Expression and prognostic significance of the PD-1/PD-L1 pathway in AIDS-related non-Hodgkin lymphoma.

OBJECTIVE: Immune tolerance and evasion play a critical role in virus-driven malignancies. However, the phenotype and clinical significance of programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, in aggressive acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (AR-NHL) remain poorly understood, particularly in the Epstein-Barr virus (EBV)-positive subset. METHODS: We used in situ hybridization with EBV-encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD-1/PD-L1/L2 pathway in a multi-institutional cohort of 58 patients with AR-NHL and compared EBV-positive and EBV-negative cases. RESULTS: The prevalence of EBV+ in AR-NHL was 56.9% and was associated with a marked increase in the expression of PD-1/PD-L1/PD-L2 in malignant cells. Patients with AR-NHLs who tested positive for both EBER and PD-1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD-L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD-1 tissue-expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD-1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD-L1 (r = 0.354, p = 0.014) expression. CONCLUSIONS: These data emphasize the importance of PD-1-mediated immune evasion in the complex landscape of immune oncology in AR-NHL co-infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup.

The Role of Infiltrated T Lymphocyte in Oral Squamous Cell Carcinoma: Insights into Clinicopathological Characteristics and Prognosis.

Background: To compare and analyze the presence of CD4+ and CD8 + lymphocyte infiltrates in Oral squamous cell carcinoma (OSCC) tissue versus adjacent tissue and their clinical significance. Methods: We enrolled a total of 152 patients diagnosed with OSCC, all of whom had confirmed diagnoses through pathological reports. Clinical and demographics data were extracted from medical records. Tissue microarrays were constructed and immunohistochemical staining for CD4 and CD8 was performed. Findings: The average number of infiltrating CD4+ T cells in OSCC tumor tissue was 1026.22±1163.36 cells/mm2, which did not significantly differ from the count in adjacent tissue, which was 1163.36±1013.23 cells/mm2. However, the number of CD8+ T cell infiltration in tumor tissue was significantly higher than in adjacent tissue (655.25±705.70 vs 504.56±659.26 cells/mm2, p = 0.026). We observed that, among patients who consumed alcohol, the CD4+ T cell infiltration in tumor tissue being significantly lower than that in adjacent tissue (P=0.036). Moreover, the CD8+ T cell infiltration in cancer tissue was significantly higher than in adjacent tissue for T1-2 patients (p=0.005). Patients with higher CD8+ T cell in tumor tissue exhibited significantly improved overall survival (p = 0.043). Multivariate analyses revealed that alcohol consumption had a significant impact on the number of CD4+T lymphocytes in tumor tissue (OR = 0.403, P = 0.033) while T stage was the independent factor affecting CD8+ T lymphocyte infiltration in tumor tissue (OR = 0.459, P = 0.031). Interpretation: OSCC patients with a higher number of CD8+ T lymphocyte infiltration in tumor tissue exhibited an improved prognosis.

Prospective observational study of baloxavir marboxil in adults and adolescents with uncomplicated influenza from China.

Introduction: There are limited data on the efficacy of baloxavir marboxil (baloxavir) versus oseltamivir in Chinese patients with influenza A. Methods: This study is an observational real-world investigation encompassing 246 patients (baloxavir, n = 147; oseltamivir, n = 99) confirmed positive for influenza A. The choice between baloxavir and oseltamivir antiviral treatments was determined collaboratively by the clinician and the patient. A thorough comparative analysis was undertaken between the two groups, examining parameters such as the duration of fever and symptoms, viral load dynamics, lymphocyte changes, and enhancements in health-related quality of life (QoL). Results: No significant differences were observed in demographic data between the two groups. The duration of fever was significantly shorter in the baloxavir group (P < 0.001). However, the duration of symptoms was not significant different (P = 0.167). Multivariable Cox analysis showed the independent factors affecting duration of fever were baloxavir treatment (HR = 2.033, P < 0.001), fever on day 1 (HR = 0.741, P = 0.010) and CRP level (HR = 1.009, P = 0.039). Moreover, sex (HR= 0.660, P = 0.019) and monocyte count (HR = 1.355, P = 0.018) were independent factors affecting the duration of symptoms. No significant difference in change of health-related quality of life (P > 0.05), positive rate of viral antigen on day 3 (P = 0.477) between the two groups. Remarkably, a mutation was observed in one case on the third-day after baloxavir treatment compared with first-day, from cysteine to serine at position 384 of the PA subunit. Conclusion: In the clinical setting, baloxavir demonstrated comparable clinical benefits to oseltamivir, establishing its efficacy as an effective antiviral therapy for Chinese patients with influenza.

