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).

Chemoradiotherapy plus tislelizumab for mismatch repair proficient rectal cancer with supraclavicular lymph node metastasis: A case report.

BACKGROUND: According to the latest report, colorectal cancer is still one of the most prevalent cancers, with the third highest incidence and mortality worldwide. Treatment of advanced rectal cancer with distant metastases is usually unsatisfactory, especially for mismatch repair proficient (pMMR) rectal cancer, which leads to poor prognosis and recurrence. CASE SUMMARY: We report a case of a pMMR rectal adenocarcinoma with metastases of multiple lymph nodes, including the left supraclavicular lymph node, before treatment in a 70-year-old man. He received full courses of chemoradiotherapy (CRT) followed by 4 cycles of programmed death 1 inhibitor Tislelizumab, and a pathologic complete response (pCR) was achieved, and the lesion of the left supraclavicular lymph node also disappeared. CONCLUSION: pMMR advanced rectal cancer with preserved intact distant metastatic lymph nodes may benefit from full-course CRT combined with immunotherapy.

Tertiary lymphoid structures predict survival and response to neoadjuvant therapy in locally advanced rectal cancer.

Tertiary lymphoid structure (TLS) contributes to the anti-tumor immune response, and predicts the prognosis of colorectal cancer patients. However, the potential impact of TLS in shaping the immune status of rectal adenocarcinoma, and the intrinsic relationship between TLS and neoadjuvant therapies (neoTx) remain unclear. We performed hematoxylin-eosin staining, immunohistochemical and biomolecular analyses to investigate TLS and tumor-infiltrating lymphocytes (TILs) in 221 neoTx-treated and 242 treatment-naïve locally advanced rectal cancer (LARC) patients. High TLS density was significantly associated with the absence of vascular invasion, a lower neutrophil-to-lymphocyte ratio, increased TLS maturity, a longer recurrence-free survival (RFS) (hazard ratio [HR] 0.2985 95% confidence interval [CI] 0.1894-0.4706, p < 0.0001) and enhanced infiltration of adaptive immune cells. Biomolecular analysis showed that high TLS-score was strongly associated with more infiltration of immune cells and increased activation of immune-related pathways. TLS+ tumors in pre-treatment specimens were associated with a higher proportion of good respond (62.5% vs. 29.8%, p < 0.0002) and pathological complete remission (pCR) (40.0% vs. 11.1%, p < 0.0001), and significantly increased RFS (HR 0.3574 95%CI 0.1489-0.8578 p = 0.0213) compared with TLS- tumors in the neoTx cohort, which was confirmed in GSE119409 and GSE150082. Further studies showed that neoTx significantly reduced TLS density and maturity, and abolished the prognostic value of TLS. Our study illustrates that TLS may have a key role in mediating the T-cell-inflamed tumor microenvironment, which also provides a new direction for neoTx, especially neoadjuvant immunotherapy, in LRAC patients.

Infiltrating characteristics and prognostic value of tertiary lymphoid structures in resected gastric neuroendocrine neoplasm patients.

Objectives: Tertiary lymphoid structures (TLSs) are lymphocyte aggregates that play an anti-tumor role in most solid tumors. However, the functions of TLS in gastric neuroendocrine neoplasms (GNENs) remain unknown. This study aimed to determine the characteristics and prognostic values of TLS in resected GNEN patients. Methods: Haematoxylin-eosin, immunohistochemistry (IHC) and multiple fluorescent IHC staining were used to assess TLS to investigate the correlation between TLSs and clinicopathological characteristics and its prognostic value. Results: Tertiary lymphoid structures were identified in 84.3% of patients with GNEN. They were located in the stromal area or outside the tumor tissue and mainly composed of B and T cells. A high density of TLSs promoted an anti-tumor immune response in GNEN. CD15+ TANs and FOXP3+ Tregs in TLSs inhibited the formation of TLSs. High TLS density was significantly associated with prolonged recurrence-free survival (RFS) and overall survival (OS) of GNENs. Univariate and multivariate Cox regression analyses revealed that TLS density, tumor size, tumor-node-metastasis (TNM) stage and World Health Organisation (WHO) classification were independent prognostic factors for OS, whereas TLS density, tumor size and TNM stage were independent prognostic factors for RFS. Finally, OS and RFS nomograms were developed and validated, which were superior to the WHO classification and the TNM stage. Conclusion: Tertiary lymphoid structures were mainly located in the stromal area or outside the tumor area, and high TLS density was significantly associated with the good prognosis of patients with GNEN. Incorporating TLS density into a nomogram may improve survival prediction in patients with resected GNEN.

Targeting Ferroptosis as a Therapeutic Implication in Lung Cancer Treatment by a Novel Naphthoquinone Inducer: Juglone.

