Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in HSCs.

BACKGROUND AND AIMS: Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies. APPROACH AND RESULTS: We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-ß2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs. CONCLUSIONS: TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease.

Endoribonuclease DNE1 Promotes Ethylene Response by Modulating EBF1/2 mRNA Processing in Arabidopsis.

The gaseous phytohormone ethylene plays a crucial role in plant growth, development, and stress responses. In the ethylene signal transduction cascade, the F-box proteins EIN3-BINDING F-BOX 1 (EBF1) and EBF2 are identified as key negative regulators governing ethylene sensitivity. The translation and processing of EBF1/2 mRNAs are tightly controlled, and their 3' untranslated regions (UTRs) are critical in these regulations. However, despite their significance, the exact mechanisms modulating the processing of EBF1/2 mRNAs remain poorly understood. In this work, we identified the gene DCP1-ASSOCIATED NYN ENDORIBONUCLEASE 1 (DNE1), which encodes an endoribonuclease and is induced by ethylene treatment, as a positive regulator of ethylene response. The loss of function mutant dne1-2 showed mild ethylene insensitivity, highlighting the importance of DNE1 in ethylene signaling. We also found that DNE1 colocalizes with ETHYLENE INSENSITIVE 2 (EIN2), the core factor manipulating the translation of EBF1/2, and targets the P-body in response to ethylene. Further analysis revealed that DNE1 negatively regulates the abundance of EBF1/2 mRNAs by recognizing and cleaving their 3'UTRs, and it also represses their translation. Moreover, the dne1 mutant displays hypersensitivity to 1,4-dithiothreitol (DTT)-induced ER stress and oxidative stress, indicating the function of DNE1 in stress responses. This study sheds light on the essential role of DNE1 as a modulator of ethylene signaling through regulation of EBF1/2 mRNA processing. Our findings contribute to the understanding of the intricate regulatory process of ethylene signaling and provide insights into the significance of ribonuclease in stress responses.

FOXA2 activates HIF2α expression to promote tumor progression and is regulated by the E3 ubiquitin ligase VHL in renal cell carcinoma.

Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system with high mortality and morbidity. However, the molecular mechanisms underlying RCC progression are still largely unknown. In this study, we identified FOXA2, a pioneer transcription factor, as a driver oncogene for RCC. We show that FOXA2 was commonly upregulated in human RCC samples and promoted RCC proliferation, as evidenced by assays of cell viability, colony formation, migratory and invasive capabilities, and stemness properties. Mechanistically, we found that FOXA2 promoted RCC cell proliferation by transcriptionally activating HIF2α expression in vitro and in vivo. Furthermore, we found that FOXA2 could interact with VHL (von Hippel‒Lindau), which ubiquitinated FOXA2 and controlled its protein stability in RCC cells. We showed that mutation of lysine at position 264 to arginine in FOXA2 could mostly abrogate its ubiquitination, augment its activation effect on HIF2α expression, and promote RCC proliferation in vitro and RCC progression in vivo. Importantly, elevated expression of FOXA2 in patients with RCC positively correlated with the expression of HIF2α and was associated with shorter overall and disease-free survival. Together, these findings reveal a novel role of FOXA2 in RCC development and provide insights into the underlying molecular mechanisms of FOXA2-driven pathological processes in RCC.

Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in hepatic stellate cells.

Background & Aims: Fibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation to myofibroblasts results in the accumulation of extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and may provide targets for fibrotic therapies. Methods: We identified lncRNA TILAM as expressed near COL1A1 in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analyses of HSCs isolated from mice defined the murine ortholog of TILAM . We then generated Tilam -deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl 4 ) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners of TILAM . Results: TILAM is conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen. Tilam is selectively induced in HSCs during the development of fibrosis in vivo . In both male and female mice, loss of Tilam results in reduced fibrosis in the setting of CCl 4 and CDA-HFD injury models. TILAM interacts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs. Conclusion: TILAM is activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end stage liver disease.

Arabidopsis EIN2 represses ABA responses during germination and early seedling growth by inactivating HLS1 protein independently of the canonical ethylene pathway.

