Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: In patients with NAFLD, those with type 2 diabetes mellitus (DM) have a high risk of progression to HCC. However, the determinants of HCC risk in these patients remain unclear. APPROACH AND RESULTS: We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death, or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (percent of follow-up time with hemoglobin A1c < 7%) on the risk of HCC while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow-up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared with no medication, metformin was associated with 20% lower risk of HCC (HR, 0.80; 95% CI, 0.93-0.98). Insulin had no effect on HCC risk (HR, 1.02; 95% CI, 0.85-1.22; p = 0.85). Insulin in combination with other oral medications was associated with a 1.6 to 1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR, 0.69; 95% CI, 0.62-0.78). CONCLUSIONS: In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is now the most common liver condition. Predicting its progression could help clinicians manage and potentially prevent complications. We evaluated the independent and joint effects of metabolic traits on the risk of cirrhosis and hepatocellular carcinoma (HCC) among patients with NAFLD. APPROACH AND RESULTS: We assembled a retrospective cohort of patients with NAFLD diagnosed at 130 facilities in the Veterans Administration between January 1, 2004, and December 31, 2008, with follow-up through December 31, 2015. We performed competing risk-adjusted cause-specific Cox models to evaluate the effects of metabolic traits (diabetes, hypertension, dyslipidemia, obesity) as additive or combined indicators on time to develop cirrhosis or HCC or a composite endpoint of both. Of the 271,906 patients, 22,794 developed cirrhosis, and 253 developed HCC during a mean of 9 years follow-up. At baseline, the mean body mass index was 31.6 (SD, 5.6), 28.7% had diabetes, 70.3% had hypertension, and 62.3% had dyslipidemia with substantial overlap among these traits. The risk of progression was the lowest in patients with only one or no metabolic trait. There was a stepwise increase in risk with each additional metabolic trait. Compared with patients with no metabolic trait, patients with both hypertension and dyslipidemia had 1.8-fold higher risk of progression to cirrhosis/HCC (hazard ratio [HR] = 1.8, 95% confidence interval [CI] = 1.59-2.06); the risk was 2.6-fold higher in patients with diabetes, obesity, dyslipidemia, and hypertension (HR = 2.6, 95% CI = 2.3-2.9). These associations were stronger for HCC. Diabetes had the strongest association with HCC in this cohort. CONCLUSIONS: Each additional metabolic trait increased the risk of cirrhosis and HCC in patients with NAFLD. Diabetes conferred the highest risk of progression to HCC. Patients with diabetes and coexisting hypertension and obesity may be important targets for secondary prevention.

Validation of a novel model for the early detection of hepatocellular carcinoma.

BACKGROUND: The biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence/antagonist-II (PIVKA-II) may be useful for detecting early-stage hepatocellular carcinoma (HCC). We evaluated the performance of AFP and PIVKA-II levels, alone and in combination with clinical factors, for the early detection of HCC. METHODS: In a case-control study, serum AFP and PIVKA-II were measured using the ARCHITECT immunoassay analyzer system in a cohort of 119 patients with HCC, 215 patients with non-malignant liver disease, and 34 healthy subjects. Five predictive models for detecting HCC were developed based on age, gender, AFP, and/or PIVKA-II levels; the best model was validated in an independent cohort of 416 patients with HCC and 412 control subjects with cirrhosis. RESULTS: In both cohorts, AFP and PIVKA-II concentrations were higher in patients with HCC compared to healthy controls and patients with non-malignant liver disease. The model that combined AFP and PIVKA-II, age, and gender had the highest AUC of 0.95 (0.95, 95% CI 0.93-0.98), with a sensitivity of 93% and a specificity of 84% in the development cohort, and an AUC of 0.87 (95% CI 0.85-0.90), sensitivity of 74%, and specificity of 85% in the validation cohort. When limiting the validation cohort to only early-stage HCC, the AUC was 0.85 (95% CI 0.81-0.88), sensitivity was 70%, and specificity was 86%. CONCLUSIONS: Compared to each biomarker alone, the combination of AFP and PIVKA-II with age and gender improved the accuracy of detecting HCC and differentiating HCC from non-malignant liver disease.

Natural genetic variation in yeast longevity.

The genetics of aging in the yeast Saccharomyces cerevisiae has involved the manipulation of individual genes in laboratory strains. We have instituted a quantitative genetic analysis of the yeast replicative lifespan by sampling the natural genetic variation in a wild yeast isolate. Haploid segregants from a cross between a common laboratory strain (S288c) and a clinically derived strain (YJM145) were subjected to quantitative trait locus (QTL) analysis, using 3048 molecular markers across the genome. Five significant, replicative lifespan QTL were identified. Among them, QTL 1 on chromosome IV has the largest effect and contains SIR2, whose product differs by five amino acids in the parental strains. Reciprocal gene swap experiments showed that this gene is responsible for the majority of the effect of this QTL on lifespan. The QTL with the second-largest effect on longevity was QTL 5 on chromosome XII, and the bulk of the underlying genomic sequence contains multiple copies (100-150) of the rDNA. Substitution of the rDNA clusters of the parental strains indicated that they play a predominant role in the effect of this QTL on longevity. This effect does not appear to simply be a function of extrachromosomal ribosomal DNA circle production. The results support an interaction between SIR2 and the rDNA locus, which does not completely explain the effect of these loci on longevity. This study provides a glimpse of the complex genetic architecture of replicative lifespan in yeast and of the potential role of genetic variation hitherto unsampled in the laboratory.