Lung cancer has garnered significant global attention as a result of its escalating rates of mortality and morbidity, necessitating focused interventions to mitigate its impact. The primary aim of this work was to investigate the anticancer activity of juglone in A549 cells, specifically focusing on its role in mediating ferroptosis. We conducted an investigation involving a range of cytotoxic and morphological assays, such as cell viability assay, fluorescence microscopic analysis, flow cytometry, and ROS assay. The findings demonstrated that the cytotoxicity of juglone was around 18.5 µM. Furthermore, the chemical was found to promote apoptotic activity as observed through fluorescent microscopic inspection and morphological analysis. In addition, the levels of ROS, MDA, GSH, ferrous iron, and colony formation study demonstrated a significant increase, indicating a correlation with the occurrence of ferroptosis. Hence, juglone exhibits promise as a prospective therapeutic drug in the treatment of lung cancer. Therefore, we put forward that the utilization of ferroptosis as a therapeutic approach for lung cancer may yield significant efficacy and warrants further investigation in subsequent studies.

Gastric adenosquamous carcinoma with an elevated serum level of alpha-fetoprotein: A case report.

BACKGROUND: Gastric adenosquamous carcinoma (ASC) is rare and characterized by coexisting of adenocarcinoma andsquamous carcinoma within the same tumor. We present a female patient with gastric ASC who had an elevated serum level of alpha-fetoprotein (AFP), which decreased to normal levels after a laparoscopic distant radical gastrectomy in a short period. The clinicopathological features in AFP-producing gastric cancer (GC) are discussed, as well as potentially available prognostic predictors. CASE SUMMARY: A 50-year-old woman presented to our department with a chief complain of a 6-mo history of bloating. She had no basic diseases including heart diseases and respiratory diseases, and she also denied any prior history of dysphagia, hematemesis, melena, rectal bleeding, hematochezia, or unintentional weight loss. Based on her symptoms, an esophagogastroduodenoscopy was performed, showing an annular cavity lesion 3 cm from the pylorus with a diameter of 6 cm. A biopsy of the lesion showed gastric ASC, whereas the pylorus biopsy showed normal mucosa. The patient further received an enhanced computed tomography scan which demonstrated an invasive lesion close to the pylorus with a still clear margin of the tumor to peripheral organs such as the pancreas and liver. Scattered lymph nodes were visible around, whereas no sign of liver metastasis was discovered. Serum tumor markers including carcinoembryonic antigen (CEA), cancer antigen 199 (CA199), CA724, CA125, and CA242 were all normal, while the level of serum AFP increased to 172 ng/mL. A laparoscopic distant radical gastrectomy was performed after exclusion of surgical contraindications. Postoperative pathology results showed that the tumor displayed an ulcerated ASC phenotype (90% of medium to highly-differentiated squamous cell carcinoma, 10% of poorly differentiated adenocarcinoma. Surprisingly, the serum level of AFP decreased to normal level on post operation day 5. The tumor cells were positive for CK5/6, p63, and CEA, and negative for AFP and Epstein-Barr encoding region. CONCLUSION: We presented a rare case of gastric ASC with elevated serum AFP level, which may be new subtype of AFP-producing GC. Follow-up detection of serum AFP might be a useful tool to predict patient prognosis.

CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.

CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits ß-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated ß-catenin translocation inactivates Wnt(Wingless and INT-1)/ß-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/ß-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.

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.

IL-17 promotes melanoma through TRAF2 as a scaffold protein recruiting PIAS2 and ELAVL1 to induce EPHA5.

An abnormal immune response induces melanoma development. IL-17 and the classical downstream signal STAT1 are associated with melanoma development. TRAF2 also mediates the downstream signaling of IL-17; however, its role in IL-17-stimulated melanoma remains unclear. Bioinformatic analysis revealed that TRAF2 can bind to PIAS2 (a SUMO E3 ligase), ELAVL1 (an RNA-binding protein), and EPHA5 (an ephrin receptor of the tyrosine kinase family). To elucidate the IL-17 downstream signal, the IL-17 receptor (R), STAT1, TRAF2, PIAS2, ELAVL1, and EPHA5 were knocked down before melanoma cells were treated with recombinant IL-17A protein. Co-immunoprecipitation and RNA immunoprecipitation were conducted to determine the interaction of TRAF2 with PIAS2, ELAVL1, and EPHA5 proteins, as well as the interaction of ELAVL1 protein with EPHA5 mRNA. STAT1 knockdown suppressed the proliferation and invasion triggered by IL-17A, but the suppressive effects were much weaker than those caused by IL-17R knockdown. This implies that another nonclassical signal mediates IL-17 effects. IL-17A induces TRAF2 recruitment of ELAVL1, PIAS2, and EPHA5 proteins. We speculated that ELAVL1 bound to the AU-rich elements in the 3' untranslated region of the EPHA5 mRNA, thereby enhancing mRNA stability. Furthermore, PIAS2 induced EPHA5 SUMOylation, which suppressed EPHA5 ubiquitination and degradation. Through pre- and post-translational regulation, IL-17A induced EPHA5 expression in melanoma, and EPHA5 knockdown markedly suppressed IL-17A-induced proliferation and invasion. This study revealed a non-classical signaling mechanism responsible for the effects of IL-17 in melanoma.

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.

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.

The emerging role of neutrophil extracellular traps in cancer: from lab to ward.

