Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction. RESULTS: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency. CONCLUSIONS: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.

Imaging of Solid Pulmonary Nodules.

Early detection with accurate classification of solid pulmonary nodules is critical in reducing lung cancer morbidity and mortality. Computed tomography (CT) remains the most widely used imaging examination for pulmonary nodule evaluation; however, other imaging modalities, such as PET/CT and MRI, are increasingly used for nodule characterization. Current advances in solid nodule imaging are largely due to developments in machine learning, including automated nodule segmentation and computer-aided detection. This review explores current multi-modality solid pulmonary nodule detection and characterization with discussion of radiomics and risk prediction models.

Photon-counting CT in Thoracic Imaging: Early Clinical Evidence and Incorporation Into Clinical Practice.

Photon-counting CT (PCCT) is an emerging advanced CT technology that differs from conventional CT in its ability to directly convert incident x-ray photon energies into electrical signals. The detector design also permits substantial improvements in spatial resolution and radiation dose efficiency and allows for concurrent high-pitch and high-temporal-resolution multienergy imaging. This review summarizes (a) key differences in PCCT image acquisition and image reconstruction compared with conventional CT; (b) early evidence for the clinical benefit of PCCT for high-spatial-resolution diagnostic tasks in thoracic imaging, such as assessment of airway and parenchymal diseases, as well as benefits of high-pitch and multienergy scanning; (c) anticipated radiation dose reduction, depending on the diagnostic task, and increased utility for routine low-dose thoracic CT imaging; (d) adaptations for thoracic imaging in children; (e) potential for further quantitation of thoracic diseases; and (f) limitations and trade-offs. Moreover, important points for conducting and interpreting clinical studies examining the benefit of PCCT relative to conventional CT and integration of PCCT systems into multivendor, multispecialty radiology practices are discussed.

Long-term prognosis analysis of surgical therapy for bilateral synchronous multiple primary lung cancer: a follow-up of 293 cases.

Background: Bilateral synchronous multiple primary lung cancer (BSMPLC) presents significant clinical challenges due to its unique characteristics and prognosis. Understanding the risk factors that influence overall survival (OS) and recurrence-free survival (RFS) is crucial for optimizing therapeutic strategies for BSMPLC patients. Methods: We retrospectively analyzed clinical characteristics and treatment outcomes of 293 patients with BSMPLC who underwent surgical treatment between January 2010 and July 2017. Results: The 10-year OS and RFS rates were 96.1% and 92.8%, respectively. Preoperative forced expiratory volume in 1 second (FEV1) ≥70% [hazard ratio (HR), 0.214; 95% confidence interval (CI): 0.053 to 0.857], identical pathology types (HR, 9.726; 95% CI: 1.886 to 50.151), largest pT1 (HR, 7.123; 95% CI: 2.663 to 19.055), and absence of lymphovascular invasion (LVI; HR, 7.021; 95% CI: 1.448 to 34.032) emerged as independent predictors of improved OS. Moreover, the sum of tumor sizes less than or equal to 3 cm (HR, 6.229; 95% CI: 1.411 to 27.502) and absence of pleural invasion (HR, 3.442; 95% CI: 1.352 to 8.759) were identified as independent predictors of enhanced RFS. The presence or absence of residual nodules after bilateral surgery did not influence patients' OS (P=0.987) and RFS (P=0.054). Conclusions: Patients with BSMPLC who underwent surgery generally had a favorable prognosis. Whether or not to remove all nodules bilaterally does not affect the patient's long-term prognosis, suggesting the need for an individualized surgical approach.

Circulating microRNA Panel for Prediction of Recurrence and Survival in Early-Stage Lung Adenocarcinoma.

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

Combined Pulmonary Fibrosis and Emphysema: A Narrative Review.

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity.

The dynamic contrast enhanced-magnetic resonance imaging and diffusion-weighted imaging features of alveolar soft part sarcoma.