CMTM6 recruits T cells within the endocervical adenocarcinoma microenvironment and suppresses cell proliferation via the p53 pathway.

Endocervical adenocarcinoma (ECA), harboring poor prognosis, is divided into human papilloma virus (HPV)-associated adenocarcinoma (HPVA) and non-HPVA (NHPVA), each consisting of a heterogeneous immune microenvironment. We aim to examine the effect of CKLF-like MARVEL transmembrane domain 6 (CMTM6), a key regulator of PD-L1, on ECA. Immunohistochemistry and RNA-sequencing (RNA-seq) were used to detect CMTM6, Programmed death ligand 1 (PD-L1), and immune cells biomarkers levels in tumors. RT-qPCR and Western Blotting were used to detect the mRNA and protein level changed in cells. The expression of CMTM6 in ECA is upregulated compared to cervical squamous cell carcinoma tissues. More infiltrating T cells were observed in CMTM6high ECA tissues, especially in CMTM6high HPVA. Higher expression of CMTM6 is associated with a higher rate of infiltrating CD8+ T cells in HPVA, but not in NHPVA. ECA patients were divided into three groups according to the co-expression status of CMTM6 and PD-L1(CPS) . Patients with CMTM6high /PD-L1(CPS+) had the longest OS and DFS, especially in NHPVA patients. Moreover, knock down of CMTM6 promotes ECA cell proliferation via the p53 pathway. CMTM6 recruits T cells, suppresses ECA cell proliferation via the p53 pathway and can be used as a novel prognostic indicator for ECA patients.

Hypoalbuminemia predicts inferior outcome in patients with AIDS-related lymphoma.

BACKGROUND: The prognostic value of serum albumin in acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL) remains covered. METHODS: We retrospectively analyzed de novo ARL patients from 2013 to 2019 across three centers. Factors correlated with progression-free survival (PFS) and overall survival (OS) were evaluated in Kaplan-Meier, univariate and multivariate Cox proportional hazard models. RESULTS: A total of 86 ARL patients were enrolled with a median follow-up of 34 months. In the cohort, the OS and 2-year PFS rates were 37.5% and 35.4%, respectively. In multivariate models, older age (PFS, hazard ratios [HR] = 1.035, p = 0.037; OS, HR = 1.034, p = 0.041) and hypoalbuminemia (OS, HR = 0.910, p = 0.038) predicted inferior survival. ARL patients with hypoalbuminemia showed worse OS and 2-year PFS (p = 0.028 and p = 0.01, respectively), which was associated with poor Eastern Cooperative Oncology Group performance status (ECOG PS) and higher International Prognosis Index (IPI) score. CONCLUSION: In conclusion, serum albumin at diagnosis is an independent prognostic factor for overall survival in AIDS-related lymphoma.

aMAP Score as a Predictor for Long-Term Outcomes in Patients with HBV-Related Acute-on-Chronic Liver Failure.

BACKGROUND AND AIM: The long-term outcomes of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) remain not well known. This study aimed to investigate whether aMAP score can predict re-hospitalization, hepatocellular carcinoma (HCC) occurrence and long-term mortality in patients with HBV-ACLF. METHODS: A total of 82 patients diagnosed with HBV-ACLF and survived over 6 months were enrolled. The median follow-up period was 105 (75.9, 134.1) months. The Cox proportional hazards or logistic regression analysis was used to determine independent risk factors. Cumulative incidence of HCC and survival rate were evaluated using Kaplan-Meier analysis. RESULTS: Multivariate analysis identified that the aMAP risk score was an independent predictor of re-hospitalization (odds ratio [OR] = 1.112, 95% confidence interval [CI]: 1.021-1.211, p = 0.015), hepatocellular carcinoma occurrence (hazards ratio [HR] = 2.277, 95% CI: 1.014-5.114, p = 0.046) and mortality (HR = 1.366, 95% CI: 1.040-1.794, p = 0.025). High-risk aMAP scores were associated with higher risk of HCC occurrence and mortality. CONCLUSION: A higher aMAP score was an independent risk predictor of re-hospitalization, HCC occurrence and mortality, respectively, in HBV-ACLF patients who survived over 6 months, which can be applicable for early risk stratification and clinical decision.

