Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes.

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Smoking contribution to the global burden of metabolic disorder: A cluster analysis.

INTRODUCTION AND OBJECTIVES: Smoking is associated with various health risks, including cancer, cardiovascular disease, and chronic obstructive pulmonary disease. In this retrospective cohort study, we aimed to determine whether smoking is harmful to the whole metabolic system. METHODS: We collected data from 340 randomly selected participants who were divided into three groups: smokers (n=137), non-smokers (n=134), and ex-smokers (n=69). We obtained information on participants' body mass index, waist circumference, indicators of glucose metabolism, lipid metabolism, bone metabolism, and uric acid from health screen data during the past three years. A cluster analysis was used to synthesize each participant's overall metabolic characteristics. RESULTS: According to the cluster analysis, the 340 participants were divided into three groups: excellent metabolizers (137, 40.3%), adverse metabolizers (32, 9.4%), and intermediate metabolizers (171, 50.3%). The Chi-squared test analysis shows that people with different smoking statuses have different metabolic patterns. Non-smokers had the highest proportion of excellent metabolizers (56%), and current smokers had the highest proportion of adverse metabolizers (15.3%). The proportion of adverse metabolizers (5.8%) in the ex-smoker group was clinically relevantly lower than that of current smokers. CONCLUSION: The statistically significant differences in the distribution of smokers into different metabolic clusters indicate that smoking has adverse effects on the whole metabolic system of the human body, which further increases the existing global burden of metabolic disorders.

The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study.

Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1-2) and high-grade CIPs (grades 3-5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs.

Clinical spectrum of Chinese hospitalized lung cancer patients with concomitant interstitial lung disease: before and after the new era of LC treatment.

This study aimed to explore the general characteristics and spectrum of hospitalized Chinese patients suffering from lung cancer with concomitant interstitial lung disease (LC-ILD). Furthermore, we compared their features before and after the period of immunotherapy for lung cancer. A retrospective analysis of the clinical characteristics of hospitalized LC patients with definite pathological diagnoses was performed from 2014 to 2021. ILD was defined after the review of chest CT imaging. There were 13,085 hospitalized LC patients. Among them, 509 patients (3.89%) had 551 cases of ILD. There were variable underlying causes of ILD, including idiopathic interstitial pneumonia (360 patients), LC treatment-associated ILD (134 cases), and connective tissue disease-associated ILD (55 patients). Although most LC-ILD patients were suffering from adenocarcinoma (204/40.1%), SCLC patients were prone to concomitant ILD (10.8% of all SCLC cases), followed by SCC (9.6% of all SCC cases). All but 10 LC-ILD patients received anti-LC treatment; however, only 39 (10.8%) LC-IIP patients received anti-ILD treatment. There were more LC-ILD patients in the 2018-2021 group than in the 2014-2017 group (5.16% vs. 2.03%, p < 0.001). The underlying causes of ILD were significantly different between the 2018-2021 group and the 2014-2017 group (p < 0.001). After adjusting for the number of hospitalized patients having the same LC pathological pattern, SCLC was determined to be the most likely to be concomitant with ILD, followed by SCC. Most LC-ILD patients were scheduled for anti-LC therapy; however, treatments for concomitant IIP were usually ignored. LC treatment-associated ILD should receive more attention than before.

Tacrolimus ameliorates bleomycin-induced pulmonary fibrosis by inhibiting M2 macrophage polarization via JAK2/STAT3 signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown cause and characterized by excessive proliferation of fibroblasts and the irregular remodeling of extracellular matrix (ECM), which ultimately cause the severe distortion of the alveolar architecture. The median survival of IPF patients is 2-5 years. IPF patients are predominantly infiltrated by M2 macrophages during the course of disease development and progression. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition. In the process of M2 macrophage polarization, JAK2/STAT3 signaling plays a key role, thus, targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach to the potential treatment of IPF. Tacrolimus is a macrolide antibiotic that as a specific inhibitor of T-lymphocyte function and has been used widely as an immunosuppressant in human organ transplantation. In this study we explored the potential effect and mechanism of tacrolimus on pulmonary fibrosis in vivo and vitro. Here, we found that tacrolimus is capable of suppressing M2 macrophages polarization by inhibiting pro-fibrotic factors secreted by M2 macrophages. This effect further alleviates M2-induced myofibroblast activation, thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, recovering of lung function, ultimately relieving the progression of fibrosis in vivo. Mechanistically, we found that tacrolimus can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2. Our findings indicate a potential anti-fibrotic effect of tacrolimus by regulating macrophage polarization and might be meaningful in clinical settings.

