Pretreatment mortality risk prediction model in patients with polymyositis/dermatomyositis-associated interstitial lung disease.

OBJECTIVES: Risk prediction for patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) is challenging due to heterogeneity in the disease course. We aimed to develop a mortality risk prediction model for PM/DM-ILD. METHODS: This prognostic study analysed patients with PM/DM-ILD admitted to Nanjing Drum Hospital from 2016 to 2021. The primary outcome was mortality within 1 year. We used a least absolute shrinkage and selection operator (LASSO) logistic regression model to identify predictive laboratory indicators. These indicators were used to create a laboratory risk score, and we developed a mortality risk prediction model by incorporating clinical factors. The evaluation of model performance encompassed discrimination, calibration, clinical utility and practical application for risk prediction and prognosis. RESULTS: Overall, 418 patients with PM/DM-ILD were enrolled and randomly divided into development (n=282) and validation (n=136) cohorts. LASSO logistic regression identified four optimal features in the development cohort, forming a laboratory risk score: C reactive protein, lactate dehydrogenase, CD3+CD4+ T cell counts and PO2/FiO2. The final prediction model integrated age, arthralgia, anti-melanoma differentiation-associated gene 5 antibody status, high-resolution CT pattern and the laboratory risk score. The prediction model exhibited robust discrimination (area under the receiver operating characteristic: 0.869, 95% CI 0.811 to 0.910), excellent calibration and valuable clinical utility. Patients were categorised into three risk groups with distinct mortality rates. The internal validation, sensitivity analyses and comparative assessments against previous models further confirmed the robustness of the prediction model. CONCLUSIONS: We developed and validated an evidence-based mortality risk prediction model with simple, readily accessible clinical variables in patients with PM/DM-ILD, which may inform clinical decision-making.

Factors influencing the accuracy and safety of preoperative computed tomography (CT)-guided soft hook-wire localization for pulmonary nodules: a comprehensive analysis.

Background: The necessity of localization of pulmonary nodules lies in ensuring the ability to locate the nodule quickly and accurately during surgery, thereby improving the success rate of the operation. The accuracy and risk of preoperative localization of pulmonary nodules need further exploration. Therefore, the purpose of this study was to investigate the factors of accuracy and safety of computed tomography (CT)-guided localization of pulmonary nodules using a flexible wire hook positioner. Methods: In this retrospective cross-sectional analysis, 281 patients with a single pulmonary nodule underwent video-assisted thoracoscopic surgery (VATS) following localization with a soft hook-wire guided by CT scan from January 2021 to July 2022 at Nanjing Drum Tower Hospital. The patients underwent VATS to remove pulmonary nodules within 24 hours after localization. The demographic, pulmonary nodule, and technical factors were analyzed retrospectively. Univariate and multivariate analysis were used to analyze the identified factors that influence pulmonary nodule localization accuracy and complications. Results: Localization was successfully performed in 280 patients, with only 1 patient being excluded due to a displaced positioner and the hook wire failing to enter the lung parenchyma as a result of pneumothorax. Out of the total cases, 191 (68.2%) were accurately positioned in group G0, whereas 89 cases (31.7%) were inaccurately positioned in group G1. Hemorrhage and self-limited hemoptysis were observed in 64 patients (22.8%), whereas pneumothorax was observed in 84 patients (29.9%). There were no serious complications such as air embolism or death. The accuracy of localization was found to be influenced by both the depth of pulmonary nodules [odds ratio (OR) =22.610, 95% confidence interval (CI): 10.351-49.391, P=0.001] and the depth of the needle used (OR =0.322, 95% CI: 0.136-0.765, P=0.010). Additionally, postoperative hemorrhage was found to be affected by several important factors, including the diameter (P=0.036) and depth of the nodule (P=0.011), as well as the thickness of the chest wall (P=0.043) and the depth of the needle used (P=0.005). Conclusions: The CT-guided flexible wire hook positioner has been found to be a safe and effective device for locating pulmonary nodules. The depth of pulmonary nodules and needle penetration are key factors affecting the accuracy of lung nodule localization under CT guidance and are important factors affecting postoperative bleeding.

Extracellular volume fraction as a potential predictor to differentiate lung cancer from benign lung lesions with dual-layer detector spectral CT.

