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Abstract Background Increasing evidence revealed that lung microbiota dysbiosis was associated with pulmonary infection in lung transplant recipients (LTRs). Pneumocystis jirovecii (P. jirovecii) is an opportunistic fungal pathogen that frequently causes lethal pneumonia in LTRs. However, the lung microbiota in LTRs with P. jirovecii pneumonia (PJP) remains unknow. Methods In this prospective observational study, we performed metagenomic next-generation sequencing (mNGS) on 72 bronchoalveolar lavage fluid (BALF) samples from 61 LTRs (20 with PJP, 22 with PJC, 19 time-matched stable LTRs, and 11 from LTRs after PJP recovery). We compared the lung microbiota composition of LTRs with and without P. jirovecii, and analyzed the related clinical variables. Results BALFs collected at the episode of PJP showed a more discrete distribution with a lower species diversity, and microbiota composition differed significantly compared to P. jirovecii colonization (PJC) and control group. Human gammaherpesvirus 4, Phreatobacter oligotrophus, and Pseudomonas balearica were the differential microbiota species between the PJP and the other two groups. The network analysis revealed that most species had a positive correlation, while P. jirovecii was correlated negatively with 10 species including Acinetobacter venetianus, Pseudomonas guariconensis, Paracandidimonas soli, Acinetobacter colistiniresistens, and Castellaniella defragrans, which were enriched in the control group. The microbiota composition and diversity of BALF after PJP recovery were also different from the PJP and control groups, while the main components of the PJP recovery similar to control group. Clinical variables including age, creatinine, total protein, albumin, IgG, neutrophil, lymphocyte, CD3+CD45+, CD3+CD4+ and CD3+CD8+ T cells were deeply implicated in the alterations of lung microbiota in LTRs. Conclusions This study suggests that LTRs with PJP had altered lung microbiota compared to PJC, control, and after recovery groups. Furthermore, lung microbiota is related to age, renal function, nutritional and immune status in LTRs.

Abstract Background Patients with work-related lung disease (WRLD) are at increased risk of death caused by severe lung tissue damage and fibrosis. This study aimed to assess the clinical outcomes of lung transplantation (LTx) for WRLD and compare the results of LTx between WRLD and idiopathic pulmonary fibrosis (IPF). Methods This single-center retrospective cohort study reviewed the clinical data of patients who underwent LTx for WRLD or IPF at our hospital between January 2015 and December 2021. Cumulative survival rates after LTx were estimated using the Kaplan-Meier method. Results The final analysis included 33 cases of WRLD and 91 cases of IPF. The 33 WRLD patients consisted of 19 (57.6%) cases of silicosis, 8 (24.2%) cases of coal workers’ pneumoconiosis, 3 (9.09%) cases of asbestosis, and 3 (9.09%) cases of other WRLD. Pneumothorax as an indication for LTx was significantly more common in the WRLD group than in the IPF group (51.5% vs. 2.2%, P

Abstract Background Donor-derived cell-free DNA (dd-cfDNA) has been applied to monitor acute rejection (AR) in kidney and heart transplantation. This study was aimed to investigate the application of dd-cfDNA levels in the diagnosis of AR and chronic lung allograft dysfunction (CLAD) among the lung transplantation recipients (LTRs). Methods One hundred and seventy LTRs were enrolled at the First Affiliated Hospital of Guangzhou Medical University between 1 June 2015 and 30 March 2021. Patients were divided into 4 groups: stable group, AR group, infection group and CLAD group. The level of dd-cfDNA was analyzed using target region sequencing and the performance characteristics of dd-cfDNA for diagnosis of AR and CLAD were determined, respectively. Results Kruskal–Wallis test showed that there were some significant differences in the level of dd-cfDNA (%) among the 4 groups, with p

Abstract Background Cytomegalovirus (CMV) infection is a leading cause of morbidity and mortality after transplantation. This study aimed to investigate CMV seroprevalence, infection, and disease in Chinese thoracic organ transplant recipients. Methods The clinical data of the patients who underwent lung and/or heart transplantation between January 2015 and October 2020 were retrospectively collected from four transplantation centers in China. Results A total of 308 patients were analyzed. The CMV serostatus was donor positive (D+) recipient negative (R−) in 19 (6.17%) patients, D+/R+ in 233 (75.65%), D−/R+ in 36 (11.69%), and D−/R− in 20 (6.50%). CMV DNAemia was detected in 52.3% of the patients and tissue-invasive CMV disease was diagnosed in 16.2% of the patients. Only 31.8% of the patients adhered to the postdischarge valganciclovir therapy. The D+/R− serostatus (odds ratio [OR]: 18.32; 95% confidence interval [CI]:1.80-188.68), no valganciclovir prophylaxis (OR: 2.64; 95% CI: 1.05–6.64), and higher doses of rabbit anti-human thymocyte globulin (> 2 mg/kg) (OR: 4.25; 95% CI: 1.92–9.42) were risk factors of CMV disease. Conclusion CMV seroprevalence was high in Chinese thoracic organ transplant donors and recipients. The low adherence rate to the postdischarge CMV prophylaxis therapy in Chinese patients is still an unresolved issue.