Preoperative false-negative transthoracic echocardiographic results in native valve infective endocarditis patients: a retrospective study from 2001 to 2018.

BACKGROUND: Infective endocarditis (IE) is a lethal disease that is difficult to diagnosis early. Although echocardiography is one of the most widely used diagnostic technique, it has limited sensitivity. This study surveyed the clinical features of IE patients who underwent surgery and compared transthoracic echocardiography and histological findings to explore the factors related to false-negative echocardiographic results. METHODS: Medical records were extracted from IE patients consecutively hospitalized between June 2001 and June 2018. RESULTS: A total of 182 patients with native valve IE who underwent surgery were included. Compared to the non-surgery group, the surgery group was more likely to have pre-existing valvular lesions and more serious cardiac conditions and a relative lack of signs of infection and cerebrovascular events, leading to a lower proportion of "definite cases" before surgery. The false-negative rate of echocardiography was 14.5%. Echocardiography has significant disadvantages in diagnosing perivalvular abscesses, valve perforations, and left-sided endocarditis, especially for subjects with both aortic and mitral valve infections. The multivariate analysis identified congenital heart disease and small vegetations (< 10 mm) as independent predictors of false-negative echocardiography results. Conversely, fever and heart murmurs on admission served as protective factors. CONCLUSIONS: Under some circumstances, echocardiography provides inconsistent results compared with surgical findings, and negative echocardiography results do not rule out IE. The diagnosis of IE depends on comprehensive evaluations using multiple methods.

Microbial cell-free DNA in plasma of patients with sepsis: a potential diagnostic methodology.

Sepsis is a life-threatening clinical condition demanding accurate and rapid diagnosis of the culprit pathogen, thereby to improve prognosis. Pathogen determination through blood culture is the gold standard for diagnosis but has limitations due to low sensitivity. Recently, circulating DNAs derived from pathogenic organisms were found in the plasma of patients with sepsis and were further proved to be more sensitive biomarkers for the diagnosis of the pathogen origin in sepsis. However, the fundamental molecular characteristics of circulating DNA in patients with sepsis remain unclear. Here, we used specific PCR and Sanger sequencing to verify the microbiology culture results via the corresponding plasma circulating DNA. We analyzed the composition and molecular characteristics of circulating DNA in septic patients using next-generation sequencing technology. We showed the presence of pathogen-derived circulating DNA in the plasma of patients with sepsis. The sizes of circulating DNA fragments derived from pathogenic bacteria showed a skewed unimodal distribution, while those derived from host cells showed a normal unimodal distribution. Lengths of fragments at peak concentration for both origins ranged from 150 bp to 200 bp, and reads mapping to pathogenic bacteria genome distributed uniformly on the reference. Our findings have improved our understanding of microbial circulating DNA in patients with sepsis as a potential methodology for the accurate diagnosis of sepsis, especially in light of an urgent need for such a diagnosis associated with the COVID-19 infection.

Depression, Anxiety, Psychological Symptoms and Health-Related Quality of Life in People Living with HIV.

OBJECTIVE: To investigate the levels of depression, anxiety, psychological symptoms and health-related quality of life (HRQOL) in people infected with human immunodeficiency virus (HIV) and to assess the risk factors. METHODS: A total of 121 people living with HIV (PLWHIV) were included, and 61 health individuals were selected as healthy controls. Their sociodemographic information was collected. The Self-Rating Depression Scale, Self-Rating Anxiety Scale, Symptom Checklist 90 and Short-Form Health Survey-36 were used. RESULTS: The depression score was higher in PLWHIV (47.83 ± 10.58 vs 36.52 ± 9.69 P<0.001). Similar results were observed in anxiety score (41.06 ± 11.24 vs 32.31 ± 7.99, P<0.001). Multivariable analysis revealed that younger age (OR=0.929, P=0.004) and smoking (OR=4.297, P=0.001) were identified as independent factors of depression while young age (OR=0.890, P=0.008) and alcohol consumption (OR=4.801, P=0.002) were independent factors of anxiety. Results of SCL-90 questionnaire showed that hostility, paranoia ideation were significantly more pronounced when PLWHIV had depression. Results of HRQOL showed that physical functioning (82.88 ± 14.73 vs 93.41 ± 9.22, P<0.001) and mental health (57.46 ± 17.64 vs 65.68 ± 17.44, P=0.012) were lower in PLWHIV with depression. For PLWHIV with anxiety, vitality (56.96 ± 14.61 vs 67.58 ± 17.57, P=0.004), social functioning (64.52 ± 23.97 vs 74.64 ± 21.47, P=0.036) and mental health (52.57 ± 14.21 vs 65.03 ± 17.98, P=0.001) were lower. High depression level was showed the independent risk factor associated with poor HRQOL (OR=0.370, P=0.001). CONCLUSION: Depression and anxiety were very common in PLWHIV. Physicians should not only focus on the antiviral treatment of these patients but also monitor their mental status, especially that of younger patients. For PLWHIV with depression and anxiety, psychological intervention should be provided, and social role rebuilding may be good for depression and anxiety alleviation.