The signaling pathways for the phytohormones ethylene and abscisic acid (ABA) have antagonistic effects on seed germination and early seedling establishment. However, the underlying molecular mechanisms remain unclear. In Arabidopsis thaliana, ETHYLENE INSENSITIVE 2 (EIN2) localizes to the endoplasmic reticulum (ER); although its biochemical function is unknown, it connects the ethylene signal with the key transcription factors EIN3 and EIN3-LIKE 1 (EIL1), leading to the transcriptional activation of ethylene-responsive genes. In this study, we uncovered an EIN3/EIL1-independent role for EIN2 in regulating the ABA response. Epistasis analysis demonstrated that this distinct role of EIN2 in the ABA response depends on HOOKLESS 1 (HLS1), the putative histone acetyltransferase acting as a positive regulator of ABA responses. Protein interaction assays supported a direct physical interaction between EIN2 and HLS1 in vitro and in vivo. Loss of EIN2 function resulted in an alteration of HLS1-mediated histone acetylation at the ABA-INSENSITIVE 3 (ABI3) and ABI5 loci, which promotes gene expression and the ABA response during seed germination and early seedling growth, indicating that the EIN2-HLS1 module contributes to ABA responses. Our study thus revealed that EIN2 modulates ABA responses by repressing HLS1 function, independently of the canonical ethylene pathway. These findings shed light on the intricate regulatory mechanisms underling the antagonistic interactions between ethylene and ABA signaling, with significant implications for our understanding of plant growth and development.

Prognostic value of extrahepatic metastasis on colon cancer with liver metastasis: a retrospective cohort study.

Introduction: The occurrence of metastasis is a threat to patients with colon cancer (CC), and the liver is the most common metastasis organ. However, the role of the extrahepatic organs in patients with liver metastasis (LM) has not been distinctly demonstrated. Therefore, this research aimed to explore the prognostic value of extrahepatic metastases (EHMs). Methods: In this retrospective study, a total of 13,662 colon patients with LM between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results database (SEER). Fine and Gray's analysis and K-M survival analysis were utilized to explore the impacts of the number of sites of EHMs and different sites of EHMs on prognosis. Finally, a prognostic nomogram model based on the number of sites of EHMs was constructed, and a string of validation methods was conducted, including concordance index (C-index), receiver operating characteristic curves (ROC), and decision curve analysis (DCA). Results: Patients without EHMs had better prognoses in cancer-specific survival (CSS) and overall survival (OS) than patients with EHMs (p < 0.001). Varied EHM sites of patients had different characteristics of primary location site, grade, and histology. Cumulative incidence rates for CSS surpassed that for other causes in patients with 0, 1, 2, ≥ 3 EHMs, and the patients with more numbers of sites of EHMs revealed worse prognosis in CSS (p < 0.001). However, patients with different EHM sites had a minor difference in cumulative incidence rates for CSS (p = 0.106). Finally, a nomogram was constructed to predict the survival probability of patients with EHMs, which is based on the number of sites of EHMs and has been proven an excellent predictive ability. Conclusion: The number of sites of EHMs was a significant prognostic factor of CC patients with LM. However, the sites of EHMs showed limited impact on survival. Furthermore, a nomogram based on the number of sites of EHMs was constructed to predict the OS of patients with EHMs accurately.

Temozolomide protects against the progression of glioblastoma via SOX4 downregulation by inhibiting the LINC00470-mediated transcription factor EGR2.