Background: Extracellular volume (ECV) fraction has been used in cardiovascular diseases, pancreatic fibrosis, and hepatic fibrosis. The diagnostic value of ECV for focal lung lesions remains to be explored. The aim of this study was to evaluate the feasibility of ECV derived from a dual-layer detector computed tomography (DLCT) to differentiate lung cancer (LC) from benign lung lesions (BLLs). Methods: Retrospectively, 128 consecutive patients with pathologically confirmed LC (n=86) or BLLs (n=42) were included. Conventional computed tomography (CT) characteristics and spectral CT parameters were assessed. All patients' hematocrits were measured to correct contrast volume distributions in blood while calculating ECV. After performing logistic regression analysis, a conventional CT-based model (Model A), DLCT-based model (Model B), combined diagnostic models (Model C), and an ECV-based model (Model D) were developed. The diagnostic effectiveness of each model was examined using the receiver operating characteristic (ROC) curve and their corresponding 95% confidence intervals (CIs). The area under the curve (AUC) of each model was compared using the DeLong test. Results: Certain conventional CT features (such as lesion size, lobulation, spiculation, pleural indentation, and enlarged lymph nodes) differed significantly between the LC and BLL groups (all P<0.05). Statistical differences were found in the following DLCT parameters (all P<0.05): effective atomic number (Zeff) (non-enhancement), electron density (ED) (non-enhancement), ECV, iodine concentration (IC), and normalized iodine concentration (NIC). Models A, B, C, and D had AUCs of 0.801 [95% confidence interval (CI): 0.721-0.866], 0.805 (95% CI: 0.726-0.870), 0.925 (95% CI: 0.865-0.964), and 0.754 (95% CI: 0.671-0.826), respectively. The AUC of Model D (ECV) showed no significant difference from that of Models A and B (DeLong test, P>0.05). Conclusions: The ECV derived from DLCT may be a potential new method to differentiate LC from BLLs, broadening the scope of ECV in clinical research.

T cell immunotherapy for cervical cancer: challenges and opportunities.

Cancer cellular immunotherapy has made inspiring therapeutic effects in clinical practices, which brings new hope for the cure of cervical cancer. CD8+T cells are the effective cytotoxic effector cells against cancer in antitumor immunity, and T cells-based immunotherapy plays a crucial role in cellular immunotherapy. Tumor infiltrated Lymphocytes (TIL), the natural T cells, is approved for cervical cancer immunotherapy, and Engineered T cells therapy also has impressive progress. T cells with natural or engineered tumor antigen binding sites (CAR-T, TCR-T) are expanded in vitro, and re-infused back into the patients to eradicate tumor cells. This review summarizes the preclinical research and clinical applications of T cell-based immunotherapy for cervical cancer, and the challenges for cervical cancer immunotherapy.

Maternal hyperglycemia inhibits pulmonary vasculogenesis during mouse fetal lung development by promoting GßL Ubiquitination-dependent mammalian target of Rapamycin assembly.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with retarded lung development and poor lung health in offspring. Mammalian target of rapamycin (mTOR) is a key regulator of vasculogenesis and angiogenesis. The aim of this study was to investigate the role mTOR plays in pulmonary vasculogenesis during fetal lung development under maternal hyperglycemia. METHODS: First, GDM was induced via streptozotocin injection in pregnant C57BL/6 mice before the radial alveolar count (RAC) in the fetal lungs was assessed using hematoxylin and eosin staining. The angiogenic ability of the cultured primary mouse fetal lung endothelial cells (MFLECs) was then assessed using the tube formation assay technique, while western blot and real-time polymerase chain reaction were performed to determine the expression of mTOR, regulatory-associated protein of mTOR (Raptor), rapamycin-insensitive companion of mTOR (Rictor), stress-activated protein kinase interacting protein 1 (Sin1), G protein beta subunit-like protein (GßL), Akt, tumor necrosis receptor associated factor-2 (TRAF2), and OTU deubiquitinase 7B (OTUD7B) in both the fetal lung tissues and the cultured MFLECs. Immunoprecipitation assays were conducted to evaluate the status of GßL-ubiquitination and the association between GßL and mTOR, Raptor, Rictor, and Sin1 in the cultured MFLECs. RESULTS: The GDM fetal lungs exhibited a decreased RAC and reduced expression of von Willebrand factor, CD31, and microvessel density. The high glucose level reduced the tube formation ability in the MFLECs, with the mTOR, p-mTOR, p-Raptor, and TRAF2 expression upregulated and the p-Rictor, p-Sin1, p-Akt, and OTUD7B expression downregulated in both the GDM fetal lungs and the high-glucose-treated MFLECs. Meanwhile, GßL-ubiquitination was upregulated in the high-glucose-treated MFLECs along with an increased GßL/Raptor association and decreased GßL/Rictor and GßL/Sin1 association. Furthermore, TRAF2 knockdown inhibited the high-glucose-induced GßL-ubiquitination and GßL/Raptor association and restored the tube formation ability of the MFLECs. CONCLUSION: Maternal hyperglycemia inhibits pulmonary vasculogenesis during fetal lung development by promoting GßL-ubiquitination-dependent mTORC1 assembly.

