As the central organ of metabolism, the liver plays a pivotal role in the regulation of the synthesis and metabolism of various nutrients within the body. Ferroptosis, as a newly discovered type of programmed cell death caused by the accumulation of iron-dependent lipid peroxides, is involved in the physiological and pathological processes of a variety of acute and chronic liver diseases. Ferroptosis can accelerate the pathogenetic process of acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, and autoimmune hepatitis; while it can slower disease progression in advanced liver fibrosis and hepatocellular carcinoma. This suggests that targeted regulation of ferroptosis may impact the occurrence and development of various liver diseases. This article reviews the latest research progress of ferroptosis in various liver diseases, including acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune hepatitis, liver fibrosis and hepatocellular carcinoma. It aims to provide insights for the prevention and treatment of acute and chronic liver diseases through targeting ferroptosis.
Humans ; Liver Diseases/etiology* ; Ferroptosis/physiology* ; Liver Neoplasms/pathology* ; Carcinoma, Hepatocellular/pathology* ; Liver Cirrhosis/etiology* ; Liver/pathology* ; Hepatitis, Autoimmune/metabolism* ; Liver Diseases, Alcoholic/metabolism*

ErbB receptor tyrosine kinase inhibitors (EGFR-TKI), gefitinib, erlotinib, icotinib and aftinib, which are approved as a frontline treatment for patients with non-small cell lung cancer (NSCLC) who have tumors harboring EGFR mutations in China. And osimertinib was approved in second line setting for patients with EGFRT 790M-positive NSCLC. Rash, paronychia, diarrhea, stomatitis, liver dysfunction and (interstitial lung disease, ILD) are frequently observed in patients treated with EGFR-TKI. Chinese Society of Lung Cancer, Chinese Anti-Cancer Association, organized Chinese experts to develop the Chinese expert consensus on EGFR-TKI adverse event (AE) management based on domestic diagnosis and treatment of ADR and also incorporating international updated theory and recommendations.
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Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; China ; Diarrhea ; etiology ; ErbB Receptors ; antagonists & inhibitors ; genetics ; metabolism ; Humans ; Liver Diseases ; etiology ; Lung Diseases ; etiology ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Stomatitis ; etiology

OBJECTIVE: Small ubiquitin-related modifiers (SUMOs) are a group of post-translational modification proteins extensively expressed in eukaryotes. Abnormal SUMOylation can lead to the development of various diseases. This article summarizes the progress on research of the role of SUMOs in various types of kidney diseases to further increase the understanding of the regulatory functions of SUMOylation in the pathogenesis of kidney diseases. DATA SOURCES: This review was based on articles published in the PubMed databases up to January 2018, using the keywords including "SUMOs," "SUMOylation," and "kidney diseases." STUDY SELECTION: Original articles and critical reviews about SUMOs and kidney disease were selected for this review. A total of 50 studies were in English. RESULTS: SUMO participates in the activation of NF-κB inflammatory signaling pathway, playing a central regulatory role in the inflammation and progression of DN, and the secretion of various chemokines in AKI. SUMO involves in the regulation of TG2 and Nrf2 antioxidant stress, affecting renal tubular injury in AKI. SUMO affects the MAPK/ERK pathway, regulating intracellular signal transduction, modulating the transcription and expression of effector molecules in DN. SUMO contributes to the TGF-β/Smad pathway, leading to fibrosis of the kidney. The conjugate combination of SUMO and p53 regulates cell proliferation and apoptosis, and participates in the regulation of tumorigenesis. In addition, SUMOylation of MITF modulates renal tumors secondary to melanoma, Similarly, SUMOylation of tumor suppressor gene VHL regulates the occurrence of renal cell carcinoma in VHL syndrome. CONCLUSIONS Tissue injury, inflammatory responses, fibrosis, apoptosis, and tumor proliferation in kidney diseases all involve SUMOs. Further research of the substrate SUMOylation and regulatory mechanisms of SUMO in kidney diseases will improve and develop new treatment measures and strategies targeting kidney diseases.
Acute Kidney Injury ; etiology ; Carcinoma, Renal Cell ; etiology ; Diabetic Nephropathies ; etiology ; Fibrosis ; Humans ; Kidney ; pathology ; Kidney Diseases ; etiology ; metabolism ; Kidney Neoplasms ; etiology ; SUMO-1 Protein ; physiology ; Sumoylation