OBJECTIVE: Temozolomide is extensively applied in chemotherapy for glioblastoma with unclear exact action mechanisms. This article seeks to address the potential molecular mechanisms in temozolomide therapy for glioblastoma involving LINC00470. METHODS: Bioinformatics analysis was conducted to predict the potential mechanism of LINC00470 in glioblastoma, which was validated by dual-luciferase reporter, RIP, ChIP, and RNA pull-down assays. LINC00470 expression and the predicted downstream transcription factor early growth response 2 (EGR2) were detected in the collected brain tissues from glioblastoma patients. Following temozolomide treatment and/or gain- and loss-of-function approaches in glioblastoma cells, cell viability, invasion, migration, cycle distribution, angiogenesis, autophagy, and apoptosis were measured. In addition, the expression of mesenchymal surface marker proteins was assessed by western blot. Tumor xenograft in nude mice was conducted for in vivo validation. RESULTS: Mechanistic analysis and bioinformatics analysis revealed that LINC00470 transcriptionally activated SRY-related high-mobility-group box 4 (SOX4) through the transcription factor EGR2. LINC00470 and EGR2 were highly expressed in brain tissues of glioblastoma patients. LINC00470 and EGR2 mRNA expression gradually decreased with increasing concentrations of temozolomide in glioblastoma cells, and SOX4 expression was reduced in cells by temozolomide and LINC00470 knockdown. Temozolomide treatment induced cell cycle arrest, diminished cell viability, migration, invasion, and angiogenesis, and increased apoptosis and autophagy in glioblastoma, which was counteracted by overexpressing LINC00470 or SOX4 but was further promoted by LINC00470 knockdown. Temozolomide restrained glioblastoma growth and angiogenesis in vivo, while LINC00470 or SOX4 overexpression nullified but LINC00470 knockdown further facilitated these trends. CONCLUSION: Conclusively, temozolomide repressed glioblastoma progression by repressing the LINC00470/EGR2/SOX4 axis.

Diagnosis and treatment of MN1 C-terminal truncation syndrome.

BACKGROUND: MN1 C-terminal truncation (MCTT) is a rare syndrome; only 27 cases have been reported. We report the first case of an 8-year-old girl with MCTT syndrome complicated with moderate obstructive sleep apnea (OSA). METHODS: MCTT syndrome was diagnosed by whole-exome sequencing (WES) and validated by Sanger sequencing. The patient received 2 years of treatment with continuous positive airway pressure (CPAP) to relieve sleep apnea and hypoxia, and a reverse sector fan-shaped expander for maxillary expansion. RESULTS: WES revealed a de novo MN1 variant, c.3760C>T (p.[Q1254*]). An arachnoid cyst was found in the right occipital brain. The patient presented mild symptoms of classic MCTT syndrome. The patient did not experience hearing loss and only mild intellectual disability. Radiological examinations showed cleft secondary palate, narrow upper arch, narrow upper airway, and mandibular skeletal retrusion. Polysomnography indicated moderate OSA, with an apnea/hypopnea index of 6.8, which decreased to 1 after CPAP during the night. Two-year maxillary expansion widened the upper arch, and the cleft secondary palate became visible. The mandible moved forward spontaneously, resulting in the improvement of profile and upper airway widening. General physical conditions, such as motor delay, muscle weakness, and developmental delay, were significantly improved two years later. CONCLUSION: In conclusion, we discovered a MN1 variant [NM_002430.2: c.3760C>T, p.Q1254*] that causes mild MCTT symptoms compared to other MN1 variants. For patients with MCTT complicated with OSA, multidisciplinary combination therapy can improve maxillofacial development, widen the upper airway and relieve sleep apnea, improving the general physical condition.

The bs-YHEDA peptide protects the brains of senile mice and thus recovers intelligence by reducing iron and free radicals.

Iron accumulates in the brain with age and catalyzes free radical damage to neurons, thus playing a pathogenic role in Alzheimer's disease (AD). To decrease the incidence of AD, we synthesized the iron-affinitive peptide 5YHEDA to scavenge the excess iron in the senile brain. However, the blood-brain barrier (BBB) blocks the entrance of macromolecules into the brain, thus decreasing the therapeutic effects. To facilitate the entrance of the 5YHEDA peptide, we linked the low-density lipoprotein receptor (LDLR)-binding segment of ApoB-100 to 5YHEDA (named "bs-YHEDA"). The results of intravenous injections of bs-5YHEDA into senescent mice demonstrated that bs-YHEDA entered the brain, increased ferriportin levels, reduced iron and free radical levels, decreased the consequences of neuronal necrosis and ameliorated cognitive disfunction without kidney or liver damage. bs-5YHEDA is a safe iron and free radical remover that potentially alleviates aging and Alzheimer's disease.