Clinical manifestations and long-term prognosis of Good syndrome: Results from a single-center cohort study from China.

OBJECTIVE: To describe clinical features and long-term prognosis in patients with Good syndrome (GS). METHODS: We retrospectively reviewed medical records of GS patients at Peking Union Medical College Hospital from January 2001 to May 2019. Data regarding clinical manifestations and treatments were collected. Patients were routinely followed-up via clinical and telephone interviews, and survival analysis was performed with Kaplan-Meier analysis. RESULTS: Twenty-four patients were identified, including eight males and 16 females, with a median age at diagnosis of 58 years (interquartile range [IQR], 52-62 years). Twelve patients (50%) had autoimmune manifestations. Multi-organ involvements included musculoskeletal (37.5%), respiratory (33.3%), gastrointestinal (29.2%), hematologic (29.2%) systems, et.al. Infections were detected in 23 (95.8%) patients, mostly located in lung (69.6%), blood (26.1%), and gastrointestinal tract (21.7%). Thymectomy was performed in 23 patients, with the most common histology of type AB (10, 47.6%). Twenty-one patients were consecutively followed-up with a median follow-up of 84 (IQR, 48-116) months and 11 (52.4%) died, mainly due to infection (8/11, 72.7%). The 5- and 10-year survival rates were 90% (95% confidence interval [CI], 77.8-100%) and 38.5% (95% CI, 19.6-75.5%), respectively. CONCLUSION: GS patients tended to present with various infections and autoimmune manifestations. The 10-year survival rate from the Chinese population was poor, mainly due to infections.

[Chest High-resolution Computed Tomography Imaging Features of Lung Involvement in Rheumatoid Arthritis].

Objective To explore the chest high-resolution computed tomography (HRCT) features in patients with rheumatoid arthritis (RA) complicated with pulmonary involvement. Methods Totally 161 patients with RA with lung involvement were collected from June 2014 to May 2018. The chest HRCT findings were retrospectively analyzed. According to the imaging features as well as the results of history taking,pulmonary function test,pathology,and bronchoalveolar lavage fluid test,RA-related lung diseases (RA-LD) were classified and their clinical characteristics were compared. Results These 161 RA-LD patients (56 males and 105 females) whose mean age at diagnosis was (60.7±12.8) years (14-85 years) included 87 cases of usual interstitial pneumonia (UIP) (including 16 cases of possible UIP),44 cases of non-specific interstitial pneumonia (NSIP),10 cases of organizing pneumonia,7 cases of lymphocytic interstitial pneumonia,9 cases of small airway disease (SAD) (including 8 cases of bronchiolitis obliterans and 1 case of follicular bronchiolitis),and 4 other lung manifestations (including 3 cases of diffuse alveolar hemorrhage and 1 case of rheumatoid nodules). The UIP group had the oldest average age [(63.3±12.1) years old] and the highest smoking rate (41.4%). The SAD group had the youngest average age [(54.7±15.1) years old] and there was no smoking history. There were significant differences between these two groups (P=0.020,P<0.001). Seventy patients (43.5%) with RA-LD were complicated with pleural lesions. Conclusions RA involving the lung is common and has varied imaging manifestations,with interstitial lung diseases (mainly UIP and NSIP) being the most important manifestations. RA patients should undergo lung HRCT as early as possible to identify the lung involvement and related types.

Obstructive uropathy associated with rheumatoid arthritis successfully treated with steroids and immunosuppressive therapy: A case report.

