METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect. METHODS: In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. RESULTS: We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice. CONCLUSIONS: These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.

Ivermectin synergizes sorafenib in hepatocellular carcinoma via targeting multiple oncogenic pathways.

Advanced hepatocellular carcinoma (HCC) results in generally poor clinical outcomes and necessitates better therapeutic strategies. Ivermectin, which is an existing anti-parasitic drug, has been recently identified as a novel anti-cancer drug. In line with previous efforts, this work demonstrates the translational potential of ivermectin to treat advanced HCC. We demonstrated that ivermectin at clinically relevant concentrations was active against growth and survival in multiple HCC cell lines. We showed that ivermectin had the potential to inhibit metastasis and target HCC stem cell functions. Mechanism studies correlated well with cellular phenotypes observed in ivermectin-treated cells, and demonstrated inhibition of mTOR/STAT3 pathway, suppression of epithelial mesenchymal transition (EMT) and reduced expression of stem cell markers. We further demonstrated that ivermectin inhibited tumor formation and growth in HCC xenograft mouse model, without causing significant toxicity in the mice. Using combination index (CI), we showed that ivermectin and sorafenib were synergistic in HCC in vitro, and this was further confirmed in vivo. Our work demonstrates the potent anti-HCC activities of ivermectin and its multiple targets on essential oncogenic pathways. Our findings provide preclinical evidence to initialize clinical trial using ivermectin and sorafenib for treating advanced HCC.

Expression of PD-L1 and PD-1 in stage T4 rectal cancer tissues and surrounding metastatic lymph nodes and correlation with prognosis.

The expressions of programmed death ligand 1 (PD-L1) and programmed death receptor 1 (PD-1) in T4 rectal cancer tissues and surrounding metastatic lymph nodes were analyzed and correlated with prognosis. For this purpose, ninety-eight patients with T4 rectal cancer treated in our hospital from July 2021 to July 2022 were selected, and surgically resected rectal cancer tissues as well as para carcinoma tissue samples, and surrounding metastatic lymph node tissues were obtained from all patients. Analysis of PD-L1 and PD-1 expression in rectal cancer tissues as well as in adjacent tissue specimens and surrounding metastatic lymph node tissues were performed using immunohistochemical staining. PD-L1 and PD-1 expression were analyzed in relation to lymph node metastasis, maximum tumor diameter, as well as histological analysis, and the relationship between the two and prognosis was analyzed. Immunohistochemistry for PD-L1, PD-1 revealed that both proteins were expressed in association with the target cytoplasm as well as within the cell membrane; The number of cases with positive expression of PD-L1 and PD-1 in cancer tissues was significantly higher than the number of cases with expression in adjacent tissues, which was statistically significant (P < 0.05); The expression rates of PD-L1, PD-1 in poor expression in progression-free survival as well as in progression survival were significantly higher than those in medium and high expression with statistical significance (P < 0.05); Compared with patients without lymph node metastasis, patients with T4 rectal cancer with lymph node metastasis had a higher number of cases with high expression levels of PD-L1 and PD-1 proteins, and the difference was statistically significant (P < 0.05); PD-L1 and PD-1 in T4 stage rectal cancer prognosis is closely related, distant metastasis as well as lymph node metastasis has a greater effect on PD-L1 and PD-1. PD-L1 and PD-1 showed abnormal expression in T4 rectal cancer tissues as well as in surrounding metastatic lymph nodes, and PD-L1 and PD-1 were closely related to prognosis in T4 rectal cancer, distant metastasis, as well as lymph node metastasis had a greater effect on PD-L1 and PD-1. Its detection is able to provide a certain data reference for the prognosis of T4 rectal cancer.

A novel RNA binding protein-associated prognostic model to predict overall survival in hepatocellular carcinoma patients.

ABSTRACT: Hepatocellular carcinoma (HCC) is 1 of the deadliest malignancies worldwide. Despite significant advances in diagnosis and treatment, the mortality rate from HCC persists at a substantial level. Construction of a prognostic model that can reliably predict HCC patients' overall survival is urgently needed.Two RNA-seq dataset (the Cancer Genome Atlas and International Cancer Genome Consortium) and 1 microarray dataset (GSE14520) were included in our study. RNA-binding proteins (RBPs) in HCC patients was examined by differentially expressed genes analysis, functional enrichment analysis and protein-protein interaction network analysis. Subsequently, the Cancer Genome Atlas dataset was randomly divided into training and testing cohort with a prognostic model developed in the training cohort. In order to evaluate the prognostic value of the model, a comprehensive survival assessment was conducted.Five RBPs (ribosomal protein L10-like, enhancer of zeste homolog 2 (EZH2), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), zinc finger protein 239, interferon-induced protein with tetratricopeptide repeats 1) were used to construct the model. The model accurately predicted the prognosis of liver cancer patients in both the training cohort and validation cohort. HCC patients could be assigned into a high-risk group and a low-risk group by this model, and the overall survival of these 2 groups was significantly different (P  < .05). Furthermore, the risk scores obtained by this model were highly correlated with immune cell infiltration.The prognostic model helps to identify HCC patients at high risk of mortality, which optimizes decision-making for individualized treatment.

