Tropheryma whipplei infection in the lung of a patient with long COVID: a case report.

BACKGROUND: Immune dysregulation in individuals with long COVID has been detected. Differential diagnosis of diffuse infiltration on chest CT in long COVID is challenging. CASE PRESENTATION: A 62-year-old man presented with a 10-month history of dyspnea after COVID-19 infection. Dyspnea became worse in the one month preceding presentation. The chest CT showed multifocal, subpleural, bilateral opacities due to long-COVID, and infiltration around the bronchovascular bundle in the bilateral lower lung field. The pathology for the transbronchial cryobiopsy (TBCB) first reported chronic inflammation (mainly interstitial pneumonia). The patient had positive results on tests for the antibody, RO-52+, EJ+. The presumptive diagnosis of connective tissue disease-interstitial lung disease was made. Prednisone and cyclophosphamide were given. At follow-up one month later, the chest CT showed new diffuse ground-glass infiltration. The previous TBCB specimen was re-evaluated. Foamy macrophages were found in the alveolar air space. Periodic acid-Schiff (PAS) staining was performed. Numerous intracytoplasmic organisms were detected, with morphologic features consistent with those of Tropheryma whipplei. The patient recovered after intravenous ceftriaxone and oral trimethoprim-sulfamethoxazole. The final diagnosis was lung T. whipplei infection and long COVID-19. CONCLUSION: This is the first case report of Tropheryma whipplei infection in the lung of a patient with long COVID-19. T. whipplei should be considered as a potential pathogen for diffuse lung infiltration in the post-COVID-19 era.

Human FcRn Is a Two-in-One Attachment-Uncoating Receptor for Echovirus 18.

Virus-receptor interactions determine viral host range and tissue tropism. CD55 and human neonatal Fc receptor (FcRn) were found to be the binding and uncoating receptors for some of the echovirus-related enterovirus species B serotypes in our previous study. Echovirus 18 (E18), as a member of enterovirus species B, is a significant causative agent of aseptic meningitis and viral encephalitis in children. However, it does not use CD55 as a critical host factor. We conducted CRISPR/Cas9 knockout screening to determine the receptors and entry mechanisms and identified FcRn working as a dual-function receptor for E18. Knockout of FCGRT and B2M, which encode the two subunits of FcRn, prevented infection by E18 and other echoviruses in the same physiological cluster. We then elucidated the underlying molecular mechanism of receptor recognition by E18 using cryogenic electron microscopy. The binding of the FCGRT subunit to the canyon region rotates the residues around the pocket, triggering the release of the pocket factor as observed for other enterovirus species B members. IMPORTANCE E18 is a member of enterovirus species B. As one of the most common enterovirus serotypes in nonpolio enterovirus detection, it easily infects children and causes various clinical symptoms. Aseptic meningitis and viral encephalitis are the most commonly reported syndromes associated with E18. No effective antiviral drugs or approved vaccines are available. Previous studies showed that CD55 and FcRn were the binding and uncoating receptors for some echoviruses. However, we found that CD55 is not the critical host factor for E18. Thus, we want to determine the receptors and elucidate the entry mechanism of E18. Our findings reveal that FcRn is a two-in-one attachment-uncoating receptor for E18.

miR-1908 Dysregulation in Human Cancers.

MiR-1908 is a miRNA located in the intron of the fatty acid desaturase 1 (FADS1) gene. The expression level of miR-1908 is abnormal in many diseases such as cancer. miR-1908 can inhibit the expression of at least 27 target genes by binding to the 3' untranslated region (3' UTR) of target genes. miR-1908 is involved in the biological processes of cell proliferation, cell differentiation, cell apoptosis, cancer cell invasion, and metastasis. The expression of miR-1908 is regulated by 11 factors, including lncRNA HOTTIP, adipokines (TNF-α, leptin, and resistin), NF-κB, free fatty acid (FFA), cholesterol, stearoyl-CoA desaturase (SCD1), immune-related transcription factors (STAT1, RB1, and IRF1). The expression of miR-1908 is also affected by the anticancer drug OSW-1, growth hormone (GH), and the anticonvulsant drug sodium valproate. In addition, the aberrant expression of miR-1908 is also related to the prognosis of a variety of cancers, including non-small cell lung cancer (NSCLC), ovarian cancer (OC), breast cancer, cervical cancer, glioma, high-grade serous ovarian carcinoma (HGSOC), osteosarcoma, etc. This article summarizes the abnormal expression pattern of miR-1908 in various diseases and its molecular regulation mechanisms. Our work will provide potential hints and direction for future miR-1908-related research.