RATIONALE: Urinary obstruction are relatively rare complications of autoimmune diseases including systemic lupus erythematosus and systemic vasculitis. It has never been reported in rheumatoid arthritis (RA). PATIENT CONCERNS: We report a case of a female patient with seropositive RA who presented with gross hematuria associated with worsening joint symptoms, found to have acute kidney injury (AKI), bilateral hydronephrosis with bilateral renal pelvis, and ureteral wall thickening. Uroscopy with biopsy demonstrated inflammation without evidence of malignancy. DIAGNOSES: Rheumatoid arthritis related inflammation and obstruction of the urinary tract. INTERVENTIONS: Prednisone 50 mg daily (tapering began 1 month later), iguratimod 50 mg daily, and leflunomide 20 mg daily were prescribed. OUTCOMES: The patient responded well to steroids and immunosuppressive therapy with complete resolution of hematuria, renal injury, and hydronephrosis. LESSONS: Our case showed that RA might cause local inflammation involving the urinary tract which leads to obstruction and AKI.

Multiple food-borne trematodiases with profound systemic involvement: a case report and literature review.

BACKGROUND: Food-borne trematodiases are an important group of neglected global diseases. Affected patients in regions with low prevalence usually experience delayed diagnosis, especially when presenting with atypical clinical symptoms. Here, we presented a rare case of a Chinese patient infected with three food-borne trematodiases. CASE PRESENTATION: A 42-year-old man presented with diarrhea, lower extremity edema, and symptoms of cardiac dysfunction. He had a history of intermittent consumption of raw freshwater fishes for 6-7 years. Upon evaluation, he had eosinophilia, anemia, intrahepatic bile duct dilatation and a growing space-occupying lesion in the left atrium. The patient underwent a cardiac surgery which revealed an endocardial hematoma due to mechanical injuries. Imaging investigations also revealed intracranial and pulmonary lesions. A total of three trematodiases were diagnosed based upon microscopic stool examination, from which eggs of Clonorchis sinensis, Heterophyidae and Echinostomatidae were identified. Deposition of Clonorchis sinensis eggs was also observed from ileocecal squash slides. The patient was successfully treated with three cycles of praziquantel. CONCLUSIONS: Food-borne trematodiases may present with systemic involvement. Patients with dietary history of high risk or atypical ingestions should be evaluated for parasitic infection, even in non-endemic areas.

Plant-derived phosphocholine facilitates cellular uptake of anti-pulmonary fibrotic HJT-sRNA-m7.

Pulmonary fibrosis, a progressive chronic disease with a high mortality rate, has limited treatment options. Currently, lung transplantation remains the only effective treatment. Here we report that a small RNA, HJT-sRNA-m7, from a Chinese herbal medicine Hong Jing Tian (HJT, RHODIOHAE CRENULATAE RADIX ET RHIZOMA, Rhodiola crenulata) can effectively reduce the expressions of fibrotic hallmark genes and proteins both in alveolar in vitro and in mouse lung tissues in vivo. We also discovered over one hundred oil-soluble chemicals from HJT decoctions, most of which are found in lipid extracts from other Chinese herbals decoctions, including Pu Gong Ying (PGY, TARAXACI HERBA, Taraxacum mongolicum), Chuan Xin Lian (CXL, changed to "ANDROGRAPHIS HERBA, Andrographis paniculata"), and Jin Yin Hua (JYH, lonicera japonica or Honeysuckle). We identified the active component in these decoctions as two forms of phosphocholines, PC (18:0/18:2) and PC (16:0/18:2). These PCs potentially could form liposomes with small RNAs to enter human alveolar and gastric cells. Our experimental results suggest an unprecendent lipid complex route through which botanic small RNA can enter human bodies. Our results provide an innovative treatment strategy for oral delivery of siRNAs as therapeutic medication.

The renal manifestations of type 4 familial partial lipodystrophy: a case report and review of literature.

BACKGROUND: Lipodystrophy syndromes are rare disorders of variable body fat loss associated with potentially serious metabolic complications. Familial partial lipodystrophy (FPLD) is mostly inherited as an autosomal dominant disorder. Renal involvement has only been reported in a limited number of cases of FPLD. Herein, we present a rare case of proteinuria associated with type 4 FPLD, which is characterized by a heterozygous mutation in PLIN1 and has not been reported with renal involvement until now. CASE PRESENTATION: A 15-year-old girl presented with insulin resistance, hypertriglyceridaemia, hepatic steatosis and proteinuria. Her glucose and glycated haemoglobin levels were within normal laboratory reference ranges. A novel heterozygous frameshift mutation in PLIN1 was identified in the patient and her mother. The kidney biopsy showed glomerular enlargement and focal segmental glomerulosclerosis under light microscopy; the electron microscopy results fit with segmental thickening of the glomerular basement membrane. Treatment with an angiotensin-converting enzyme inhibitor (ACEI) decreased 24-h protein excretion. CONCLUSIONS: We report the first case of proteinuria and renal biopsy in a patient with FPLD4. Gene analysis demonstrated a novel heterozygous frameshift mutation in PLIN1 in this patient and her mother. Treatment with ACEI proved to be beneficial.