Neutrophil extracellular traps (NETs) are web-like structures derived from neutrophils, which typically consist of DNA, released from the nucleus or mitochondria, and decorated with histones and granule proteins. They are well known as an important structure in innate immunity to eliminate pathogenic bacteria, similar to neutrophils. Initially, NETs are reported to take part in the progression of inflammatory diseases; now, they have also been implicated in the progression of sterile inflammation such as autoimmune disease, diabetes, and cancer. In this review, we will describe the recent studies which have investigated the role of NETs in the development of cancer, especially metastasis. We also prescribe the strategies for targeting NETs in the multiple cancer types, which suggest that NETs are a promising treatment for cancer patients.

Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond.

Myeloid-derived suppressor cells (MDSCs) are one of the major negative regulators in tumor microenvironment (TME) due to their potent immunosuppressive capacity. MDSCs are the products of myeloid progenitor abnormal differentiation in bone marrow, which inhibits the immune response mediated by T cells, natural killer cells and dendritic cells; promotes the generation of regulatory T cells and tumor-associated macrophages; drives the immune escape; and finally leads to tumor progression and metastasis. In this review, we highlight key features of MDSCs biology in TME that are being explored as potential targets for tumor immunotherapy. We discuss the therapies and approaches that aim to reprogram TME from immunosuppressive to immunostimulatory circumstance, which prevents MDSC immunosuppression activity; promotes MDSC differentiation; and impacts MDSC recruitment and abundance in tumor site. We also summarize current advances in the identification of rational combinatorial strategies to improve clinical efficacy and outcomes of cancer patients, via deeply understanding and pursuing the mechanisms and characterization of MDSCs generation and suppression in TME.

Design, Fabrication and Analysis of a Hybrid-Order Monolithic Imaging Diffractive Lens on a Germanium Substrate.

Diffractive optical elements are gradually replacing some conventional optical elements and becoming a key component of optical systems due to their unique phase modulation function. However, the imaging performance will be reduced due to the fact that this single-sided microstructured lens still produces chromatic aberration. Therefore, the key issue for the application of diffractive optical elements in optical systems is the reduction of chromatic aberration, and diffractive lenses with double-sided microstructures are proposed as a solution. This research describes the design and analysis of a 70-mm-diameter, 296-mm-focal-length double-sided microstructured hybrid-order monolithic imaging diffractive lens operating in the mid-wave infrared region (3.7-4.7 µm). The design minimizes chromatic aberration by up to 30 times compared to a standard harmonic diffractive lens and improves the image performance of a single-lens optical system operating in the infrared range. Experiments indicate that this design is capable of achieving single-lens imaging with high sensitivity for optical systems with a measured NETD ≤ 50 mK. The analysis of the experiments yielded suggestions for future research.

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.

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.

Analysis of eye movements of workers in safe and unsafe behaviors using a video-based method.

Analyzing eye movements of workers in safe and unsafe behaviors can reduce accidents. With a video-based method, the angular velocity of gaze direction (AVGD) represents micro-movements in gaze and angular velocity in saccade is used to analyze eye movements. A similar behavior simulation experiment is designed to collect operation videos, and an eye movement information extraction and processing framework is constructed to quantify and analyze eye movements. The results show that: the root mean square and movement frequency of AVGD can be used to recognize unsafe behavior; in operations with attention target fixation, compared with safe behavior, workers in unsafe behavior have higher angular velocity, movement frequency and turn frequency of eye movements; and in operations with attention target change, eye movement rules of workers in safe and unsafe behaviors depend on operation types. The results can provide features for unsafe behavior recognition and theoretical bases for safety training.

Neutrophil Extracellular Trap is Surrogate Biomarker for Prognosis and Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer.

Purpose: To demonstrate the intrinsic association of Neutrophil extracellular traps (NETs) with outcome and neoadjuvant therapy response of locally advanced rectal cancer (LARC), and the mechanisms. Patients and Methods: We enrolled 240 patients with LARC who underwent surgery without neoadjuvant therapy in two independent sets (training and validation), and 153 patients who received neoadjuvant therapy with biopsy followed by surgery. Immunohistochemistry, immunofluorescence staining and bioinformatics analysis were performed in formalin-fixed paraffin-embedded sections. NETs were identified by costaining for myeloperoxidase and citrullinated histone H3. Results: NETs were associated with recurrence-free survival in the surgical training and validation sets. High-NET density predicted poor postoperative survival of patients with LARC. Multivariate analysis identified NETs, TNM stage, and neutrophil-to-lymphocyte ratio as independent prognostic factors for recurrence-free survival. Low-NETs LARC demonstrated increased CD8+ T cell and lower T regulatory cell infiltration, which indicated a tumor immune microenvironment with strong antitumor capacity. High-NET density was associated with epithelial-mesenchymal transition, which is considered to contribute to tumor progression. In the neoadjuvant therapy cohort, high-NET density on biopsy was significantly associated with reduced likelihood of complete/near complete response. Conclusion: NET was an independent prognostic factor in LARC that were associated with patients' survival, and NET density in pretreatment biopsies was an independent predictive biomarker of response to neoadjuvant therapy. This biomarker may be helpful in predicting survival in LARC with improved accuracy and selecting patients who will respond to neoadjuvant therapy.

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.