LINC00520: A Potential Diagnostic and Prognostic Biomarker in Cancer.

Long non-coding RNA (lncRNA) is important in the study of cancer mechanisms. LINC00520 is located on human chromosome 14q22.3 and is a highly conserved long non-coding RNA. LINC00520 is widely expressed in various tissues. The expression of LINC00520 is regulated by transcription factors such as Sp1, TFAP4, and STAT3. The high expression of LINC00520 is significantly related to the risk of 11 cancers. LINC00520 can competitively bind 10 miRNAs to promote tumor cell proliferation, invasion, and migration. In addition, LINC00520 is involved in the regulation of P13K/AKT and JAK/STAT signaling pathways. The expression of LINC00520 is significantly related to the clinicopathological characteristics and prognosis of tumor patients and is also related to the sensitivity of HNSCC to radiotherapy. Here, this article summarizes the abnormal expression pattern of LINC00520 in cancer and its potential molecular regulation mechanism and points out that LINC00520 can be used as a potential biomarker for cancer diagnosis, prognosis, and treatment.

Bleeding with gastrointestinal and ureteral ulcers after gefitinib treatment: a case report.

Epidermal growth factor receptor (EGFR) inhibitors, as a first-line drug treatment in the EGFR-sensitive mutation of advanced non-small-cell lung cancer (NSCLC), has been used in a wide variety of malignancies. These therapies have various troublesome side effects including diarrhea, stomatitis, mucositis, rash, dry skin and paronychia which may impact a patient's clinical outcome in addition to their beneficial effects. Here, we report a rare case of a 69-year-old male having advanced NCSLC treated with gefitinib, who developed EGFR tyrosine kinase inhibitor (TKI)-related multiple ulcers accompanied by bleeding. After a detailed examination and multidisciplinary discussion, we have learnt that early identification of gastrointestinal (GI) bleeding and blood in urine is due to targeted drugs rather than other causes such as ulcer and stones. Good results have also been achieved by reducing drug dosage under close observation. So far, the patient has been followed up for 15 months, and his condition remained stable. Up to now, there is no case of such severe side effect having been found, and no guidelines recommended for handling such adverse events. Through clinical case sharing, early recognition and proactive management are particularly important in order to minimize appropriately the effect of these adverse events. The whole course of a disease can be vividly illustrated through a case report, so as to provide more effective guiding principles for clinicians.

Validation of novel automatic ultra-wideband radar for sleep apnea detection.

BACKGROUND: To validate the accuracy of ultra-wideband (UWB) wireless radar for the screening diagnosis of sleep apnea. METHODS: One hundred and seventy-six qualified participants were successfully recruited. Apnea-hypopnea index (AHI) results from polysomnography (PSG) were reviewed by physicians, while the radar device automatically calculated AHI values with an embedded chip. All results were statistically analyzed. RESULTS: A UWB radar-based AHI algorithm was successfully developed according to respiratory movement and body motion signals. Of all 176 participants, 63 exhibited normal results (AHI <5/hr) and the remaining 113 were diagnosed with obstructive sleep apnea. Significant correlation was detected between radar AHI and PSG AHI (Intraclass correlation coefficient 0.98, P<0.001). Receiver operating characteristic curve (ROC) analysis revealed high sensitivity and specificity. High concordance in participants with varying gender, age, BMI, and PSG AHI was reached. CONCLUSIONS: The UWB radar may be a portable, convenient, and reliable device for obstructive sleep apnea screening.