To investigate the effect of manganese superoxide dismutase (MnSOD) silence on the in vitro tumorigenicity in human small cell lung cancer NCI-H446 cells and the underlying mechanisms.
 Methods: Sphere formation cells from NCI-H446 cells were obtained by suspension culture, while the expression of MnSOD and urokinase type plasminogen activator (uPAR) was analyzed by Western blot. Silence of MnSOD was performed by adenovirus infection in the second passage formation cells, and the effect of MnSOD silence on tumorigenicity in NCI-H446 cells was evaluated by sphere formation assay and soft-agar colony formation assay, while the expression of uPAR was analyzed by Western blot.
 Results: Compared with NCI-H446 cells, the sphere formation rate, colony formation rate, and the expression of MnSOD and uPAR were significantly increased in the second passage sphere formation cells in NCI-H446 cells (P<0.05). Silence of MnSOD inhibited the sphere formation rate, colony formation rate, and the expression level of uPAR in the second passage sphere formation cells in NCI-H446 cells.
 Conclusion: MnSOD may promote tumorigenicity in NCI-H446 cells by up-regulation of uPAR expression in vitro.
Adenoviridae ; Carcinogenesis ; Cell Line, Tumor ; Humans ; In Vitro Techniques ; Lung Neoplasms ; etiology ; metabolism ; RNA Interference ; Receptors, Urokinase Plasminogen Activator ; genetics ; metabolism ; Small Cell Lung Carcinoma ; etiology ; metabolism ; Spheroids, Cellular ; pathology ; Superoxide Dismutase ; genetics ; metabolism ; Tumor Stem Cell Assay ; Up-Regulation

OBJECTIVETo investigate the application of bundles of intervention in the treatment of esophageal carcinoma anastomotic leak.

METHODSFrom January 2014 to May 2015, 44 cases of esophageal carcinoma anastomotic fistula were treated by bundles of intervention (through the collection of a series of evidence-based treatment and care measures for the treatment of diseases) in Department of Thoracic Surgery, Huai'an First Hospital, Nanjing Medical University (bundles of intervention group), and 68 patients with esophageal carcinoma postoperative anastomotic leak from December 2013 to January 2012 receiving traditional therapy were selected as the control group. The clinical and nutritional indexes of both groups were compared.

RESULTSThere were no significant differences in general data and proportion of anastomotic leak between the two groups. Eleven patients died during hospital stay, including 3 cases in bundles of intervention group(6.8%) and 8 cases in control group (11.8%) without significant difference(P = 0.390). In bundles of intervention group, 1 case died of type III( intrathoracic anastomotic leak, 2 died of type IIII( intrathoracic anastomotic leak. In control group, 2 cases died of type III( cervical anastomotic leak, 2 died of type III( intrathoracic anastomotic leak and 4 of type IIII( intrathoracic anastomotic leak. The mortality of bundles of intervention group was lower than that of control group. The duration of moderate fever [(4.1±2.4) days vs. (8.3±4.4) days, t=6.171, P=0.001], the time of antibiotic use [(8.2±3.8) days vs.(12.8±5.2) days, t=5.134, P = 0.001], the healing time [(21.5±12.7) days vs.(32.2±15.8) days, t=3.610, P=0.001] were shorter, and the average hospitalization expenses[(63±12) thousand yuan vs. (74±19) thansand yuan, t=3.564, P=0.001] was lower in bundles of intervention group than those in control group. Forty-eight hours after occurrence of anastomotic leak, the levels of hemoglobin, albumin and prealbumin were similar in both groups. However, at the time of fistula healing, the levels of hemoglobin [(110.6±10.5) g/L vs.(103.8±11.1) g/L, t=3.090, P=0.002], albumin [(39.2±5.2) g/L vs.(36.3±5.9) g/L, t=2.543, P=0.013] and prealbumin [(129.3±61.9) g/L vs.(94.1±66.4) g/L, t=2.688, P=0.008] were significantly higher in bundles of intervention group.