Background: Alveolar soft part sarcoma (ASPS) is a rare type of soft tissue sarcoma that predominantly affects adolescents and young adults. Early diagnosis of ASPS is crucial for optimal therapeutic planning and improving prognosis, but its diagnostic features are not well delineated. This study aimed to retrospectively analyze the imaging features of ASPS with an emphasis on the dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) findings to identify imaging findings that might suggest the diagnosis to radiologists. Methods: The imaging features of 34 patients with pathologically proven limb ASPS were retrospectively analyzed. A total of 23 underwent DCE-MRI, and 12 underwent DWI. Results: Among the 34 cases of ASPS, 31 tumors were in the lower extremities, and 3 were in the upper extremities. The maximum tumor diameters ranged from 3.0 to 19.4 cm (mean, 8.7±3.96 cm). A total of 28 cases had well-defined borders. The masses demonstrated heterogeneous high signal intensity on T2-weighted imaging (T2WI) and the fat-suppressed (FS) T2WI sequence and slight hyperintensity on T1-weighted imaging (T1WI). A total of 25 lesions had thin hypointense bands on T1WI and T2WI. Intra- and peri-tumoral tubular areas of flow void were exhibited on both T1WI and T2WI in all cases. A total of 12 cases showed a high signal on DWI, and the mean apparent diffusion coefficient (ADC) value was (0.86±0.07)×10-3 mm2/s [range, (0.6-1.4)×10-3 mm2/s]. Persistent remarkable enhancement of the lesion was displayed on contrast-enhanced scans. The time-intensity curves (TICs) of 23 masses showed early arterial enhancement and slow washout of contrast. Conclusions: ASPS most commonly presents in the lower extremities of adolescents or young adults. Hyperintense T1WI, T2WI, and DWI signals, low ADC, flow voids, early arterial enhancement are frequent MRI features.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms 'diffuse' and 'idiopathic.' We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Recent Advancements in Computed Tomography Assessment of Fibrotic Interstitial Lung Diseases.

Interstitial lung disease (ILD) is a heterogeneous group of disorders with complex and varied imaging manifestations and prognosis. High-resolution computed tomography (HRCT) is the current standard-of-care imaging tool for ILD assessment. However, visual evaluation of HRCT is limited by interobserver variation and poor sensitivity for subtle changes. Such challenges have led to tremendous recent research interest in objective and reproducible methods to examine ILDs. Computer-aided CT analysis to include texture analysis and machine learning methods have recently been shown to be viable supplements to traditional visual assessment through improved characterization and quantification of ILDs. These quantitative tools have not only been shown to correlate well with pulmonary function tests and patient outcomes but are also useful in disease diagnosis, surveillance and management. In this review, we provide an overview of recent computer-aided tools in diagnosis, prognosis, and longitudinal evaluation of fibrotic ILDs, while outlining some of the pitfalls and challenges that have precluded further advancement of these tools as well as potential solutions and further endeavors.

Transition-Metal-Free Upscaling of 2,5-Furandicarboxylic Acid Synthesis and Investigation of the Reaction Mechanism.

An environmentally friendly oxidation system has proposed for the practical and scalable production of value-added 2,5-furandicarboxylic acid from 1 kg of 5-hydroxymethylfurfural. The system is composed of a simple base, oxygen, and a green solvent, thereby providing a sustainable and economical approach to organic synthesis. To gain insight into the mechanism of this oxidation process, NMR spectroscopic analysis and kinetic study are used for the mechanistic investigation of this environmentally friendly oxidation process.

Analysis of Immune Intratumor Heterogeneity Highlights Immunoregulatory and Coinhibitory Lymphocytes as Hallmarks of Recurrence in Stage I Non-Small Cell Lung Cancer.