Novel Aspects of Insulin-like Growth Factor 1/insulin Network in Chronic Inflammatory Airway Disease.

At least a proportion of patients suffering from chronic inflammatory airway diseases respond poorly to the bronchodilator and corticosteroid therapies. There is a need for the development of improved anti-inflammatory treatment. Insulin Growth Factor 1 (IGF1) and insulin participate in not only metabolism and glucose homeostasis, but also many other physiological and pathophysiological processes, including growth and inflammation. Recently, it was shown that not only the classical IGF1 and IGF1 Receptor (IGF1R), but also the other molecules in the IGF1/insulin network, including insulin, insulin-like growth factor-binding protein (IGFBP), and IGFBP protease, have roles in chronic inflammatory airway diseases. This review aims to provide a comprehensive insight into recent endeavors devoted to the role of the IGF1/insulin network in chronic inflammatory airway diseases. Its participation in airway inflammation, remodeling, and hyper-responsiveness (AHR), as well as acute exacerbation, has been conclusively demonstrated. Its possible relation to glucocorticoid insensitivity has also been indicated. A better understanding of the IGF1/insulin network by further bench-to-bedside research may provide us with rational clinical therapeutic approaches against chronic inflammatory airway diseases.

Downregulated level of insulin in COPD patients during AE; role beyond glucose control?

Objective: The purpose of this study was to explore the insulin level in the serum of chronic obstructive pulmonary disease (COPD) patients during acute exacerbation (AE). Methods: The study population consisted of 22 acute exacerbation chronic obstructive pulmonary disease (AECOPD) patients, 20 COPD patients and 20 healthy controls. Fasting blood glucose, insulin and serum lipid levels were measured. After the patients recovered from AE, the insulin and glucose levels were also analyzed. Results: Insulin level, glucose level and homeostasis model assessment of insulin resistance (HOMA-IR) of AECOPD patients were higher than healthy controls (7.19±6.02 vs 3.28±1.09 µIU/mL, P<0.05, 126.61±50.92 vs 96.21±12.66 mg/dL, P<0.05, 2.66±2.72 vs 0.78±0.26, P<0.05). For stable COPD patients, the insulin level, glucose level and HOMA-IR were 6.52±2.56 µIU/mL, 95.58±11.44 mg/dL, and 1.52±0.53, respectively. The triglyceride (TG) level, total cholesterol (CHOL) level and low-density lipoprotein cholesterol (LDL-CHOL) level were decreased in AECOPD patients (0.78±0.33 vs 1.05±0.35 mmol/L, P<0.05, 3.88±0.72 vs 4.49±0.7 mmol/L, P<0.05, 2.01±0.59 vs 2.59±0.58 mmol/L, P<0.05). When the patients had recovered from AE, the insulin levels increased (10.67±6.22 vs 7.12±6.19 µIU/mL, P<0.05) and the glucose levels decreased (122.69±41.41 vs 134.08±53.19 mg/dL, P>0.05). Conclusion: A high insulin level and a high HOMA-IR status in COPD patients were demonstrated. Downregulated levels of insulin during AE compared with the convalescent state were detected, while the variation in the glucose level was not as great as expected, indicating a potentially important role for insulin in AECOPD.

Impact of Taurine on the proliferation and apoptosis of human cervical carcinoma cells and its mechanism.