Cryptogenic Organizing Pneumonia Complicated With Cutaneous Disseminated Nocardia Infection: A Case Report and Literature Review.

Nocardia disease is a rare opportunistic infection that usually occurs in individuals with solid organ transplantation, malignant tumors, human immunodeficiency virus (HIV) infection, or chronic lung disease history. Here, we reported a rare case of cryptogenic organizing pneumonia (COP) combined with disseminated Nocardia infection. A 75-year-old man was admitted to the respiratory department due to weakness and poor appetite for 3 months. The chest CT scan showed dense patchy shadows in the dorsal lower lobe of both lungs. After the transbronchial lung biopsy, the histopathological findings supported the diagnosis of COP. During the period of glucocorticoid reduction (oral methylprednisolone tablets 24 mg one time a day), the patient presented with masses on the back and bilateral upper limbs and intermittent fever for 3 days. After admission, the patient underwent a series of examinations and an ultrasound puncture of the mass. The puncture fluid was caseous necrosis, which was confirmed to be Nocardia infection after bacterial culture, so the diagnosis was disseminated Nocardia infection. After 13 days of admission, the patient developed a headache, accompanied by decreased visual acuity and blurred vision. An imaging (enhanced brain CT) examination revealed intracranial space-occupying lesions. The neurosurgeon was consulted and performed transcranial abscess puncture and drainage, intravenous antibiotics (meropenem, etc.) for 2 months, and trimethoprim/sulfamethoxazole (TMP-SMX) for 6 months. The patient was followed up for 3 years and has remained relapse-free. The mortality rate of disseminated Nocardia infection is as high as 85%, especially when combined with brain abscesses. Therefore, timely diagnosis and correct treatment are crucial for the prevention of fatal consequences. The report of this case can enable more patients to receive early diagnosis and effective treatment, so as to obtain a satisfied prognosis.

Perturbation of biological processes with small molecule kinase inhibitors.

The reversible phosphorylation of substrates mediated by kinases and phosphatases affects their subcellular localization, catalytic activity, and/or interaction with other molecules. It is essential for signal transduction and the regulation of nearly all cellular processes, such as proliferation, apoptosis, metabolism, motility, and differentiation. Small molecule kinase inhibitors (SMKIs) have served as critical chemical probes to reveal the biological functions and mechanisms of kinases and their potential as therapeutic targets. In this review, we focused on a few novel SMKIs and their recent application in biological and preclinical studies to showcase how highly selective and potent SMKIs can be developed and utilized to propel the investigations on kinases and the biology behind.

Evaluation of a non-contact ultra-wideband bio-radar sleep monitoring device for screening of sleep breathing disease.

PURPOSE: Ultra-wideband bio-radar (UWB) is a new non-contact technology that can be used to screen for obstructive sleep apnea (OSA). However, little information is available regarding its reliability. This study aimed to evaluate the effectiveness of UWB and to determine if UWB could provide a novel and reliable method for the primary screening of sleep-related breathing disorders. METHOD: Subjects with suspected OSA from the sleep center of the First Hospital of the China Medical University were assessed over the period of September 2018 to April 2019 for enrollment in the study. Three detection methods were simultaneously used, including the STOP-Bang questionnaire (SBQ), UWB, and standard polysomnography (PSG). The data were analyzed using a fourfold table, receiver operating characteristic curves, Spearman rank correlation coefficients, Bland-Altman plots, and epoch-by-epoch analysis. RESULT: Of 67 patients, 56 were men, mean age was 43 ± 11 years, mean body mass index was 27.8 ± 4.8 kg/m2, and mean SBQ score was 4.8 ± 1.6. The apnea-hypopnea index (AHI) (r = 0.82, p < 0.01) and minimum arterial oxygen saturation (r = 0.80, p < 0.01) of the UWB were positively correlated with those obtained from the PSG. UWB performed better than SBQ, as indicated by the larger area under the curve (0.85 vs. 0.632). The sensitivity and specificity of the UWB-AHI were good (100%, 70%, respectively). CONCLUSIONS: UWB performs well in the screening of OSA and can provide reliable outcomes for the screening of OSA at the primary level.