Our understanding of the molecular mechanisms underlying postsurgical recurrence of non-small cell lung cancer (NSCLC) is rudimentary. Molecular and T cell repertoire intratumor heterogeneity (ITH) have been reported to be associated with postsurgical relapse; however, how ITH at the cellular level impacts survival is largely unknown. Here we report the analysis of 2880 multispectral images representing 14.2% to 27% of tumor areas from 33 patients with stage I NSCLC, including 17 cases (relapsed within 3 years after surgery) and 16 controls (without recurrence ≥5 years after surgery) using multiplex immunofluorescence. Spatial analysis was conducted to quantify the minimum distance between different cell types and immune cell infiltration around malignant cells. Immune ITH was defined as the variance of immune cells from 3 intratumor regions. We found that tumors from patients having relapsed display different immune biology compared with nonrecurrent tumors, with a higher percentage of tumor cells and macrophages expressing PD-L1 (P =.031 and P =.024, respectively), along with an increase in regulatory T cells (Treg) (P =.018), antigen-experienced T cells (P =.025), and effector-memory T cells (P =.041). Spatial analysis revealed that a higher level of infiltration of PD-L1+ macrophages (CD68+PD-L1+) or antigen-experienced cytotoxic T cells (CD3+CD8+PD-1+) in the tumor was associated with poor overall survival (P =.021 and P =.006, respectively). A higher degree of Treg ITH was associated with inferior recurrence-free survival regardless of tumor mutational burden (P =.022), neoantigen burden (P =.021), genomic ITH (P =.012) and T cell repertoire ITH (P =.001). Using multiregion multiplex immunofluorescence, we characterized ITH at the immune cell level along with whole exome and T cell repertoire sequencing from the same tumor regions. This approach highlights the role of immunoregulatory and coinhibitory signals as well as their spatial distribution and ITH that define the hallmarks of tumor relapse of stage I NSCLC.

Etiological diagnostic value of metagenomic next-generation sequencing in peritoneal dialysis-related peritonitis / 中华肝脏病杂志

Objective: To explore the etiological diagnostic value of metagenomic next-generation sequencing (mNGS) in peritoneal dialysis (PD)-related peritonitis. Methods: The study was a retrospective cohort study. The clinical data of patients with PD-related peritonitis who were treated and underwent microbial cultivation and mNGS test at the same time from June 2020 to July 2021 in the Affiliated Drum Tower Hospital, Medical School of Nanjing University were analyzed. The positive rate, detection time and consistency between mNGS test and traditional microbial culture were compared. Results: A total of 18 patients with age of (50.4±15.4) years old and median dialysis time of 34.0 (12.4, 62.0) months were enrolled in the study, including 11 males and 7 females. Pathogenic microorganisms were isolated in 17 patients by mNGS test, with a positive rate of 17/18, which was higher than 13/18 of microbial culture, but the difference was not statistically significant (P=0.219). Both mNGS test and microbial culture isolated positive pathogenic bacteria in 12 patients, and mNGS test isolated the same types of pathogenic bacteria as microbial cultivation did in 11 patients. In five patients with negative microbial culture, mNGS test also isolated pathogenic microorganisms, including 3 cases of Staphylococcus epidermidis, 1 case of Mycobacterium tuberculosis and 1 case of Ureaplasma urealyticum. In 1 patient, microbial culture isolated pathogenic bacteria (Escherichia coli) whereas mNGS test did not. The detection time of mNGS was 25.0 (24.0, 27.0) h, which was significantly shorter than 89.0 (72.8, 122.0) h of microbial culture (Z=3.726, P<0.001). Conclusions: mNGS test can improve the detection rate of pathogenic microorganisms in PD-related peritonitis and greatly shorten the detection time, and has good consistency with microbial culture. mNGS may provide a new approach for pathogen identification of PD-related peritonitis, especially refractory peritonitis.

Anatomic Approach to Common and Uncommon Manifestations of Thoracic Leukemias with Radiologic-Pathologic Correlation.

Leukemias are hematopoietic malignancies characterized by the production of abnormal leukocytes in the bone marrow. Clinical manifestations arise from either bone marrow suppression or leukemic organ infiltration. Lymphadenopathy is the most common direct manifestation of intrathoracic leukemia. However, leukemic cells may also infiltrate the lungs, pleura, heart, bones, and soft tissues. Pulmonary complications in patients with leukemia typically include pneumonia, hemorrhage, pulmonary edema, and sequelae of leukemia treatment. However, pulmonary abnormalities can also be related directly to leukemia, including leukemic pulmonary infiltration. The direct, non-treatment-related effects of leukemia on intrathoracic structures will be the focus of this imaging essay. Given the typical anatomic approach for image interpretation, an organ-based depiction of common and less common intrathoracic findings directly caused by leukemic involvement is presented, emphasizing imaging findings with pathologic correlations. Keywords: Leukemia, Pulmonary, Thorax, Soft Tissues/Skin, Hematologic, Bone Marrow © RSNA, 2023.