BACKGROUND: Cervical cancer has the fourth highest incidence and mortality rate of all cancers in women worldwide; it seriously harms their physical and mental health. The aim of this study was to observe the roles and preliminary mechanism of Taurine (Tau)-induced apoptosis in cervical cancer cells. METHODS: Cells from the human cervical cancer cell line SiHa were transfected with the recombinant plasmid pEGFP-N1-MST1 (mammalian sterile 20-like kinase 1); then, the cell proliferation activity was analyzed by the MTT assay, cell apoptosis by flow cytometry, and the related protein levels by Western blotting. RESULTS: Tau inhibited the proliferation of SiHa cells and induced apoptosis in these cells (the apoptotic rate was 21.95% in the Tau 160 mmol/L group and 30% in the Tau 320 mmol/L group), upregulated the expression of the MST1 (control, 0.53; Tau 40-320 mmol/L groups, 0.84-1.45) and Bax (control, 0.45; Tau 40-320 mmol/L groups, 0.64-1.51) proteins (P < 0.01), and downregulated the expression of Bcl-2 (control, 1.28, Tau 40-320 mmol/L groups, 0.93-0.47) (P < 0.01). The overexpression of MST1 promoted the apoptosis of SiHa cells, enhanced the apoptosis-inductive effects of Tau (P < 0.01), upregulated the expression of the proapoptotic proteins p73, p53, PUMA (p53 upregulated modulator of apoptosis), and caspase-3, and promoted the phosphorylation of YAP (Yes-associated protein). CONCLUSIONS: Tau inhibited the proliferation and induced the apoptosis of cervical cancer SiHa cells. The MST1 protein plays an important role in the Tau-induced apoptosis of cervical cancer cells.

Pulmonary vascular involvement of IgG4-related disease: Case series with a PRISMA-compliant systemic review.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized, immune-mediated chronic fibrotic inflammation that can involve almost all organs, causing tumefaction and dysfunction. Its presence in pulmonary circulation is underestimated and has not yet been investigated. OBJECTIVES: We describe a representative IgG4-RD patient with pulmonary artery stenosis and pulmonary embolism, leading to reversible pulmonary hypertension. Literature review of IgG4-RD with pulmonary circulation involvement was conducted. DATA SOURCES: References for this review were identified through searches via PubMed, EBSCO, and Web of Science for published articles before November 2016. RESULTS: There were 15 published cases of IgG4-RD with pulmonary vascular involvement, 3 with pulmonary arteritis, 2 with pulmonary artery aneurysm, 3 with pulmonary artery stenosis, 1 with obliterative phlebitis, and 1 with pulmonary embolism. Possible immunity and inflammation mechanisms were summarized. CONCLUSIONS: IgG4-RD with pulmonary vascular involvement is rare. Echocardiogram and contrast-enhanced chest CT are helpful to screen the disease. Clinical manifestations were found from asymptomatic to dyspnea or even syncope. And nearly all cases had more than 1 organ affected, with significantly increased serum IgG4 levels. PET/CT aided in identifying affected organs and determining candidate biopsy sites. More awareness is urged to evaluate the pulmonary vascular manifestations of this disease.

Serum levels of IGFBP7 are elevated during acute exacerbation in COPD patients.

OBJECTIVE: The purpose of this study was to explore the insulin-like growth factor binding protein 7 (IGFBP7) level in the serum of chronic obstructive pulmonary disease (COPD) patients during acute exacerbation (AE). METHODS: The study population consisted of 47 AECOPD patients, including 25 patients enrolled between January 2011 and February 2011 (the first group) and 22 patients enrolled from December 2011 to August 2012 (the second group) and 29 healthy controls. Chemiluminescence-linked immunoassay was used to detect serum IGFBP7 levels. For the second group patients, IGFBP7 and C-reactive protein (CRP) levels were measured both on the admission day and on the discharge day. RESULTS: Among the first group AECOPD patients, serum IGFBP7 levels were significantly elevated in AECOPD patients in the intensive care unit (ICU; 52.92±16.32 ng/mL), and in hospitalized AECOPD patients not in ICU (40.66±13.9), compared to healthy subjects (30.3±7.09 ng/mL; P<0.01). For the second group AECOPD patients, the increased IGFBP7 levels reduced after the patients had recovered (34.42±11.88 vs 27.24±7.2 ng/mL; P<0.01). During AE, the correlation coefficient between IGFBP7 and CRP was 0.357. In receiver operating characteristic analysis, the area under the curve was 0.799 for CRP, and 0.663 for IGFBP7 in distinguishing patients with AECOPD on the admission day from the discharge day. CONCLUSION: Serum IGFBP7 levels were raised during AECOPD. Similar to the expression pattern of CRP, the IGFBP7 levels reduced after convalescence, suggesting that IGFBP7 might have a candidate role as a biomarker of AECOPD. No significant linear correlation was detected between IGFBP7 and CRP, indicating the probable different role for the two molecules in assessing AECOPD. Further study is needed to explore the value of IGFBP7 in differentiating phenotypes of AECOPD.