LncRNA RBPMS-AS1 promotes NRGN transcription to enhance the radiosensitivity of glioblastoma through the microRNA-301a-3p/CAMTA1 axis.

OBJECTIVE: Glioblastoma (GBM) is the most frequent brain malignancy with high incidence, and long noncoding RNAs (lncRNAs) exerts functions in GBM. In this research, we focused on the capabilities of lncRNA RBPMS-AS1 in radiosensitivity of GBM. METHODS: RBPMS-AS1 and CAMTA1 expression levels were determined in GBM tissues and cells. StarBase v3.0 database was searched for predicting miRNAs that simultaneously bound to RBPMS-AS1 and CAMTA1. pcDNA3.1-RBPMS-AS1, pcDNA3.1-CAMTA1, miR-301a-3p mimic, or pcDNA3.1-RBPMS-AS1/pcDNA3.1-CAMTA1 and miR-301a-3p mimic were transfected into GBM cells to test radiosensitivity, cell proliferation and apoptosis. The interactions of miR-301a-3p with RBPMS-AS1 and CAMTA1, as well as CAMTA1 and NRGN, were confirmed. In vivo imaging technology was utilized to detect tumor growth in orthotopic xenograft tumors, and Ki67 expression was tested in intracranial tumors. RESULTS: RBPMS-AS1 and CAMTA1 levels were reduced in GBM tissues and cells. miR-301a-3p had a binding site with both RBPMS-AS1 and CAMTA1 and it was the most significantly-upregulated one. Upregulation of RBPMS-AS1 or CAMTA1 enhanced the radiosensitivity and cell apoptosis while suppressing proliferation of GBM cells. Conversely, miR-301a-3p overexpression diminished the radiosensitivity and cell apoptosis while inducing proliferation of GBM cells. Overexpression of RBPMS-AS1 or CAMTA1 reversed the effects of overexpressed miR-301a-3p in GBM cells. Mechanistically, RBPMS-AS1 enhanced CAMTA1 expression in GBM cells through sponging miR-301a-3p, and CAMTA1 promoted NRGN expression. In animal experiments, overexpressed RBPMS-AS1 inhibited tumor growth and the positive expression of Ki67 both before and after radiation therapy. CONCLUSION: RBPMS-AS1 promotes NRGN transcription through the miR-301a-3p/CAMTA1 axis and enhances the radiosensitivity of GBM.

TRIP4 transcriptionally activates DDIT4 and subsequent mTOR signaling to promote glioma progression.

In spite of significant advances in the understanding of glioma biology and pathology, survival remains poor. Therefore, it is still of great significance to further explore the key factors involved in tumorigenesis and development in glioma and find potential new therapeutic targets. Here, we show that thyroid hormone receptor interactor 4 (TRIP4) is highly expressed in glioma cells and tissues. Patients of glioma with high expression of TRIP4 possess poor overall survival. Knockdown of TRIP4 inhibited tumor cell proliferation, metastasis, and apoptosis suppression, whereas overexpression of TRIP4 displays the opposite effects. Further research showed that TRIP4 promoted glioma progression through regulating DDIT4 expression and subsequent activation of mTOR signaling. DDIT4 overexpression restored the inhibition of tumor growth by TRIP4 knockdown in vitro and in vivo. Consistently, mTOR activity inhibition reversed TRIP4 overexpression-mediated tumor promotion in vitro and in vivo. Moreover, molecular mechanism exploration demonstrates that TRIP4 functions as a specific transcriptional activator to anchor at the promoter region of DDIT4 gene (-196 to -11) to regulate its transcription and such regulation was affected by HIF1α. Clinically, TRIP4 expression is positively correlated with DDIT4 expression in glioma samples based on tissue microarray analysis and both of their high expression predicts the malignancy of the disease. Altogether, our findings identify TRIP4 as a critical promoter of glioma progression by targeting DDIT4 and mTOR signaling successively and suggest that TRIP4-DDIT4 axis has potential to be a novel therapeutic target in glioma treatment.