Magnetic resonance radiomic feature performance in pulmonary nodule classification and impact of segmentation variability on radiomics.

OBJECTIVE: Investigate the performance of multiparametric MRI radiomic features, alone or combined with current standard-of-care methods, for pulmonary nodule classification. Assess the impact of segmentation variability on feature reproducibility and reliability. METHODS: Radiomic features were extracted from 74 pulmonary nodules of 68 patients who underwent nodule resection or biopsy after MRI exam. The MRI features were compared with histopathology and conventional quantitative imaging values (maximum standardized uptake value [SUVmax] and mean Hounsfield unit [HU]) to determine whether MRI radiomic features can differentiate types of nodules and associate with SUVmax and HU using Wilcoxon rank sum test and linear regression. Diagnostic performance of features and four machine learning (ML) models were evaluated with area under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs). Concordance correlation coefficient (CCC) assessed the segmentation variation impact on feature reproducibility and reliability. RESULTS: Elevn diffusion-weighted features distinguished malignant from benign nodules (adjusted p < 0.05, AUC: 0.73-0.81). No features differentiated cancer types. Sixty-seven multiparametric features associated with mean CT HU and 14 correlated with SUVmax. All significant MRI features outperformed traditional imaging parameters (SUVmax, mean HU, apparent diffusion coefficient [ADC], T1, T2, dynamic contrast-enhanced imaging values) in distinguishing malignant from benign nodules with some achieving statistical significance (p < 0.05). Adding ADC and smoking history improved feature performance. Machine learning models demonstrated strong performance in nodule classification, with extreme gradient boosting (XGBoost) having the highest discrimination (AUC = 0.83, CI=[0.727, 0.932]). We found good to excellent inter- and intrareader feature reproducibility and reliability (CCC≥0.80). CONCLUSION: Eleven MRI radiomic features differentiated malignant from benign lung nodules, outperforming traditional quantitative methods. MRI radiomic ML models demonstrated good nodule classification performances with XGBoost superior to three others. There was good to excellent inter- and intrareader feature reproducibility and reliability. ADVANCES IN KNOWLEDGE: Our study identified MRI radiomic features that successfully differentiated malignant from benign lung nodules and demonstrated high performance of our MR radiomic feature-based ML models for nodule classification. These new findings could help further establish thoracic MRI as a non-invasive and radiation-free alternative to standard practice for pulmonary nodule assessment.

The cooperative interplay among inflammation, necroptosis and YAP pathway contributes to the folate deficiency-induced liver cells enlargement.

Change in cell size may bring in profound impact to cell function and survival, hence the integrity of the organs consisting of those cells. Nevertheless, how cell size is regulated remains incompletely understood. We used the fluorescent zebrafish transgenic line Tg-GGH/LR that displays inducible folate deficiency (FD) and hepatomegaly upon FD induction as in vivo model. We found that FD caused hepatocytes enlargement and increased liver stiffness, which could not be prevented by nucleotides supplementations. Both in vitro and in vivo studies indicated that RIPK3/MLKL-dependent necroptotic pathway and Hippo signaling interactively participated in this FD-induced hepatocytic enlargement in a dual chronological and cooperative manner. FD also induced hepatic inflammation, which convenes a dialog of positive feedback loop between necroptotic and Hippo pathways. The increased MMP13 expression in response to FD elevated TNFα level and further aggravated the hepatocyte enlargement. Meanwhile, F-actin was circumferentially re-allocated at the edge under cell membrane in response to FD. Our results substantiate the interplay among intracellular folate status, pathways regulation, inflammatory responses, actin cytoskeleton and cell volume control, which can be best observed with in vivo platform. Our data also support the use of this Tg-GGH/LR transgenic line for the mechanistical and therapeutic research for the pathologic conditions related to cell size alteration.