IGFBP, a novel target of lung cancer?

The insulin-like growth factor-1 receptor (IGF-1R) is a central component of lung cancer signal transduction pathways. A phase III study failed for carboplatin, paclitaxel, with or without figitumumab in first-line treating metastatic non-small cell lung cancer (NSCLC). There is an urgent need for a better understanding of signaling in IGF system. Insulin-like growth factor-binding proteins (IGFBPs) function as modulators for IGF signaling through sequestration of IGFs in serum and the extracellular fluid. IGFBPs can also act as transporters or modulators for IGF action and insulin action. IGFBPs have attracted increased attention for their lung cancer-related role in recent years. Recent studies have demonstrated the critical role of IGFBPs in risk assessment, early detection, prognosis evaluation, and drug resistance appraisal for lung cancer. These observations suggest a potential new approach to understand the pathogenesis of lung cancer, have important clinical implications, while additional investigations are necessary.

Latcripin-13 domain induces apoptosis and cell cycle arrest at the G1 phase in human lung carcinoma A549 cells.

Latcripin-13 domain, isolated from the transcriptome of Lentinula edodes C91-3, contains a regulator of chromosome condensation (RCC1) domain/ß-lactamase-inhibitor protein II (BLIP-II) and a plant homeodomain (PHD). Latcripin-13 domain has been shown to have antitumor effects. However, the underlying molecular pharmacology is largely unknown. We report here that Latcripin-13 domain induced cell cycle arrest in the G1 phase and caused the apoptosis of human lung carcinoma A549 cells via the GSK3ß-cyclin D1 and caspase-8/NF-κB signaling pathways. Western blot analysis showed that Latcripin-13 domain decreased cyclin D1 and cyclin-dependent kinase 4 (CDK4), while it increased the ratio of GSK3ß/phosphorylated GSK3ß. Importantly, Latcripin-13 domain induced nuclear fragmentation and chromatin condensation in the A549 cells. In addition, treatment of the A549 cells with Latcripin-13 domain resulted in the loss of mitochondrial membrane potential, accompanied by an increase in the Bax/Bcl-2 ratio and activation of caspase-3, -8, and -9. Intriguingly, western blot analysis revealed that NF-κB was significantly downregulated by Latcripin-13 domain. These results demonstrated that Latcripin-13 domain induced apoptosis and cell cycle arrest at G1 phase in the A549 cells, providing a mechanism for the antitumor effects of Latcripin-13 domain.

Interaction between IGFBP7 and insulin: a theoretical and experimental study.

Insulin-like growth factor binding protein 7 (IGFBP7) can bind to insulin with high affinity which inhibits the early steps of insulin action. Lack of recognition mechanism impairs our understanding of insulin regulation before it binds to insulin receptor. Here we combine computational simulations with experimental methods to investigate the interaction between IGFBP7 and insulin. Molecular dynamics simulations indicated that His200 and Arg198 in IGFBP7 were key residues. Verified by experimental data, the interaction remained strong in single mutation systems R198E and H200F but became weak in double mutation system R198E-H200F relative to that in wild-type IGFBP7. The results and methods in present study could be adopted in future research of discovery of drugs by disrupting protein-protein interactions in insulin signaling. Nevertheless, the accuracy, reproducibility, and costs of free-energy calculation are still problems that need to be addressed before computational methods can become standard binding prediction tools in discovery pipelines.

LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of dominant-inherited Parkinson's disease (PD), and yet we do not fully understand the physiological function(s) of LRRK2. Various components of the clathrin machinery have been recently found mutated in familial forms of PD. Here, we provide molecular insight into the association of LRRK2 with the clathrin machinery. We report that through its GTPase domain, LRRK2 binds directly to clathrin-light chains (CLCs). Using genome-edited HA-LRRK2 cells, we localize LRRK2 to endosomes on the degradative pathway, where it partially co-localizes with CLCs. Knockdown of CLCs and/or LRRK2 enhances the activation of the small GTPase Rac1, leading to alterations in cell morphology, including the disruption of neuronal dendritic spines. In Drosphila, a minimal rough eye phenotype caused by overexpression of Rac1, is dramatically enhanced by loss of function of CLC and LRRK2 homologues, confirming the importance of this pathway in vivo. Our data identify a new pathway in which CLCs function with LRRK2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD.

Insulin-like growth factor binding protein-related protein 1 and cancer.

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) belongs to the IGFBP family whose members have a conserved structural homology. It has a low affinity for IGFs and a high affinity for insulin, suggesting that IGFBP-rP1 may have a biological function distinct from other members of the family. IGFBP-rP1 is ubiquitously expressed in normal human tissues and has diverse biological functions, regulating cell proliferation, apoptosis and senescence; it may also have a key role in vascular biology. Increasing evidence suggests that IGFBP-rP1 acts as a tumor suppressor. It elicits its biological effects by both insulin/IGF-dependent and -independent mechanisms. This paper provides a brief overview of the structure and regulation of IGFBP-rP1 and its various biological functions in cancer, as well as the underlying molecular mechanisms.

High expression of IGFBP7 in fibroblasts induced by colorectal cancer cells is co-regulated by TGF-ß and Wnt signaling in a Smad2/3-Dvl2/3-dependent manner.

Fibroblasts in the tumor microenvironment are a key determinant in cancer progression and may be a promising target for cancer therapy. Insulin-like growth factor binding protein 7 (IGFBP7) is known as a tumor suppressor in colorectal cancer (CRC). The present study investigated the inductive mechanism of IGFBP7 expression in fibroblasts by supernatant from the CRC cell line, SW620. The results showed that the expression of IGFBP7 was up-regulated in the fibroblasts when treated with SW620 supernatant and exogenous TGF-ß1. The IGFBP7 induced by SW620 supernatant or TGF-ß1 was partially inhibited by the TGF-ß1 specific antibody AF and TGF-ß1 receptor antagonist SB431542. The Wnt signaling-targeted genes, c-Myc, CCND1 and the proteins Dvl2/3, were all up-regulated in fibroblasts expressing high levels of IGFBP7, and the up-regulation could be inhibited both by the Wnt signaling antagonist Dickkopf-1 (DKK1) and by the TGF-ß1 receptor antagonist SB431542. In conclusion, CRC cells promote the high expression of IGFBP7 in fibroblasts, most likely through the co-regulation of TGF-ß and Wnt signaling in a Smad2/3-Dvl2/3 dependent manner. Taken together, these data suggest that the fibroblasts could be a novel therapeutic target in tumor therapy.

Wengen, the sole tumour necrosis factor receptor in Drosophila, collaborates with moesin to control photoreceptor axon targeting during development.

Photoreceptor neurons (R cells) in the Drosophila eye define a map of visual space by connecting to targets in distinct layers of the optic lobe, with R1-6 cells connecting to the lamina (the first optic ganglion) and R7 and R8 cells connecting to the medulla (the second optic ganglion). Here, we show that Wengen (Wgn) directly binds Moesin (Moe) through a cytosolic membrane proximal domain and this interaction is important for mediating two distinct aspects of axonal targeting. First, we show that loss of wgn or moe function disrupts cell autonomous R8 axon targeting. Second, we report that wgn or moe mutants show defects in R2-R5 targeting that result from disruption of non-cell autonomous effects, which are secondary to the cell autonomous R8 phenotype. Thus, these studies reveal that the Wgn-Moe signaling cascade plays a key role in photoreceptor target field innervations through cell autonomous and non-cell autonomous mechanisms.