Protective Effects of Aminooxyacetic Acid on Colitis Induced in Mice with Dextran Sulfate Sodium.

As a known inhibitor of pyridoxal phosphate-dependent transaminase glutamic-oxaloacetic transaminase 1 (GOT1), aminooxyacetic acid (AOAA) has been pointed out to have potential pharmacological effects in antiepileptic, anticonvulsant, antibacterial, cancer cell proliferation inhibition, and acute myocardial infarction (MI) relief. However, its role in inflammatory bowel disease (IBD) has not been reported. Through the in vivo experiment of dextran sulfate sodium- (DSS-) induced colitis in mice, it was found that AOAA significantly attenuated the symptoms, signs, and pathological changes of colitis. In addition, AOAA treatment prevented gut barrier damages by enhancing the expression of zona occludens- (ZO-) 1, occludin, claudin-1, and E-cadherin and recovering the upregulation of the most abundant intermediate filament protein (vimentin). Moreover, the release of interleukin- (IL-) 1ß, IL-6, and tumour necrosis factor- (TNF-) α was suppressed, yet the level of IL-10 was upregulated by AOAA treatment compared to the model group. Furthermore, it was shown that AOAA administration boosted M2-like phenotype and effectively reduced M1 macrophage phenotype in the lamina propria of mouse colonic epithelium. Similarly, the effect of AOAA was verified in vitro. AOAA effectively inhibited the classically activated M1 macrophage phenotype and proinflammatory cytokine (IL-1ß, TNF-α, and IL-6) expression induced by lipopolysaccharide (LPS) and promoted M2-like phenotype. Collectively, this study reveals for the first time that short-term treatment of AOAA can significantly alleviate DSS-induced acute colitis by regulating intestinal barrier function and macrophage polarization, which provides a theoretical basis for the potential use of AOAA in the treatment of IBD.

Multisystemic Sarcoidosis Presenting With Leg Ulcers, Pancytopenia, and Polyserositis Was Successfully Treated With Glucocorticoids: A Case Report and Literature Review.

INTRODUCTION: Sarcoidosis is a chronic granulomatous disease of unknown etiology. A variety of studies have pointed out that almost every part of the body can be affected, but it most often affected the lungs and intrathoracic lymph nodes. However, cases of sarcoidosis involving multiple organs in one patient are rarely reported. We describe a unique case of sarcoidosis, which was characterized by multiorgan involvement, including leg ulcers, splenomegaly, pancytopenia, and polyserositis. Glucocorticoids were effective during the treatment of the above lesions. This case highlights the diversity of clinical manifestations of sarcoidosis and emphasizes the importance of its differential diagnosis and the periodical follow-up. These are crucial to physicians in the diagnosis and treatment of sarcoidosis. MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS: A 30-year-old male complained about intermittent fever 3 years ago. A computed tomographic scan of the chest showed lymphadenopathy in the mediastinum and hilar regions. Routine blood tests showed leukopenia and mild anemia. The pathologic result of mediastinal lymph node biopsy was granulomatous lesions; thus, the patient was diagnosed with type II sarcoidosis without glucocorticoid therapy. In the following 2 years, the patient suffered from intermittent fever accompanied by dyspnea, fatigue, occasional cough, less sputum, and apparent weight loss. Abnormal physical examinations included leg ulcers and splenomegaly. Laboratory and physical tests revealed pancytopenia, polyserositis, and enlargement of lymph nodes. The pathological findings of leg ulceration, pleura, and left supraclavicular lymph node all suggested granulomas. DIAGNOSIS INTERVENTIONS AND OUTCOMES: It strongly suggested sarcoidosis since tuberculosis, lymphoma, and connective tissue disease were all excluded. Due to severe conditions and multiorgan involvement, we tried to provide methylprednisolone for this patient. After 9 months of oral glucocorticoids therapy, his subjective symptoms as well as hematological and radiological findings were all improved. His leg skin ulceration and scab were also completely disappeared. CONCLUSION: Sarcoidosis has diverse clinical presentations, and many patients present with atypical symptoms. It needs to be timely identified by the clinician and carefully differentiated from other diseases with similar findings so as to make an accurate diagnosis. In this case, the patient had a poor clinical response to glucocorticoids in the early stage of treatment due to the severe condition and multi-organ involvement. It is worth noting that the patient had improved significantly after 9 months of treatment of corticosteroids, which suggested that follow-up is critical.