Quantitative chest CT assessment of pulmonary alveolar proteinosis with deep learning: a real-world longitudinal study.

Background: High-resolution computed tomography (HRCT) plays an important role in accessing the severity of pulmonary alveolar proteinosis (PAP). Visual evaluation of changes between two HRCT scans is subjective. This study was conducted to quantitatively evaluate lung burden changes in patients with PAP using HRCT-based automated deep-learning method following 12 months of statin therapy. Methods: In this prospective real-world observational study, patients with PAP who underwent chest HRCT were evaluated from November 28, 2018, to April 12, 2021. Oral statin administration was initiated as therapy for these PAP patients with 12 months of follow-up. HRCT-derived lung ground-glass opacification percentage of the whole lung and 5 lobes and the percentage of different densities of ground glass were automatically quantified with deep-learning software. Longitudinal changes of the HRCT quantitative parameter were also compared. Results: The study enrolled 50 patients with PAP, including 25 mild-moderate PAP cases and 25 severe PAP cases. The percentage of lung ground-glass opacification of the whole lung and 5 lobes and the percentage of different densities of ground glass were significantly different among the 2 different clinical types at baseline (all P values <0.05). Overall, the percentage of whole-lung ground-glass opacification significantly decreased between the baseline HRCT and the HRCT results after 12 months of follow-up (P=0.023; 95% CI: 1.384-18.684). Changes in the total opacification of the whole lung were positively correlated with changes in partial pressure of arterial oxygen (PaO2; r=0.716; P<0.001) and percentage of predicted diffusion capacity for carbon monoxide (DLCO%pred; r=0.664; P<0.001). Conclusions: A quantitative image parameter automatically generated by a deep-learning tool from chest HRCT scans may be used to evaluate the severity of PAP and may help to evaluate and quantify the response to statin therapy.

Case Report: Small intestinal metastatic breast cancer: A case report and literature review.

Breast cancer is considered a malignant tumor with the highest incidence among women and is prone to develop distant metastasis. Small intestinal metastasis of breast cancer, however, is relatively rare. This case report describes a 49-year-old Chinese female patient who presented with small intestinal obstruction and was diagnosed with lobular breast cancer with small intestinal and contralateral breast metastasis. Clinical manifestations, clinicopathological features and potential mechanisms of metastasis, along with diagnosis and treatment, are discussed with a review of the relevant literature. Although small intestinal metastasis is rare in breast cancer, we should keep high alert on the possibility of gastrointestinal metastasis when treating lobular breast cancer patients.

Assessment of Statin Treatment for Pulmonary Alveolar Proteinosis without Hypercholesterolemia: A 12-Month Prospective, Longitudinal, and Observational Study.

Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder which is characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy has been reported to be a novel therapy for PAP with hypercholesterolemia. We aimed to evaluate the safety and efficacy of oral statin therapy for PAP without hypercholesterolemia. Methods: In a prospective real-world observational study, 47 PAP patients without hypercholesterolemia were screened. Oral statin was initiated as therapy for these PAP patients with 12 months of follow-up. Results: Forty PAP patients completed the study. 26 (65%) of 40 PAP patients responded to statin therapy according to the study criteria. Partial pressure of arterial oxygen (PaO2) and percentage of diffusion capacity predicted (DLCO%) significantly increased while disease severity score (DSS) and radiographic abnormalities decreased after 12 months of statin therapy (all p < 0.05). The factors associated with response were higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody and baseline total cholesterol/high-density lipoprotein cholesterol (TC/HDL) (p = 0.015 and p = 0.035, respectively). The area under the receiver operating characteristic curve (AUROC) of dose of atorvastatin for predicting the response to statin therapy for PAP was 0.859 (95% CI: 0.738-0.979, p < 0.001). The cutoff dose of atorvastatin was 67.5 mg daily with their corresponding specificity (64.3%) and sensitivity (96.2%). No severe side effects were observed during the study. Conclusions: In PAP patients without hypercholesterolemia, statin therapy resulted in improvements in arterial blood gas (ABG) measurement, pulmonary function, and radiographic assessment.