CONCLUSIONIn the treatment of postoperative esophageal carcinoma anastomotic leak, application of bundles of intervention concept can significantly improve the nutritional status and improve the clinical outcomes.

Anastomotic Leak ; mortality ; therapy ; Anti-Infective Agents ; therapeutic use ; Carcinoma ; complications ; surgery ; Esophageal Fistula ; complications ; mortality ; therapy ; Esophageal Neoplasms ; complications ; surgery ; Esophagectomy ; adverse effects ; mortality ; Female ; Fever ; epidemiology ; etiology ; Hemoglobins ; metabolism ; Hospital Costs ; statistics & numerical data ; Humans ; Male ; Middle Aged ; Nutritional Status ; Patient Care Bundles ; mortality ; statistics & numerical data ; Prealbumin ; metabolism ; Serum Albumin ; metabolism ; Treatment Outcome

BACKGROUND: The incidence and etiology of hepatocellular carcinoma (HCC) vary widely according to race and geographic regions. The insertional mutagenesis of adeno-associated virus 2 (AAV2) has recently been considered a new viral etiology of HCC. The aim of this study was to investigate the frequency and clinical characteristics of AAV2 in Korean patients with HCC. METHODS: A total of 289 unrelated Korean patients with HCC, including 159 Hepatitis-B-related cases, 16 Hepatitis-C-related cases, and 114 viral serology-negative cases, who underwent surgery at the Samsung Medical Center in Korea from 2009 to 2014 were enrolled in this study. The presence of AAV2 in fresh-frozen tumor tissues was investigated by DNA PCR and Sanger sequencing. The clinical and pathological characteristics of AAV2-associated HCC in these patients were compared with previous findings in French patients. RESULTS: The AAV2 detection rate in Korean patients (2/289) was very low compared with that in French patients (11/193). Similar to the French patients, the Korean patients with AAV2-related HCC showed no signs of liver cirrhosis. The Korean patients were younger than the French patients with the same AAV2-associated HCC; the ages at diagnosis of the two Korean patients were 47 and 39 yr, while the median age of the 11 French patients was 55 yr (range 43-90 yr). CONCLUSIONS: AAV2-associated HCC was very rare in Korean patients with HCC. Despite a limited number of cases, this study is the first to report the clinical characteristics of Korean patients with AAV2-associated HCC. These findings suggest epidemiologic differences in viral hepatocarcinogenesis between Korean and European patients.
Adult ; Asian Continental Ancestry Group ; Capsid Proteins/genetics ; Carcinoma, Hepatocellular/etiology/*pathology/virology ; DNA, Viral/chemistry/genetics/metabolism ; DNA-Binding Proteins/genetics ; Dependovirus/*genetics/isolation & purification/pathogenicity ; Female ; Humans ; Incidence ; Inverted Repeat Sequences/genetics ; Liver Neoplasms/etiology/*pathology/virology ; Male ; Middle Aged ; Parvoviridae Infections/complications/epidemiology ; Polymerase Chain Reaction ; Republic of Korea ; Sequence Analysis, DNA ; Viral Proteins/genetics

Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.
Biomarkers, Tumor/genetics/metabolism ; Carcinoma, Hepatocellular/*etiology ; Hepacivirus/genetics/*pathogenicity ; Hepatitis C/complications/pathology/virology ; Humans ; Liver Neoplasms/*etiology ; Risk