A risk score based on baseline risk factors for predicting mortality in COVID-19 patients.

BACKGROUND: To develop a sensitive and clinically applicable risk assessment tool identifying coronavirus disease 2019 (COVID-19) patients with a high risk of mortality at hospital admission. This model would assist frontline clinicians in optimizing medical treatment with limited resources. METHODS: 6415 patients from seven hospitals in Wuhan city were assigned to the training and testing cohorts. A total of 6351 patients from another three hospitals in Wuhan, 2169 patients from outside of Wuhan, and 553 patients from Milan, Italy were assigned to three independent validation cohorts. A total of 64 candidate clinical variables at hospital admission were analyzed by random forest and least absolute shrinkage and selection operator (LASSO) analyses. RESULTS: Eight factors, namely, Oxygen saturation, blood Urea nitrogen, Respiratory rate, admission before the date the national Maximum number of daily new cases was reached, Age, Procalcitonin, C-reactive protein (CRP), and absolute Neutrophil counts, were identified as having significant associations with mortality in COVID-19 patients. A composite score based on these eight risk factors, termed the OURMAPCN-score, predicted the risk of mortality among the COVID-19 patients, with a C-statistic of 0.92 (95% confidence interval [CI] 0.90-0.93). The hazard ratio for all-cause mortality between patients with OURMAPCN-score >11 compared with those with scores ≤ 11 was 18.18 (95% CI 13.93-23.71; p < .0001). The predictive performance, specificity, and sensitivity of the score were validated in three independent cohorts. CONCLUSIONS: The OURMAPCN score is a risk assessment tool to determine the mortality rate in COVID-19 patients based on a limited number of baseline parameters. This tool can assist physicians in optimizing the clinical management of COVID-19 patients with limited hospital resources.

Up-Regulation of circEIF6 Contributes to Pancreatic Cancer Development Through Targeting miR-557/SLC7A11/PI3K/AKT Signaling.

BACKGROUND: Accruing evidences have pointed out that abnormal expression of circular RNAs (circRNAs) was closely related to the development of many malignancies. The present study intended to disclose the role of circRNA eukaryotic translation initiation factor 6 (circEIF6; hsa_circ_0060055) in pancreatic cancer progression. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circEIF6, EIF6 messenger RNA (mRNA), microRNA-557 (miR-557) and solute carrier family 7 member 11 (SLC7A11) mRNA. Cell proliferation ability, migration and invasion abilities and apoptosis were evaluated by Cell Counting Kit 8 (CCK8) assay, transwell migration and invasion assays and flow cytometry. Western blot assay was performed for the expression determination of all proteins. The predicted interaction between miR-557 and circEIF6 or SLC7A11 was confirmed by dual-luciferase reporter assay. Xenograft tumor model was used for exploring the biological function of circEIF6 in vivo. RESULTS: CircEIF6 abundance was aberrantly up-regulated in pancreatic tumor tissues and cell lines. Cell proliferation, migration and invasion were significantly restrained while cell apoptosis was induced with the silencing of circEIF6 in pancreatic cancer cells. CircEIF6 silencing also hampered the activation of phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway. CircEIF6 bound to miR-557, and circEIF6 silencing elevated the expression of miR-557 in pancreatic cancer cells. MiR-557 knockdown partly overturned circEIF6 silencing-induced effects in pancreatic cancer cells. SLC7A11 was a target of miR-557, and miR-557 overexpression suppressed malignant potential of pancreatic cancer cells partly through reducing the expression of SLC7A11. CircEIF6 knockdown blocked xenograft tumor growth in vivo. CONCLUSION: CircEIF6 aggravated pancreatic cancer development through promoting cell proliferation, migration and invasion and suppressing cell apoptosis through targeting miR-557/SLC7A11/PI3K/AKT signaling.

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19.

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.

Overriding sorafenib resistance via blocking lipid metabolism and Ras by sphingomyelin synthase 1 inhibition in hepatocellular carcinoma.