This study explored the epidemiology, risk factors, and prognosis of invasive fungal disease (IFD) in Chinese lung transplant recipients (LTRs). This retrospective cohort study included patients who received lung transplants at four hospitals in South China between January 2015 and June 2019. The participants were divided into IFD and non-IFD (NIFD) groups. The final analysis included 226 LTRs (83.2% males) aged 55.0 ± 14.2 years old. Eighty-two LTRs (36.3%) developed IFD (proven or probable diagnosis). The most common pathogens were Aspergillus (57.3%), Candida (19.5%), and Pneumocystis jiroveci (13.4%). Multivariate logistic regression revealed that anastomotic disease [odds ratio (OR): 11.86; 95% confidence interval (95%CI): 4.76–29.54; P < 0.001], cytomegalovirus (CMV) pneumonia (OR: 3.85; 95%CI: 1.88–7.91; P = 0.018), and pre-transplantation IFD (OR: 7.65; 95%CI: 2.55–22.96; P < 0.001) were associated with higher odds of IFD, while double-lung transplantation (OR: 0.40; 95%CI: 0.19–0.79; P = 0.009) was associated with lower odds of IFD. Logistic regression analysis showed that anastomotic disease was associated with higher odds of death (OR: 5.01; 95%CI: 1.24–20.20; P = 0.02) and that PJP prophylaxis was associated with lower odds of death (OR: 0.01; 95%CI: 0.001–0.11; P < 0.001). Invasive fungal disease is prevalent among LTRs in southern China, with Aspergillus the most common pathogen. Prophylaxis should be optimized based on likely pathogens.

Cardiovascular disease is the leading cause of global mortality, with anticoagulant therapy being the main prevention and treatment strategy. Recombinant hirudin (r-hirudin) is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous (SC) and intravenous (IV) administration, but there is a risk of haemorrhage via SC and IV. Thus, microneedle (MN) provides painless and sanitary alternatives to syringes and oral administration. However, the current technological process for the micro mould is complicated and expensive. The micro mould obtained via three-dimensional (3D) printing is expected to save time and cost, as well as provide a diverse range of MNs. Therefore, we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch. The results show that r-hirudin-loaded and hyaluronic acid (HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models. These results indicate that based on 3D printing technology, MNs combined with r-hirudin are expected to achieve diverse customizable MNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.

Although the blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has become a promising treatment strategy for several types of cancers, the constitutive activation of c-Met in tumors may cause a low overall response rate to PD-1 inhibitors. Increasing evidence indicates that the dual inhibition of c-Met and PD-1 could improve the efficacy of anti-PD-1/PD-L1 monoclonal antibodies for tumor immunotherapy. In this study, we developed two bispecific single-chain diabodies targeting c-Met and PD-1 for the treatment of solid tumors based on protein homology modeling, and we identified that the binding affinity of diabody-mp to c-Met was 50-folds higher than that of diabody-pm. The results of in vitro studies revealed that both diabodies suppressed HGF-induced proliferation, migration, and invasion of tumor cells, inhibiting the activation of c-Met signaling by antagonizing HGF binding to c-Met. Moreover, they promoted T cell activation by blocking the PD-1 pathway, mediating tumor cellular cytotoxicity through T cell engagement. In vivo studies with mice models demonstrated that diabody-mp exhibited higher therapeutic efficacy than other structural antibodies, greatly enhancing the survival of c-Met-positive tumor-bearing mice compared to single or combined c-Met and PD-1 blockade therapy. Furthermore, diabody-mp, which had a higher c-Met binding affinity, showed better anti-tumoral activity than diabody-pm, which had a lower c-Met binding affinity. In conclusion, bispecific anti-PD-1/c-Met diabody-mp, with high c-Met-associated affinity, inhibited tumor growth by activating T cells, suggesting its therapeutic potential for c-Met-positive solid tumors.

Vascular cell adhesion molecular 1 (VCAM1), an important member of the immunoglobulin superfamily, is related to the development of malignant tumors, such as breast cancer, melanoma, and renal clear cell carcinoma. However, the molecular role and mechanism of VCAM1 in the regulation of the progression of colorectal cancer (CRC) has rarely been studied. The results of IHC and RT-PCR analyses proved that VCAM1 was upregulated in human CRC tissues compared with matched adjacent normal intestinal epithelial tissues. Moreover, analysis of data from the TCGA and Gene Expression Omnibus (GEO) databases revealed that a higher level of VCAM1 was strongly correlated with poor differentiation, metastasis, and short survival in CRC patients. Furthermore, VCAM1 significantly influenced the invasion and metastasis of CRC cells in vitro and in vivo and activated the EMT program, by which cancer cells adhere to the endothelium and cross the vessel wall by forming pseudopodia and invadopodia. The current findings demonstrate that VCAM1 promotes tumor progression in CRC.