Association Between Clinical Manifestations and Prognosis in Patients with COVID-19.

PURPOSE: The purpose of this study was to determine the risk factors associated with pneumonia, acute respiratory distress syndrome (ARDS), and clinical outcome among patients with novel coronavirus disease 2019 (COVID-19). METHODS: This was a cross-sectional multicenter clinical study. A total of 95 patients infected with COVID-19 were enrolled. The COVID-19 diagnostic standard was polymerase chain reaction detection of target genes of 2019 novel coronavirus (2019-nCoV). Clinical, laboratory, and radiologic results, as well as treatment outcome data, were obtained. ARDS was defined as an oxygenation index (arterial partial pressure of oxygen/fraction of inspired oxygen) ≤300 mm Hg. FINDINGS: Multivariate analysis showed that older age (odds ratio [OR], 1.078; p = 0.008) and high body mass index (OR, 1.327; p = 0.024) were independent risk factors associated with patients with pneumonia. For patients with ARDS, multivariate analysis showed that only high systolic blood pressure (OR, 1.046; p = 0.025) and high lactate dehydrogenase level (OR, 1.010; p = 0.021) were independent risk factors associated with ARDS. A total of 70 patients underwent CT imaging repeatedly after treatment. Patients were divided in a disease exacerbation group (n = 19) and a disease relief group (n = 51). High body mass index (OR, 1.285; p = 0.017) and tobacco smoking (OR, 16.13; p = 0.032) were independent risk factors associated with disease exacerbation after treatment. IMPLICATIONS: These study results help in the risk stratification of patients with 2019-nCoV infection. Patients with risk factors should be given timely intervention to avoid disease progression.

Smoking behavior and smoking index as prognostic indicators for patients with esophageal squamous cell carcinoma who underwent surgery: A large cohort study in Guangzhou, China.

INTRODUCTION: This study aimed to evaluate the association between smoking and smoking index with clinical outcomes of esophageal squamous cell carcinoma patients. METHODS: This is a retrospective analysis conducted on consecutive patients with esophageal carcinoma who underwent esophagectomy from January 2005 to December 2010. All patients had pathologically confirmed esophageal squamous cell carcinoma. The association between smoking and sociodemographic characteristics with overall survival and disease-free survival was analyzed. Serum carcinoembryonic antigen was measured using an electrochemiluminescence immunoassay. RESULTS: A total of 944 patients were enrolled. Kaplan-Meier analysis indicated that esophageal squamous cell carcinoma patients who smoked had a significantly worse prognosis in terms of both overall survival (p=0.007) and disease-free survival (p= 0.010). Multivariate analysis demonstrated that age (p=0.001), carcinoembryonic antigen (p=0.012), tumor-node-metastasis (TNM) staging (p<0.001) and smoking (p=0.048) were independently correlated with overall survival, while only TNM stage (p<0.001) and smoking (p=0.041) were identified as independent factors of disease-free survival. We divided the smoking population into two groups (smoking index <400 and ≥400). Kaplan-Meier survival analysis indicated that a smoking index <400 was associated with a significantly better prognosis in terms of both overall survival (p=0.003) and favorable disease-free survival (p=0.032). Multivariate analysis showed that age (p<0.001), TNM staging (p<0.001), and smoking index (p=0.025) were independent factors of overall survival, whereas for disease-free survival, only TNM stage (p=0.001) and smoking index (p=0.025) were identified. CONCLUSIONS: Overall survival was significantly associated with smoking in esophageal squamous cell carcinoma patients. For esophageal squamous cell carcinoma patients who smoke, a higher smoking index is associated with worse clinical outcomes. Therefore, smoking may be used as a predictive indicator for pretreatment evaluation and adjustment of treatment regimen.