BACKGROUND: The survival benefit of sorafenib, the most used drug for advanced hepatocellular carcinoma (HCC), is unsatisfactory due to the development of adaptive resistance. Exploring the mechanisms underlying sorafenib resistance is important to develop sensitizing strategy. Sphingomyelin synthase (SMS) plays a critical role in sphingolipid metabolism which is involved in oncogenesis and drug resistance. METHODS: SMS1 and SMS2 levels in HCC cells in response to prolonged chemotherapy were analyzed using ELISA. mRNA and protein levels of SMS in HCC and adjacent normal tissues were analyzed by ELISA and real-time PCR. The roles of SMS and its downstream targets were investigated using cellular and biochemical assays and mass spectrometry. RESULTS: SMS1, but not SMS2, was upregulated in HCC in response to sorafenib treatment, although HCC displayed similar RNA and protein level of SMS1 compared to adjacent normal liver tissues. Overexpression of SMS1 promoted HCC growth and migration, and alleviated sorafenib's toxicity. SMS1 inhibition via genetic and pharmacological approaches consistently resulted in inhibition of growth and migration, and apoptosis induction in sorafenib-resistance HCC cells. SMS1 inhibition also augmented the efficacy of sorafenib in sensitive HCC cells. SMS1 inhibition disrupted sphingolipid metabolism via accumulating ceramide and decreasing sphingomyelin, inducing mitochondrial dysfunction and oxidative stress, and decreasing Ras activity in resistant cells. Overexpression of constitutively active Ras reversed the inhibitory effects of SMS1 inhibition. Although SMS1 overexpression did not affect Ras expression and activity, Pearson correlation coefficient analysis of SMS1 and Ras expression demonstrated that there was positive correlation between SMS1 and RAS (NRAS, R = 0.55, p < 0.01; KRAS, R = 0.44, p < 0.01). CONCLUSIONS: Our work is the first to suggest that SMS1 plays a more important role in sorafenib resistance than tumorigenesis, and provides preclinical evidence to overcome sorafenib resistance with SMS1 inhibition in HCC.

Kidney Function Indicators Predict Adverse Outcomes of COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is a recently emerged respiratory infectious disease with kidney injury as a part of the clinical complications. However, the dynamic change of kidney function and its association with COVID-19 prognosis are largely unknown. METHODS: In this multicenter retrospective cohort study, we analyzed clinical characteristics, medical history, laboratory tests, and treatment data of 12,413 COVID-19 patients. The patient cohort was stratified according to the severity of the outcome into three groups: non-severe, severe, and death. FINDINGS: The prevalence of elevated blood urea nitrogen (BUN), elevated serum creatinine (Scr), and decreased blood uric acid (BUA) at admission was 6.29%, 5.22%, and 11.66%, respectively. The trajectories showed the elevation in BUN and Scr levels, as well as a reduction in BUA level for 28 days after admission in death cases. Increased all-cause mortality risk was associated with elevated baseline levels of BUN and Scr and decreased levels of BUA. CONCLUSIONS: The dynamic changes of the three kidney function markers were associated with different severity and poor prognosis of COVID-19 patients. BUN showed a close association with and high potential for predicting adverse outcomes in COVID-19 patients for severity stratification and triage. FUNDING: This study was supported by grants from the National Key R&D Program of China (2016YFF0101504), the National Science Foundation of China (81630011, 81970364, 81970070, 81970011, 81870171, and 81700356), the Major Research Plan of the National Natural Science Foundation of China (91639304), the Hubei Science and Technology Support Project (2019BFC582, 2018BEC473, and 2017BEC001), and the Medical Flight Plan of Wuhan University.

Haemorrhagic retroperitoneal paraganglioma initially manifesting as acute abdomen: a rare case report and literature review.