Prediction model for the pretreatment evaluation of mortality risk in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease.

Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early. Methods: This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846-0.957), good calibration (Hosmer-Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001). Conclusions: We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.

Iodine-Rich Nanoadjuvants for CT Imaging-Guided Photodynamic Immunotherapy of Breast Cancer.

Immunotherapy, which stimulates the body's own immune system to kill cancer cells, has shown great promise in the field of cancer therapy. However, the uncontrolled biodistribution of immunotherapeutic drugs may cause severe side effects. Herein, we report an iodine-rich nanoadjuvant (INA) for photo-immunotherapy. INA is prepared by encapsulating a toll-like receptor 7 agonist (R837) and a photosensitizer (phthalocyanine) into an iodine-rich amphiphilic copolymer PEG-PHEMA-I. By virtue of the enhanced permeation and retention (EPR) effect, INA can effectively accumulate into the tumor site. Under light irradiation, photodynamic therapy (PDT) triggered by INA will induce immunogenic cell death (ICD) in the tumor region to trigger the release of immune-associated cytokines. Such a process may further induce the maturation of dendritic cells which will be accelerated by R837, leading to the proliferation of effector T cells for immunotherapy. The photo-immunotherapy mediated by INA shows good anticancer efficacy both in vitro and in vivo. Meanwhile, INA is also a CT contrast agent owing to its high density of iodine, which can successfully illuminate tumors by CT imaging. Thus, our study develops a light-triggered nanoadjuvant for CT imaging-guided enhanced photo-immunotherapy.

Brain morphological alterations and their correlation to tumor differentiation and duration in patients with lung cancer after platinum chemotherapy.

Objective: Chemotherapy-related brain impairments and changes can occur in patients with lung cancer after platinum chemotherapy and have a substantial impact on survivors' quality of life. Therefore, it is necessary to understand the brain neuropathological alterations and response mechanisms to provide a theoretical basis for rehabilitation strategies. This study aimed to investigate the related brain morphological changes and clarified their correlation with clinical and pathological indicators in patients with lung cancer after platinum chemotherapy. Methods: Overall, 28 patients with chemotherapy, 56 patients without chemotherapy, and 41 healthy controls were categorized in three groups, matched for age, sex, and years of education, and included in the cross-sectional comparison of brain volume and cortical thickness. 14 matched patients before and after chemotherapy were subjected to paired comparison for longitudinal observation of brain morphological changes. Three-dimensional T1-weighted images were acquired from all participants, and quantitative parameters were calculated using the formula of the change from baseline. Correlation analysis was performed to evaluate the relationship between abnormal morphological indices and clinical information of patients. Results: Brain regions with volume differences among the three groups were mainly distributed in frontal lobe and limbic cortex. Additionally, significant differences in cerebrospinal fluid were observed in most ventricles, and the main brain regions with cortical thickness differences were the gyrus rectus and medial frontal cortex of the frontal lobe, transverse temporal gyrus of the temporal lobe, insular cortex, anterior insula, and posterior insula of the insular cortex. According to the paired comparison, decreased brain volumes in the patients after chemotherapy appeared in some regions of the frontal, parietal, temporal, and occipital lobes; limbic cortex; insular cortex; and lobules VI-X and decreased cortical thickness in the patients after chemotherapy was found in the frontal, temporal, limbic, and insular cortexes. In the correlation analysis, only the differentiation degree of the tumor and duration after chemotherapy were significantly correlated with imaging indices in the abnormal brain regions. Conclusions: Our findings illustrate the platinum-related brain reactivity morphological alterations which provide more insights into the neuropathological mechanisms of patients with lung cancer after platinum chemotherapy and empirical support for the details of brain injury related to cancer and chemotherapy.

A Bibliometric Analysis of 8271 Publications on Thyroid Nodules From 2000 to 2021.