PURPOSE: It is well known that testicular germ cell tumors arise with increased frequency in patients with cryptorchidism. In addition, intratubular germ cell neoplasia (ITGCN) is a precursor lesion to testicular germ cell tumor. Approximately 50% of patients with ITGCN will develop an invasive of testicular germ cell tumors within 5 years. Therefore, we evaluated that the incidence of ITGCN in postpubertal cryptorchidism. MATERIALS AND METHODS: Between January 2002 and August 2012, orchiectomy specimens from 31 postpubertalpatients (aged 12 or over) with cryptorchid testis were reviewed. The specimens were evaluated for ITGCN using immunohistochemical stains of placental-like alkaline phosphatase and Oct 3/4 with routine hematoxylin-eosin stain. Additionally, the degree of spermatogenesis was assessed using the Johnsen score. RESULTS: Mean age was 34 years (range, 17 to 74 years) at surgery. All patients were diagnosed as unilateral cryptorchidism. One patient (3.2%) of 20-year-old had ITGCN in surgical specimen with all positive markers. Histological assessment of spermatogenesis showed that mean Johnsen score was 3.42 (range, 1 to 9). Majority of patients (27 of 31) presented impaired spermatogenesis with low Johnsen score lesser than 5. CONCLUSIONS: Considering the risk of malignancy and low spermatogenesis, we should perform immunohistochemical stains and discuss preventative orchiectomy for the postpubertal cryptorchidism.
Adolescent ; Adult ; Aged ; Alkaline Phosphatase/metabolism ; Biomarkers, Tumor/metabolism ; Carcinoma in Situ/diagnosis/*etiology/pathology ; Cryptorchidism/*complications/surgery ; Disease Progression ; Humans ; Infertility, Male/etiology ; Isoenzymes/metabolism ; Male ; Middle Aged ; Neoplasms, Germ Cell and Embryonal/diagnosis/*etiology/pathology/prevention & control ; Orchiectomy ; Puberty ; Retrospective Studies ; Spermatogenesis ; Testicular Neoplasms/diagnosis/*etiology/pathology/prevention & control ; Young Adult

OBJECTIVE: To evaluate the safety and clinical outcomes of chemoembolization in Child-Pugh class C patients with hepatocellular carcinomas (HCC). MATERIALS AND METHODS: The study comprised 55 patients with HCC who were classified as Child-Pugh class C and who underwent initial chemoembolization between January 2003 and December 2012. Selective chemoembolization was performed in all technically feasible cases to minimize procedure-related complications. All adverse events within 30 days were recorded using the Common Terminology Criteria for Adverse Events (CTCAE). The tumor response to chemoembolization was evaluated using the modified Response Evaluation Criteria In Solid Tumors. RESULTS: Thirty (54.5%) patients were within the Milan criteria, and 25 (45.5%) were beyond. The mortality of study subjects at 30 days was 5.5%. Major complications were observed in five (9.1%) patients who were all beyond the Milan criteria: two hepatic failures, one hepatic encephalopathy, and two CTCAE grade 3 increases in aspartate aminotransferase/alanine aminotransferase abnormality. The mean length of hospitalization was 6.3 ± 8.3 days (standard deviation), and 18 (32.7%) patients were discharged on the next day after chemoembolization. The tumor responses of the patients who met the Milan criteria were significantly higher (p = 0.014) than those of the patients who did not. The overall median survival was 7.1 months (95% confidence interval: 4.4-9.8 months). CONCLUSION: Even in patients with Child-Pugh class C, chemoembolization can be performed safely with a selective technique in selected cases with a small tumor burden.
Adult ; Aged ; Alanine Transaminase/metabolism ; Aspartate Aminotransferases/metabolism ; Carcinoma, Hepatocellular/mortality/*pathology/therapy ; Chemoembolization, Therapeutic/adverse effects ; Female ; Hepatic Encephalopathy/etiology ; Humans ; Length of Stay ; Liver Neoplasms/mortality/*pathology/therapy ; Liver Transplantation ; Male ; Middle Aged ; Proportional Hazards Models ; Severity of Illness Index ; Survival Rate ; Treatment Outcome ; Tumor Burden

Inflammation is one of the most prominent characteristic features of chronic liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most of HCC cases develop in patients with cirrhosis and cirrhosis develops in patients with chronic liver inflammation. Therefore, there is no doubt that there exist some strong connection among inflammation, fibrosis, and cancer. In fact, chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. This review will discuss the common mechanism of inflammation and fibrosis in chronic liver diseases, and then demonstrate why HCC develops in inflammatory and fibrotic conditions.
Carcinoma, Hepatocellular/*etiology ; Gram-Negative Bacteria/growth & development ; Hepatitis, Chronic/*complications/metabolism/microbiology ; Humans ; Hypoxia ; *Inflammation ; Lipopolysaccharides/metabolism ; Liver/metabolism/pathology ; Liver Cirrhosis/*complications ; Liver Neoplasms/*etiology ; Toll-Like Receptors/metabolism