Comparison of pegylated interferon monotherapy and de novo pegylated interferon plus tenofovir combination therapy in patients with chronic hepatitis B.

Background and aim: We aimed to evaluate the effectiveness of pegylated interferon (Peg-IFN) monotherapy (IFN group) and combination therapy with tenofovir (TDF) and Peg-IFN (IFN+TDF group) in chronic hepatitis B (CHB) patients. Patients and methods: Data of 143 CHB patients were analyzed in this study. All patients enrolled received liver biopsy. Virologic responses were defined as hepatitis B virus (HBV) DNA <100 IU/mL, biochemical responses were defined as normalization of alanine aminotransferse (ALT) levels, and HBeAg serological response was defined as HBeAg loss or HBeAg seroconversion to HBeAb. HBsAg serological response was defined as HBsAg loss or HBsAg seroconversion to HBsAb. Results: We observed that a total of 16.7% (11/66) and 33.8% (26/77) patients in IFN and IFN+TDF group achieved complete viral suppression after 48 weeks treatment (P=0.02). Although HBeAg levels in CHB patients in the IFN+TDF group decreased more rapidly during the 48-week treatment, we did not observe significant differences in HBeAg serological loss or seroconversion rates between the two groups at 24 and 48 weeks. HBsAg loss was observed in 13.0% (10/77) of CHB patients in the IFN+TDF group at 48 weeks, compared with only 3% (2/66) patients in the IFN group (P=0.032). No significant difference was observed in HBsAg seroconversion rate between the two groups during 48-week treatment. The biochemical response rate was also significantly higher in the IFN+TDF group than that in the IFN group at week 48 (P=0.015). Multivariate logistic analysis showed that IFN+TDF treatment (OR=4.41, P=0.003), severe baseline hepatic inflammation (OR=4.16, P<0.001), and lower baseline serum HBV DNA levels (OR=0.98, P=0.03) were strong predictors for the virological response. Younger age (OR=0.89, P=0.01), higher baseline ALT level (OR=1.01, P=0.038), and lower baseline HBeAg level (OR=0.99, P=0.008) were independent predictors for HBeAg sero-response after 48 weeks treatment. While only severe liver fibrosis (OR=1.69, P=0.028) and lower baseline HBsAg level (OR=0.22, P=0.005) were independent factors associated with HBsAg sero-response after 48 weeks treatment. Conclusion: Peg-IFN combined with TDF may increase the virological response rate, biochemical response rate, and HBsAg loss rate in patients with CHB infection. The combination treatment is more suitable for those patients who are likely to respond to the treatment.

Altered epidermal fatty acid-binding protein expression in hepatocellular carcinoma predicts unfavorable outcomes.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a rapidly proliferating malignancy that requires large amounts of fatty acids to synthesize cellular membranes and provide energy. Epidermal fatty acid-binding protein (EFABP) is uniquely expressed in epidermal cells, but its role and expression in HCC are not clear. SUBJECTS AND METHODS: A total of 804 HCC specimens were collected to construct a tissue microarray (TMA) and for immunohistochemistry (IHC) analysis. The relationship between EFABP expression and clinical features of patients with HCC was analyzed. RESULTS: The EFABP IHC score for HCC tissue was 0.76±0.69, being significantly higher than that for matched nontumorous tissue (0.48±0.55; P<0.001). Using the median IHC score (ie, 0.8) in the tumorous tissue, a high level of EFABP expression was found in 57.3% (461/804) of the cases. Patients with HCC displaying high EFABP expression had poorer tumor differentiation (P=0.029), more vascular invasion (P=0.006), and a higher proportion of late TNM stage disease (P=0.042). Kaplan-Meier analysis revealed that the patients with high EFABP expression had significantly worse outcomes in terms of overall survival (P=0.003), worse disease-free survival (P=0.021), and a higher probability of recurrence (P=0.014). Multivariate analysis indicated that EFABP expression was an independent prognostic variable for overall survival (P=0.021) and disease-free survival (P=0.044). For HCC recurrence, only vascular invasion (P=0.020) and EFABP expression (P=0.026) were independent risk factors. CONCLUSION: Our data revealed that EFABP expression was increased in HCC samples. High EFABP expression was correlated with shorter survival times in patients with HCC and served as an independent factor for worse outcomes. Our study therefore provides a promising bio-marker for the prognostic prediction of HCC and a potential therapeutic target for the disease.