BACKGROUND: Paragangliomas (PGLs) are extremely rare neuroendocrine tumours arising from extra-adrenal chromaffin cells. PGLs are clinically rare, difficult to diagnose and usually require surgical intervention. PGLs mostly present catecholamine-related symptoms. We report a case of Acute abdomen as the initial manifestation of haemorrhagic retroperitoneal PGL. There has been only one similar case reported in literature. CASE PRESENTATION: We present a unique case of a 52-year-old female with acute abdomen induced by haemorrhagic retroperitoneal PGL. The patient had a 5-h history of sudden onset of serve right lower quadrant abdominal pain radiating to the right flank and right lumbar region. Patient had classic symptoms of acute abdomen. Abdominal ultrasound revealed a large abdominal mass with a clear boundary. A Computed Tomography Angiography (CTA) of superior mesenteric artery was also performed to in the emergency department. The CTA demonstrated a large retroperitoneal mass measured 9.0 × 7.3 cm with higher density inside. A provisional diagnosis of retroperitoneal tumour with haemorrhage was made. The patient received intravenous fluids, broad-spectrum antibiotics and somatostatin. On the 3rd day of admission, her abdominal pain was slightly relieved, but haemoglobin decreased from 10.9 to 9.4 g/dL in 12 h suggesting that there might be active bleeding in the abdominal cavity. Thus, we performed a midline laparotomy for the patient. Haemorrhage was successfully stopped during operation. The retroperitoneal tumour with haemorrhage was completely removed. The abdominal pain was significantly relieved after surgery. The patient initially presented with acute abdomen instead of catecholamine-related symptoms. The diagnosis of retroperitoneal PGL with haemorrhage was finally confirmed by postoperative pathological and immunohistochemical results. The postoperative course was uneventful. At the 1-year follow-up visit, no tumour recurrence was observed by Single Photon Emission Computed Tomography. A literature review was performed to further understand and analyse the aforementioned disease. CONCLUSION: Acute abdomen as the initial manifestation of haemorrhagic retroperitoneal paraganglioma is extremely rare. Abdominal Computed Tomography is essential to locate the lesion and differentiate between other causes of acute abdomen. PGLs are hypervascular tumours. We should be aware that ruptured retroperitoneal PGL with massive bleeding could be life threatening and require emergency laparotomy.

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.

Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes.

Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.

Adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma: propensity score analysis.

AIM: To compare survival and recurrence in hepatocellular carcinoma (HCC) patients who did or did not receive adjuvant transarterial chemoembolization (TACE). METHODS: A consecutive sample of 229 patients who underwent curative resection between March 2007 and March 2010 in our hospital was included. Of these 229 patients, 91 (39.7%) underwent curative resection followed by adjuvant TACE and 138 (60.3%) underwent curative resection alone. In order to minimize confounds due to baseline differences between the two patient groups, comparisons were conducted between propensity score-matched patients. Survival data and recurrence rates were compared using the Kaplan-Meier method. Independent predictors of overall survival and recurrence were identified using Cox proportional hazard regression. RESULTS: Among 61 pairs of propensity score-matched patients, the 1-, 2-, and 3-year overall survival rates were 95.1%, 86.7%, and 76.4% in the TACE group and 86.9%, 78.5%, and 73.2% in the control group, respectively. At the same time, the TACE and control groups also showed similar recurrence rates at 1 year (13.4% vs 24.8%), 2 years (30.6% vs 32.1%), and 3 years (40.1% vs 34.0%). Multivariate Cox regression identified serum alpha-fetoprotein level ≥ 400 ng/mL and tumor size > 5 cm as independent risk factors of mortality (P < 0.05). CONCLUSION: As postoperative adjuvant TACE does not improve overall survival or reduce recurrence in HCC patients, further study is needed to clarify its clinical benefit.

Quantitative study of GaAs nanowires catalyzed by Au film of different thicknesses.

In this letter, we quantitatively investigated epitaxial GaAs nanowires catalyzed by thin Au films of different thicknesses on GaAs (111)B substrates in a metal-organic chemical vapor deposition reactor. Prior to nanowire growth, the de-wetting of Au thin films to form Au nanoparticles on GaAs (111)B in AsH3 ambient at different temperatures is investigated. It is found that with increasing film thickness, the size of the Au nanoparticles increases while the density of the nanoparticles reduces. Furthermore, higher annealing temperature produces larger Au nanoparticles for a fixed film thickness. As expected, the diameters and densities of the as-grown GaAs nanowires catalyzed by these thin Au films reflect these trends.

Ti-Zr-O nanotube arrays with controlled morphology, crystal structure and optical properties.

A series of Ti-Zr-O nanotube arrays on Ti-Zr alloys with different ratios of Ti to Zr were prepared by a simple anodization process, and their morphologies, crystal structures and optical properties were investigated. It is found that the morphology, length, crystal structure and optical properties of Ti-Zr-O tubes can be well controlled by adjusting the ratio of Ti to Zr in Ti-Zr alloys. The tubes obtained evolved from circa (ca.) 100 nm to 50 nm in diameter, from ca. 2 to 10 microm in length with increasing Zr content in Ti-Zr alloys. As-prepared tubes grown on the alloys with a Zr content of <70 mol% are amorphous, while cubic phase of ZrO2 is predominately formed in the 90 mol% Zr-Ti alloy. The absorption edge of such tubes was found to span from 250 to 370 nm, and their emission band from 400 nm to 750 nm in photoluminescence spectra decays with the decrease of Zr content. In addition, upon calcination of varied Zr content Ti-Zr-O nanotubes, Zr doped anatase TiO2, zirconium titanate and Ti doped ZrO2 in were obtained.