident macrophages in physiological situation.

Monocytes and macrophages are critical effectors and regulators of innate immune response. They not only play crucial and distinctive roles in homeostasis, but also contribute to some pathologic processes. The heterogeneity of the macrophage lineage has been widely recognized and, in part, is a result of the specialization of resident macrophages in particular tissue microenvironments. Monocytes are usually known to originate in the bone marrow from a common myeloid progenitor that is shared with neutrophils, and they are then released into the peripheral blood. However, the origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. During embryonic organogenesis, macrophages derived from yolk sac and fetal liver precursors are seeded throughout tissues, persisting in the adulthood as resident, self-maintaining populations. After birth, bone marrow-derived monocytes can replenish tissue resident macrophages following injury, infection and inflammation. In this review, we will mainly summarize our current understanding on the origin, ontogeny and fates of tissue macrophages and will briefly discuss the molecular regulation of resident macrophage homeostasis in physiological situation.

Crocin reduces Aspergillus fumigatus-induced airway inflammation and NF-κB signal activation.

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammation and its exacerbation is often accompanied by Aspergillus fumigatus (A. fumigatus) infection. Increasing evidences demonstrated the potent antioxidant and -inflammatory effects of crocin. However, the role of crocin in A. fumigatus-induced inflammation is still unknown. We aimed to evaluate the role of crocin in inflammation response induced by A. fumigatus in human bronchial epithelial cells and the possible mechanisms. BEAS-2B and NHBE cells were pretreated with crocin for 24 h, and then A. fumigatus conidia were added for 24 h. A. fumigatus treatment exhibited a significant higher TNF-α, IL-8, IL-6, and IL-1ß level (P < 0.05), whereas crocin pretreatment significantly inhibited A. fumigatus induced the pro-inflammatory cytokines (P < 0.05). NF-κB inhibitor PDTC inhibited pro-inflammatory cytokines release triggered by A. fumigatus (P < 0.05). Furthermore, crocin suppressed A. fumigatus induced NF-κB p65 nuclear translocation, the phosphorylation of IKKα and IκBα, the degradation of IκBα and NF-κB reporter activity. Crocin pretreatment also resulted in an inhibition of A.fumigatus-induced ROS production (P < 0.05). Taken together, these results indicate that crocin may prevent A. fumigatus-induced inflammation through suppressing NF-κB signal pathway.

KLF2 attenuates bleomycin-induced pulmonary fibrosis and inflammation with regulation of AP-1.

Pulmonary fibrosis (PF) is a chronic, fibrosing interstitial pneumonia and devastating disease. Here we investigated the potential roles of Kruppel-like factor 2 (KLF2) on pulmonary fibrosis and inflammation response. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). The mRNA and protein levels of KLF2 were assayed by RT-PCR and Western blotting respectively. The extent of lung fibrosis was determined using hematoxylin and eosin (HE) staining and Masson's trichrome staining, and the hydroxyproline content was quantified. RT-PCR was used to evaluate the mRNA expression of collagen type 1a1 (col1a1), col3a1, α-SMA, TNF-α, IL-1ß and IL-6. The concentrations of TNF-α, IL-1ß, and IL-6 in bronchoalveolar lavage fluid (BALF) and lung tissue were examined by ELISA. Also, the effects of KLF2 on activator protein-1 (AP-1) were evaluated by measuring the c-Jun and c-Fos protein levels. We found that KLF2 was remarkably downregulated in BLM-treated rats, both in mRNA and protein levels. Additionally, overexpression of KLF2 attenuated the destruction of the alveolar space and pulmonary interstitial collagen hyperplasia, and deposition reduced the expression of col1a1, col3a1, and α-SMA, and blocked the production of TNF-α, IL-1ß, and IL-6 in BALF and lung tissue in vivo. Moreover, adenoviral transduction of KLF2 inhibited TGF-ß1-induced expression of col1a1, col3a1, and α-SMA in vitro. Mechanically, BLM up-regulated c-Jun and c-Fos expression, which was impeded by KLF2 overexpression. Taken together, our data indicate that KLF2 attenuates pulmonary fibrosis and inflammation, possibly through the regulation of AP-1.

Prevalence, Risk Factors, Outcomes, and Treatment of Obstructive Sleep Apnea in Patients with Cerebrovascular Disease: A Systematic Review.