Introduction: Thyroid nodules (TNs) are a common clinical condition. The probability of thyroid nodules being malignant is 7-15%. However, in recent decades, a number of publications on TNs have not been well summarized and discussed. The aim of this study was to summarize and sort out medical publications on TNs over the past 2 decades using a bibliometric method. Materials and Methods: Medical publications from January 1st, 2000, to November 1st, 2021, were searched in the Web of Science Core Collection database using the Medical Subject Heading (MeSH) term "thyroid nodule". Full associated data were downloaded, and detailed information was extracted using the bibliometric analysis platform VOSviewer. Results: A total of 8271 publications related to TNs from the last 2 decades were found and included in this study. An increasing trend was presented in the annual number of publications. The United States, China and Italy contributed the most publications. Carcinoma, management, ultrasound, and fine-needle aspiration were the most popular subjects in the field of TNs. The topics of the studies could be stratified into four clusters. The first cluster was using ultrasound to evaluate the nodules, including the thyroid imaging reporting and data system (TI-RADS), elastography and benign features. The second cluster was the fine-needle aspiration method, including the Bethesda system, cytology and BRAF mutations. The third cluster was the management of nodules, including radiofrequency and thermal ablation, surgery, and consensus statements. The last cluster was carcinoma, which is correlated with all three clusters described above. The preoperative diagnosis of cytologically indeterminate nodules was particularly highlighted in the top 10 most cited publications in recent years. Conclusion: How to diagnose thyroid nodules as malignant or benign, especially in cytologically indeterminate nodules, is still the most concerning topic in TN research. Although the fine-needle aspiration method and gene-expression classifiers show promising results, there is still a crucial need for translations from fundamental studies to clinical applications.

Anti-Ro52 antibodies are associated with the prognosis of adult idiopathic inflammatory myopathy-associated interstitial lung disease.

OBJECTIVES: In the present study, we aimed to assess the prevalence and clinical significance of anti-Ro52 antibodies in a cohort of patients with idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) with different myositis-specific autoantibodies (MSAs). METHODS: A cohort of 267 IIM-ILD patients, including 62 patients with PM, 126 patients with DM and 79 patients with clinically amyopathic DM (CADM) were retrospectively analysed in this study. Clinical and laboratory findings, pulmonary function tests (PFTs), HRCT patterns and treatment information were compared between patients with and without anti-Ro52 antibodies. The association between prognosis and anti-Ro52 antibodies was also evaluated based on different MSA subgroups. RESULTS: Anti-Ro52 antibodies were more frequent in patients with anti-MDA5 (62.1%, P < 0.01) and anti-Jo1 (64.9%, P < 0.01) antibodies than in those with other MSAs. The proportion of patients with anti-Jo1 antibodies was higher in the anti-Ro52 antibody-positive group than in the anti-Ro52 antibody-negative group. Patients with anti-Ro52 antibodies were more likely to exhibit the Gottron sign than the anti-Ro52 antibody-negative group (P < 0.001). Furthermore, it was a predictive factor for rapid progression interstitial lung disease (RP-ILD) (P = 0.001) and was also associated with a higher mortality rate (log-rank test, P = 0.001). Furthermore, RP-ILD was more frequently exhibited in anti-MDA5- and anti-Ro52-positive patients. Moreover, anti-Ro52 antibody positivity was closely associated with a higher mortality rate in anti-MDA5-ILD patients (log-rank test, P < 0.05). CONCLUSIONS: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5 and anti-Jo1 antibodies. Within all patients with IIM-ILD, those with anti-Ro52 autoantibodies had a higher frequency of RP-ILD and a poorer prognosis, especially in the anti-MDA5 antibody subgroup.

Heterogeneity response to afatinib in gastric cancer patient with uncommon epidermal growth factor receptor (EGFR) mutations: a case report.