A model combining TNM stage and tumor size shows utility in predicting recurrence among patients with hepatocellular carcinoma after resection.

OBJECTIVE: Hepatocellular carcinoma (HCC) recurrence is a clinical challenge. An accurate prediction system for patients with HCC is needed, since the choice of HCC treatment strategies is very important. PATIENTS AND METHODS: A total of 804 patients with HCC who underwent curative resection at Sun Yat-sen University Cancer Center were included in this study. Demographics, clinicopathological data, and follow-up information were collected. RESULTS: A logistic regression analysis was conducted to investigate the relationships between clinical features and HCC recurrence. Tumor size (OR=1.454, 95% CI: 1.047-2.020, P=0.026) and TNM stage (OR=1.360, 95% CI: 1.021-1.813, P=0.036) were independent predictors of HCC recurrence after curative resection. Therefore, the following equation was established to predict HCC recurrence: 0.308×TNM+0.374×tumor size-0.639. The equation score was 0.53±0.23 in patients who experienced HCC recurrence compared with 0.47±0.24 in other patients. A similar trend was observed in patients who survived after the last follow-up, compared with those who did not, with scores of 0.37±0.26 vs 0.52±0.22, respectively (P<0.001). The Kaplan-Meier analysis showed that patients with HCC with equation values >0.5 had significantly worse outcomes than those with equation values ≤0.5 (P<0.001) for overall survival (OS) and recurrence (P=0.043). Multivariate Cox analyses showed that tumor multiplicity (P=0.039), involucrum (P=0.029), vascular invasion (P<0.001), and equation value (P<0.001) were independent prognostic variables for OS, whereas tumor multiplicity (P=0.01), tumor differentiation (P=0.007), vascular invasion (P<0.001), involucrum (P=0.01), and equation value (P<0.001) were independent prognostic variables for HCC recurrence. CONCLUSION: We established a novel and effective equation for predicting the probability of recurrence and OS after curative resection. Patients with a high recurrence score, based on this equation, should undergo additional high-end imaging examinations.

PRAF2 expression indicates unfavorable clinical outcome in hepatocellular carcinoma.

INTRODUCTION: Prenylated Rab acceptor 1 domain family member 2 (PRAF2), a novel oncogene, has been shown to be essential for the development of several human cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. MATERIALS AND METHODS: PRAF2 mRNA and protein expressions were examined in fresh tissues by quantitative reverse transcription-polymerase chain reaction and Western blot, respectively, and in 518 paraffin-embedded HCC samples by immunohistochemistry. The correlation of PRAF2 expression and clinical outcomes was determined by the Student's t-test, Kaplan-Meier test, and multivariate Cox regression analysis. The role of PRAF2 in HCC was investigated by cell viability, colony formation, and migration assays in vitro and with a nude mouse model in vivo. RESULTS: In our study, the PRAF2 expression was noticeably increased in HCC tissues at both the mRNA and protein levels compared with that of the nontumorous tissues. Kaplan-Meier analysis indicated that high PRAF2 expression was correlated with worse overall survival in a cohort of 518 patients with HCC. The prognostic implication of PRAF2 was verified by stratified survival analysis. The multivariate Cox regression model revealed PRAF2 as an independent poor prognostic factor for overall survival (hazard ratio = 1.244, 95% CI: 1.039-1.498, P<0.017) in HCC. The in vitro data demonstrated that PRAF2 overexpression markedly enhanced cell viability, colony formation, and cell migration. Moreover, ectopic expression of PRAF2 promoted tumor growth and metastasis in vivo. CONCLUSION: Collectively, we conclude that PRAF2 is increased in HCC and is a novel unfavorable biomarker for prognostic prediction for patients with HCC.

Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) has a close relationship with lipid metabolism. Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the regulation of fatty acid oxidation in the liver. However, the role of PPARα in HCC remains unclear. METHODS: A total of 804 HCC specimens were collected to construct a tissue microarray and for immunohistochemical analysis. The relationship between PPARα expression and clinical features of HCC patients was analyzed. Kaplan-Meier analysis was conducted to assess the prognostic value of PPARα expression levels. RESULTS: The expression of PPARα in HCC was noticeably decreased in HCC tissues. HCC patients with high levels of PPARα expression in cytoplasm had smaller tumors (P=0.027), less vascular invasion (P=0.049), and a higher proportion of complete involucrum (P=0.038). Kaplan-Meier analysis showed that HCC patients with low PPARα expression in the cytoplasm had significantly worse outcomes in terms of overall survival (P<0.001), disease-free survival (P=0.024), and the probability of recurrence (P=0.037). Similarly, overall survival was significantly shorter in HCC patients with negative PPARα expression in the nucleus (P=0.034). Multivariate Cox analyses indicated that tumor size (P=0.001), TNM stage (P<0.001), vascular invasion (P<0.001), and PPARα expression in the cytoplasm (P<0.001) were found to be independent prognostic variables for overall survival. CONCLUSION: Our data revealed that PPARα expression was decreased in HCC samples. High PPARα expression was correlated with longer survival times in HCC patients, and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

Risk factors associated with liver steatosis and fibrosis in chronic hepatitis B patient with component of metabolic syndrome.

BACKGROUND: We investigated whether metabolic syndrome exacerbated the risk of liver fibrosis among chronic hepatitis B patients and risk factors associated with liver steatosis and fibrosis in chronic hepatitis B patients with components of metabolic syndrome. METHODS: This study included 1236 chronic hepatitis B patients with at least one component of metabolic syndrome. The controlled attenuation parameter and liver stiffness, patient information and relevant laboratory data were recorded. RESULTS: Controlled attenuation parameter was increased progressively with the number of metabolic syndrome components (p < 0.001). Multivariate analysis indicated younger age, high gamma-glutamyltransferase level, high waist-hip ratio, and high body mass index were independent risk factors associated with nonalcoholic fatty liver disease among chronic hepatitis B patients with metabolic syndrome. In the fibrosis and non-fibrosis groups, most of blood lipid was relatively lower in fibrosis group. An increased proportion of chronic hepatitis B patients with liver fibrosis was found concomitant with an increasing number of components of metabolic syndrome. Male gender, older age, smoking, aspartate aminotransferase levels, high body mass index, and low platelet level were identified as independent risk factors associated with liver fibrosis. CONCLUSIONS: For chronic hepatitis B patients with coexisting components of metabolic syndrome, stratification by independent risk factors for nonalcoholic fatty liver disease and fibrosis can help with management of their disease.

POH1 Knockdown Induces Cancer Cell Apoptosis via p53 and Bim.

The ubiquitin-proteasome system is implicated in cell apoptosis that is frequently dysregulated in human cancers. POH1/rpn11/PSMD14, as a part of the 19S proteasomal subunit, contributes to the progression of malignancy, but its role in apoptosis remains unclear. Here, we showed that POH1 expression was increased and associated with poor outcomes in three independent cohorts of patients with hepatocellular carcinoma (HCC), esophageal cancer (EC), and colorectal cancer (CRC). The knockdown of POH1 significantly inhibited tumor cell proliferation and induced apoptosis mediated by the mitochondrial pathway in vitro. Intratumoral injection of POH1 small interfering RNA (siRNA) significantly reduced the progression of tumor growth and induced apoptosis in vivo. Furthermore, p53 or Bim siRNA markedly attenuated the apoptosis induced by POH1 depletion. POH1 depletion resulted in cell apoptosis by increasing the stability of p53 and Bim and inhibiting their ubiquitination. Overall, POH1 knockdown induced cell apoptosis through increased expression of p53 and Bim via enhanced protein stability and attenuated degradation. Thus, POH1 may serve as a potential prognostic marker and therapeutic target in human cancers.

Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. METHODS: A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan-Meier analysis was conducted to assess the prognostic value of P2-HNF4α. RESULTS: The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression (p = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC (p = 0.002) and vascular invasion (p = 0.017). Kaplan-Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group (p = 0.01), validation group (p = 0.034), and overall group of patients with HCC (p < 0.001). CONCLUSIONS: Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.