BACKGROUND: Obstructive sleep apnea (OSA) is known to increase the risk of cerebrovascular disease (CVD), and patients with CVD have high incidence of OSA. The study aimed to systematically evaluate the prevalence of OSA in patients with CVD. MATERIALS AND METHODS: Medline, Embase, Science Citation Index, Wanfang, CNKI, and Wiley Online Library were thoroughly searched to identify relevant studies. Random-effects models were used to calculate the pooled rate estimates. Meta-regression and subgroup analysis were performed to explore potential sources of heterogeneity. RESULTS: Thirty-seven studies with 3242 patients were analyzed. The prevalence of OSA (apnea hypopnea index [AHI] >10) ranged from 34.5% to 92.3%, the random-effects pooled prevalence was 61.9%. Furthermore, the prevalence of sleep disordered breathing (SDB) with AHI greater than 5 was 70.4%, with AHI greater than 20 was 39.5%, and with AHI greater than 30 was 30.1%. Only 8.3% of the SDB was primarily central apnea. Seventeen studies reported risk factors for OSA, 6 of which used multivariate analyses to extract risk factors. In univariate meta-regression analysis, male had higher prevalence than female (P = .041). OSA was associated with increased length of hospitalization in 2 studies, and 1 long-term study reported severe sleep apnea was associated with poor functional outcome. Among the 5 studies on treatment, 3 indicated that early treatment with CPAP was effective; the remaining studies did not find benefit from CPAP treatment and reported the CPAP acceptance was poor. CONCLUSIONS: There is high prevalence of OSA in patients with CVD (61.9%). Therefore, accurate diagnosis and treatment to OSA is very important so as to prevent CVD.

Neutrophil dysregulation during sepsis: an overview and update.

Sepsis remains a leading cause of death worldwide, despite advances in critical care, and understanding of the pathophysiology and treatment strategies. No specific therapy or drugs are available for sepsis. Neutrophils play a critical role in controlling infection under normal conditions, and it is suggested that their migration and antimicrobial activity are impaired during sepsis which contribute to the dysregulation of immune responses. Recent studies further demonstrated that interruption or reversal of the impaired migration and antimicrobial function of neutrophils improves the outcome of sepsis in animal models. In this review, we provide an overview of the associated mediators and signal pathways involved which govern the survival, migration and antimicrobial function of neutrophils in sepsis, and discuss the potential of neutrophils as a target to specifically diagnose and/or predict the outcome of sepsis.

STAT3 potentiates the ability of airway smooth muscle cells to promote angiogenesis by regulating VEGF signalling.

NEW FINDINGS: What is the central question of this study? Airway angiogenesis occurs in asthma, and airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis. What is the potential mechanism by which ASM cells harvested from patients with asthma are capable of promoting airway angiogenesis? What is the main finding and its importance? Endogenous STAT3 mediated the pro-angiogenic ability of ASM cells by directly activating VEGF signalling. These findings contribute to the understanding of airway angiogenesis in pathology and could represent a possible therapeutic target for asthma. Airway angiogenesis indicates the specific vascular structure remodelling that occurs in asthma. Airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis; however, the potential mechanism is not yet fully defined. Herein, we investigated the role of signal transducer and activator of transcription 3 (STAT3) in the progress of airway angiogenesis. Western blot analysis showed that STAT3 activation was aberrantly upregulated in ASM tissues of patients with asthma and ASM cells that were exposed to cytokines to imitate the airway conditions in patients with asthma. Compared with the control group, both the inhibition of STAT3 activation and the silencing of endogenous STAT3 in ASM cells significantly reduced the proliferation, migration and tube-forming ability of human lung microvascular endothelial cells induced by the conditioned medium (CM) of ASM cells. The increased proliferation and migration of human aortic vascular smooth muscle cells were also repressed by inhibition of STAT3 in ASM cells. Besides, the increased activity of VEGF signalling was observed in ASM cells and the CM by RT-PCR and Western blotting assay, whereas this increased activity was reduced by STAT3 silencing. Further studies indicated that STAT3 regulated VEGF activation by directly interacting with the binding site on the 5' region of the VEGF gene. The increase in STAT3-induced pro-angiogenic activity of ASM cells was significantly decreased by administration of VEGF neutralizing antibody. In conclusion, we provided evidence that endogenous STAT3 mediates the pro-angiogenic ability of ASM cells by directly activating VEGF signalling, which could represent a possible therapeutic target for asthma.