Despite concerted efforts that have been made to characterize and understand the genomic landscape of gastric cancer (GC), only HER2 has been validated as a molecular target for GC treatment. Identifying new valid therapeutic targets is important for the treatment of this disease. The present report describes a Chinese male with a history of smoking two packs per day, who did not have a family history of cancer or other hereditary diseases, we discovered a small painless lump in the right groin in February 2018. Histopathology revealed a primary gastric adenocarcinoma. Positron emission tomography-computed tomography (PET-CT) showed multiple hypermetabolic nodules in the right upper lung, greater curvature of the stomach, and muscles. The patient had received treatment included oxaliplatin, docetaxel, and tegafur for two cycles, and second-line therapy of irinotecan and capecitabine, inguinal mass excision followed by concurrent radio-chemotherapy. However, the disease rapidly progressed. Whole exome sequencing (WES) showed uncommon epidermal growth factor receptor (EGFR) mutation of G719S + L861Q. The following EGFR tyrosine kinase inhibitors (TKIs) afatinib demonstrated partial response. Two months after targeted therapy, gastroscopy indicated rapid progression. With subsequent gastric specimen WES analysis, secondary MET amplification was found. The patient received local radiotherapy for gastric lesions as well as oral administration of apatinib. However, the disease rapidly progressed. A month later, he died of hepatic encephalopathy caused by obstructive jaundice combined with pulmonary and biliary tract infection. The present study indicated that afatinib might be a beneficial therapeutic option for a subset of GC patients with rare EGFR mutation in their tumors.

Long-term follow-up and successful treatment of pulmonary alveolar proteinosis without hypercholesterolemia with statin therapy: a case report.

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy is a novel treatment for PAP with hypercholesterolemia. However, this treatment has never been described in a patient without hypercholesterolemia. Here, we present a case of successful treatment with atorvastatin for a patient with possibly unclassified PAP without hypercholesterolemia who responded poorly to whole lung lavage therapy and inhaled granulocyte-macrophage colony-stimulating factor. After 18 months of atorvastatin treatment, the patient experienced improvements in dyspnea, radiographic abnormalities and pulmonary function. The present case study supports the feasibility of statin therapy for PAP regardless of the level of cholesterol.

Guiding-Strand-Controlled DNA Nucleases with Enhanced Specificity and Tunable Kinetics for DNA Mutation Detection.

Nucleases are powerful tools in various biomedical applications, such as genetic engineering, biosensing, and molecular diagnosis. However, the commonly used nucleases (endonuclease IV, apurinic/apyrimidinic endonuclease-1, and λ exonuclease) are prone to the nonspecific cleavage of single-stranded DNA, making the desired reactions extremely low-yield and unpredictable. Herein, we have developed guiding-strand-controlled nuclease systems and constructed theoretical kinetic models to explain their mechanisms of action. The models displayed excellent agreement with the experimental results, making the kinetics highly predictable and tunable. Our method inhibited the nonspecific cleavage of single-stranded probes while maintaining highly efficient cleavage of double-stranded DNA. We also demonstrated the clinical practicability of the method by detecting a low-frequency mutation in a genomic DNA sample extracted from the blood of a patient with cancer. The limit of detection could be 0.01% for PTEN rs121909219. We believe that our findings provide a powerful tool for the field and the established model provides us a deeper understanding of the enzymatic activities of DNA nucleases.

Cytokeratin 19 fragment is associated with severity and poor prognosis of interstitial lung disease in anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: In the present study, we aimed to assess the clinical significance of cytokeratin 19 fragment (CYFRA21-1) in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-interstitial lung disease (MDA5-DM-ILD). METHODS: A total of 73 MDA5-DM-ILD patients were retrospectively analysed in this work. Their clinical characteristics, including clinical manifestations, laboratory findings, peripheral blood lymphocyte subsets and lung function, were compared between patients with acute/subacute interstitial pneumonia (A/SIP) and chronic interstitial pneumonia (CIP). The level of serum CYFRA21-1 was also compared between the above-mentioned two groups of patients, and its association with the clinical features and mortality of MDA5-DM-ILD was also evaluated. RESULTS: Of the 73 MDA5-DM-ILD patients, 26 patients exhibited the A/SIP pattern. The level of serum CYFRA21-1 was higher in MDA5-DM patients with A/SIP compared with the CIP group (P = 0.009). Lower oxygenation index (OI), CD3+CD4+ T cell counts and percentage of CD3+CD4+ cells were also observed in MDA5-DM patients with A/SIP compared with the CIP group. Higher serum CYFRA21-1, lower OI, and lower zone consolidation were associated with a higher risk of A/SIP in MDA5-DM-ILD. In addition, 38 decedents with MDA5-DM-ILD exhibited a greater level of CYFRA21-1 compared with 35 survivors (P < 0.001). Furthermore, it was a prognostic factor and also associated with a higher mortality rate (log-rank test, P < 0.001). CONCLUSIONS: CYFRA21-1 could be a useful serum indicator associated with occurrence of A/SIP in MDA5-DM-ILD. Moreover, it was associated with a poor survival in MDA5-DM-ILD patients.