Smoking and sleep apnea duration mediated the sex difference in daytime sleepiness in OSA patients.

PURPOSE: Daytime sleepiness is a common symptom of obstructive sleep apnea (OSA) and is more common in men, but the underlying mechanism remains unclear. The aim of this study was to assess whether or not sex differences in daytime sleepiness persisted after controlling for age and OSA severity and to explore the factors contributing to daytime sleepiness in patients with OSA. METHODS: A total of 104 pairs of patients with OSA, matched by age and apnea-hypopnea index (AHI), were enrolled in this retrospective study. Demographic data were collected; daytime sleepiness was measured by the Epworth Sleepiness Scale (ESS); and polysomnography (PSG) was performed on each participant. These measurements were compared between sexes, and the factors affecting daytime sleepiness were explored with correlation and multivariate linear regression analyses. RESULTS: Men had significantly higher ESS scores (p = 0.021) than women. Regarding demographics, BMI, neck/height ratio, and proportion of habitual smoking and alcohol intake were significantly higher in men. Regarding PSG findings, men had more rapid eye movement sleep, a longer mean apnea-hypopnea duration, and a longer mean apnea duration (MAD). Regression analysis showed that two sex-associated variables, habitual smoking (ß = 0.189, p = 0.006) and MAD (ß = 0.154, p = 0.024), had the strongest association with ESS scores. Further analysis revealed that MAD was significantly influenced by apnea index (ß = 0.306, p < 0.001) and sex (ß = - 0.193, p = 0.003). CONCLUSION: The sex difference in daytime sleepiness persists in patients with OSA, even after matching AHI and age. The difference is mediated by sex-specific smoking habits and sex differences in apnea duration.

CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation.

CRSP8 plays an important role in recruiting mediators to genes through direct interaction with various DNA-bound transactivators. In this study, we uncovered the unique function of CRSP8 in suppressing thyroid cancer differentiation and promoting thyroid cancer progression via targeting IKKα signaling. CRSP8 was highly expressed in human thyroid cancer cells and tissues, especially in anaplastic thyroid cancer (ATC). Knockdown of CRSP8 suppressed cell growth, migration, invasion, stemness, and induced apoptosis and differentiation in ATC cells, while its overexpression displayed opposite effects in differentiated thyroid cancer (DTC) cells. Mechanistically, CRSP8 downregulated IKKα expression by binding to the IKKα promoter region (-257 to -143) to negatively regulate its transcription. Knockdown or overexpression of IKKα significantly reversed the expression changes of the differentiation and EMT-related markers and cell growth changes mediated by CRSP8 knockdown or overexpression in ATC or DTC cells. The in vivo study also validated that CRSP8 knockdown inhibited the growth of thyroid cancer by upregulating IKKα signaling in a mouse model of human ATC. Furthermore, we found that CRSP8 regulated the sensitivity of thyroid cancer cells to chemotherapeutics, including cisplatin and epirubicin. Collectively, our results demonstrated that CRSP8 functioned as a modulator of IKKα signaling and a suppressor of thyroid cancer differentiation, suggesting a potential therapeutic strategy for ATC by targeting CRSP8/IKKα pathway.

SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression.

Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism-based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull-down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem-like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human-derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co-control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6-SND1-hTERT axis may create a therapeutic vulnerability in CRC.

Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2.

SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associated with poor prognosis in ER- breast cancer patients.