Overexpression of synuclein-γ predicts lack of benefit from radiotherapy for breast cancer patients.

BACKGROUND: Although radiotherapy following mastectomy was demonstrated to reduce the recurring risk and improve the prognosis of patients with breast cancer, it is also notorious for comprehensive side effects, hence only a selected group of patients can benefit. Therefore, the screening of molecular markers capable of predicting the efficacy of radiotherapy is essential. METHODS: We have established a cohort of 454 breast cancer cases and selected 238 patients with indications for postoperative radiotherapy. Synuclein-γ (SNCG) protein levels were assessed by immunohistochemistry, and SNCG status was retrospectively correlated with clinical features and survival in patients treated or not treated with radiotherapy. Gene Set Enrichment Analysis (GSEA) and survival analysis for online datasets were also performed for further validation. RESULTS: Among patients that received radiotherapy (82/238), those demonstrating positive SNCG expression had a 55.0 month shorter median overall survival (OS) in comparison to those demonstrating negative SNCG expression (78.4 vs. 133.4 months, log rank χ (2) = 16.13; p < 0.001). Among the patients that received no radiotherapy (156/238), SNCG status was not correlated with OS (log rank χ (2) = 2.40; p = 0.121). A COX proportional hazard analysis confirmed SNCG as an independent predictor of OS, only for patients who have received radiotherapy. Similar results were also obtained for distant metastasis-free survival (DMFS). A GSEA analysis indicated that SNCG was strongly associated with genes related to a radiation stress response. A survival analysis was performed with online databases consisting of breast cancer, lung cancer, and glioblastoma and further confirmed SNCG's significance in predicting the survival of patients that have received radiotherapy. CONCLUSION: A positive SNCG may serve as a potential marker to identify breast cancer patients who are less likely to benefit from radiotherapy and may also be extended to other types of cancer. However, the role of SNCG in radiotherapy response still needs to be further validated in randomized controlled trials prior to being exploited in clinical practice.

Endobronchial Ultrasound-guided Transbronchial Needle Aspiration versus Standard Bronchoscopic Modalities for Diagnosis of Sarcoidosis: A Meta-analysis.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an effective technique used to precisely detect enlarged mediastinal lymph nodes. The efficacy of EBUS-TBNA versus standard modalities for the diagnosis of sarcoidosis remains to be elucidated. In this meta-analysis, we compared the efficacies of these methods. METHODS: We searched PubMed, Embase, The Cochrane Library, Wanfang, Cpvip, CNKI, and the bibliographies of the relevant references. We analyzed the data obtained with Revman 5.2 (Nordic Cochrane Center, Copenhagen, Denmark) and Stata 12.0 software (Stata Corporation, College Station, TX, USA). The Mantel-Haenszel method was used to calculate the pooled odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: Sixteen studies with a total of 1823 participants met the inclusion criteria, and data were extracted regarding the diagnostic yield of each approach. The ORs for EBUS-TBNA versus transbronchial lung biopsy (TBLB) for the diagnosis of sarcoidosis ranged from 0.26 to 126.58, and the pooled OR was 5.89 (95% CI, 2.20-15.79, P = 0.0004). These findings indicated that EBUS-TBNA provided a much higher diagnostic yield than TBLB. The pooled OR for EBUS-TBNA + TBLB + endobronchial biopsy (EBB) versus TBNA + TBLB + EBB was 1.54 (95% CI, 0.61-3.93, P = 0.36), implying that there was no significant difference between their diagnostic yields. However, clinical heterogeneity was reflected in the nature of the studies and in the operative variables. CONCLUSIONS: The results of this meta-analysis suggest that EBUS-TBNA + TBLB + EBB could be used for the diagnosis of sarcoidosis, if available. At medical centers without EBUS-TBNA, TBNA + TBLB + EBB could be used instead.