Analysis of carcinogenic signaling networks in endometrial cancer identifies RAB17 as a potential target.

Endometrial cancer is one of the most common malignancies in postmenopausal women. Several potential therapeutic targets have been investigated in current research, but few have been used clinically. Therefore, further investigating the potential pathogenesis of endometrial cancer and new effective therapeutic targets for endometrial malignancies is still necessary. Our study used a The Cancer Genome Atlas dataset and two Gene Expression Omnibus datasets for weighted gene coexpression network analysis to identify important genes associated with the histological grades of endometrial cancer. In addition, we performed gene set enrichment analysis on the three datasets and found that abnormally activated signaling pathways and metabolic pathways are the main biological behaviors of endometrial cancer. Moreover, we further used different algorithms and identified the RAB17 gene as a potential study object. To further illustrate the potential role of the genes we analyzed in clinical and cellular aspects, we performed a clinical correlation analysis. Finally, we demonstrated the important roles and mechanisms of the RAB17 gene in the cell cycle, proliferation, and metastasis of endometrial cancer. Using repeated database analysis and cell-level assays, we propose RAB17 as a potential target gene for endometrial cancer for further study.

Surfactant protein D is associated with 3-month mortality of anti-MDA5 antibody-interstitial lung disease.

OBJECTIVES: To investigate the associations between serum levels of matrix metalloproteinase 7 (MMP7), surfactant protein D (SPD), interleukin 18 (IL-18) and chemokine ligand 18 (CCL18) with dermatomyositis and polymyositis-associated interstitial lung disease (DM/PM-ILD) and evaluate their prognostic values in the disease. METHODS: Seventy-eight patients with multiple disciplinary team diagnosis of DM/PM-ILD were enrolled and classified as anti-melanoma differentiation-associated protein 5 antibody (MDA5)-ILD, anti-synthetase antibodies (ARS)-ILD and other antibodies-ILD upon autoantibodies profiles. Clinical data were collected and serum levels of four biomarkers were analysed. The primary endpoint was 3-month mortality. The cut-off values of biomarkers for mortality were figured out by receiver operating characteristic (ROC) analysis. Cox regression was performed to evaluate predictive values. RESULTS: Serum levels of MMP7 (p=0.036), SPD (p<0.001), IL-18 (p<0.001) and CCL18 (p<0.001) in patients with DM/PM-ILD were significantly higher than healthy controls with levels of MMP7 (p=0.029) and SPD (p=0.029) in patients with MDA5-ILD significantly lower than patients with ARS-ILD. The 3-month mortality in MDA5-ILD was 54.5% (12/22). Multivariate analysis showed that age (p=0.001, HR 1.151, 95% CI 1.063-1.247) and an increased level of SPD (>75.90ng/ml, p=0.005, HR 16.411, 95% CI 2.369-113.711) were significant predictors for 3-month mortality in patients with MDA5-ILD. CONCLUSIONS: Elevated serum biomarkers were associated with DM/PM-ILD with differential levels between MDA5-ILD and ARS-ILD. Age and an increased SPD had prognostic values for predicting short-term mortality in patients with MDA5-ILD. Our study was important in providing a clue for understanding the classification and prognosis of DM/PM-ILD.

Integration of immunogenic activation and immunosuppressive reversion using mitochondrial-respiration-inhibited platelet-mimicking nanoparticles.

Here, we developed platelet membranes (PM) as nano-carriers to co-encapsulate metformin (Met) and IR780 (PM-IR780-Met NPs). The resulting nano-carrier ensured a longer circulation lifetime and facilitated the greater accumulation of IR780 and Met in tumors owing to the active adhesion between PM and tumor cells. As a photodynamic therapy (PDT) agent, IR780 could effectively kill the tumor by producing toxic reactive singlet oxygen species (ROS), while the introduction of Met inhibited mitochondrial respiration and reduced tumor oxygen consumption, thereby evoking an oxygen-boosted PDT and propelling the immunogenic cell death (ICD)-based immunogenic pathway. Meanwhile, the reversed tumor hypoxia also impeded the myeloid derived suppressor cell (MDSC)-regulated immunosuppressive pathway. Finally, tremendous T cells were recruited and activated, providing a promising platform to eliminate the primary tumors and synchronously opening a new avenue for the effective ablation of tumor metastasis.