Analysis of serum haptoglobin fucosylation in hepatocellular carcinoma and liver cirrhosis of different etiologies.

We have developed herein a quantitative mass spectrometry-based approach to analyze the etiology-related alterations in fucosylation degree of serum haptoglobin in patients with liver cirrhosis and hepatocellular carcinoma (HCC). The three most common etiologies, including infection with hepatitis B virus (HBV), infection with hepatitis C virus (HCV), and heavy alcohol consumption (ALC), were investigated. Only 10 µL of serum was used in this assay in which haptoglobin was immunoprecipitated using a monoclonal antibody. The N-glycans of haptoglobin were released with PNGase F, desialylated, and permethylated prior to MALDI-QIT-TOF MS analysis. In total, N-glycan profiles derived from 104 individual patient samples were quantified (14 healthy controls, 40 cirrhosis, and 50 HCCs). A unique pattern of bifucosylated tetra-antennary glycan, with both core and antennary fucosylation, was identified in HCC patients. Quantitative analysis indicated that the increased fucosylation degree was highly associated with HBV- and ALC-related HCC patients compared to that of the corresponding cirrhosis patients. Notably, the bifucosylation degree was distinctly increased in HCC patients versus that in cirrhosis of all etiologies. The elevated bifucosylation degree of haptoglobin can discriminate early stage HCC patients from cirrhosis in each etiologic category, which may be used to provide a potential marker for early detection and to predict HCC in patients with cirrhosis.

Mass-selected site-specific core-fucosylation of ceruloplasmin in alcohol-related hepatocellular carcinoma.

A mass spectrometry-based methodology has been developed to study changes in core-fucosylation of serum ceruloplasmin that are site-specific between cirrhosis and hepatocellular carcinoma (HCC). The serum samples studied for these changes were from patients affected by cirrhosis or HCC with different etiologies, including alcohol, hepatitis B virus, or hepatitis C virus. The methods involved trypsin digestion of ceruloplasmin into peptides followed by Endo F3 digestion, which removed most of the glycan structure while retaining the innermost N-acetylglucosamine (GlcNAc) and/or core-fucose bound to the peptide. This procedure simplified the structures for further analysis by mass spectrometry, where four core-fucosylated sites (sites 138, 358, 397, and 762) were detected in ceruloplasmin. The core-fucosylation ratio of three of these sites increased significantly in alcohol-related HCC samples (sample size = 24) compared to that in alcohol-related cirrhosis samples (sample size = 18), with the highest AUC value of 0.838 at site 138. When combining the core-fucosylation ratio of site 138 in ceruloplasmin and the alpha-fetoprotein (AFP) value, the AUC value increased to 0.954 (ORsite138 = 12.26, p = 0.017; ORAFP = 3.64, p = 0.022), which was markedly improved compared to that of AFP (AUC = 0.867) (LR test p = 0.0002) alone. However, in HBV- or HCV-related liver diseases, no significant site-specific change in core-fucosylation of ceruloplasmin was observed between HCC and cirrhosis.

APOE ϵ4, rated life experiences, and affect among centenarians.

OBJECTIVES: The purpose of this study was to assess the relationship between apolipoprotein E (APOE), life events and engagement, and subjective well-being (as measured by positive and negative affect) among centenarians. Based on the life stress paradigm, we predicted that higher levels of stress would allow APOE to influence positive and negative affect. METHOD: 196 centenarians and near-centenarians (98 years and older) of the Georgia Centenarian Study participated in this research. The APOE, positive and negative affect, the number of recent (last 2 years) and lifelong (more than 20 years prior to testing) events, as well as a number of life engagement tasks were assessed. RESULTS: Results suggested that centenarians carrying the APOE ϵ4 allele rated lower in positive affect, the number of lifelong events, and in engaged lifestyle, when compared to centenarians without the APOE ϵ4 allele (t = 3.43, p < .01; t = 3.19, p < .01; and t = 2.33, p < .05, respectively). Blockwise multiple regressions indicated that the APOE ϵ4 predicted positive but not negative affect after controlling for demographics. Gene-environment interactions were obtained for the APOE ϵ4 and lifelong events, suggesting that carriers of the APOE ϵ4 allele had higher scores of negative affect after having experienced more events, whereas noncarriers had reduced negative affect levels after having experienced more events. CONCLUSION: APOE ϵ4 is directly related to positive affect and is related to negative affect in interaction with life events.

Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades.

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

[Effect of acupuncture on serum MIP-2 and MIP-2 mRNA expressions in isolated Fei and Dachang of severe acute pancreatitis induced acute lung injury rats in the acute phase].

OBJECTIVE: To observe effect of acupuncture on serum macrophage inflammatory protein-2 (MIP-2) and MIP-2 mRNA expressions in isolated Fei and Dachang of severe acute pancreatitis (SAP) induced acute lung injury (ALI) rats in the acute phase. METHODS: Forty male Wistar rats were randomly divided into four groups, i.e., the sham-operation group, the SAP group, the acupuncture treatment group, and the acupuncture control group, 10 in each group. The SAP model was induced by retrograde infusion of 3.5% sodium taurocholate into the pancreatobiliary duct. Under the guidance of "Fei and Dachang exterior-inferiorly related", points were acupunctured along Fei, Dachang, and Pi channels, as well as those points on the back of rats in the acupuncture treatment group 0.5 h after modeling. Besides, points were acupunctured along Fei and Pi channels, as well as those points on the back of rats in the acupuncture control group 0.5 h after modeling. Serum levels of tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO), and MIP-2 expressions were examined 6 h after modeling. Expressions of MIP-2 mRNA in isolated lung and large intestine tissues were detected by reverse transcription PCR. RESULTS: Compared with the sham-operation group, serum levels of TNF-alpha and NO, and expressions of MIP-2 and MIP-2 mRNA in isolated lung and large intestine tissues were significantly higher in the SAP group (P < 0.05). Each index was lower in the acupuncture treatment group than in the SAP group and the acupuncture control group (P < 0.05). Besides, the serum level of MIP-2 and the MIP-2 mRNA expression in isolated lung and large intestine tissues were positively correlated in all groups except the sham-operation group (P < 0.05). CONCLUSIONS: Under the guidance of "Fei and Dachang exterior-inferiorly related", acupuncture could remarkably reduce the severity of SAP induced ALI rats in the acute phase. Its mechanism might be related to suppressing over-expressions of MIP-2 mRNA in isolated lung and large intestine tissues, and lowering the serum MIP-2 expression level.

Attitudes of Palliative Care Specialists Toward Assessing Sexual Dysfunction in Patients With Cancer.

CONTEXT: The sexual health of patients is frequently neglected. OBJECTIVES: To evaluate the attitudes and beliefs of palliative care providers toward discussing the presence of sexual dysfunction (SD) in patients with cancer METHODS: In this pilot study, an anonymous survey was conducted among palliative care professionals about their attitudes toward discussing SD RESULTS: Forty-nine (89%) palliative care providers completed the survey. Thirty-four (69%) responded that they rarely or never discussed sexuality with their patients and most believed it is the oncologist's responsibility. The top reasons for not discussing SD were that the patient did not raise the issue, lack of time and the presence of a third party. The majority acknowledged the need of more training and that printed materials would be helpful. CONCLUSION: Palliative care providers infrequently address the presence of SD among patients with cancer. Additional training and routine screening for SD might help addressing this problem.

Health Care Provider Attitudes and Beliefs Toward Nonmedical Opioid Use in Patients with Cancer Pain.

Background: Data on health care providers' (HCPs') perceptions about patients with cancer pain and nonmedical opioid use (NMOU) are lacking. We examined the perceptions and attitudes of HCPs and assessed the usefulness of an interdisciplinary opioid stewardship program (OSP) while caring for these patients. Methods: An anonymous cross-sectional survey was conducted among the supportive care HCPs between September and November 2021. Results: Of 85 HCPs, 64 responded (75%) to the survey. Participants perceived that NMOU is underdiagnosed (42/64; 67%), and caring for such patients is difficult (58/64, 91%) and time consuming (54/64, 87%). A majority (50/51, 98%) were aware of the OSP, and (48/51; 94%) found it helpful. Conclusion: HCPs reported that NMOU is underdiagnosed and is challenging to manage. They endorsed the utility of an OSP in managing patients with concurrent cancer pain and NMOU. Future research should identify ways to standardize care and integrate OSP in routine supportive oncology practice.

Hybrid Work from Home Clinical Academic Environment: A One-Year Follow-Up Survey of Attitudes and Beliefs of Members of a Department of Palliative Care, Rehabilitation, and Integrative Medicine.

Context: Palliative, Rehabilitation, and Integrative Medicine (PRIM) department members anonymously reported a positive experience with work from home (WFH) two months after its rapid pandemic transition in March 2020. Data are limited on the stability of such preferences and experiences over time. Objectives: The objectives of this study were to survey the attitudes and beliefs of PRIM employees toward remote work 16 months after the start of the coronavirus disease 2019 (COVID-19) pandemic since vaccines and to determine changes in perceptions of WFH. Methods: All 138 PRIM employees were invited to participate in an anonymous survey from mid-July to mid-August 2021. The 30-question survey included demographics, perceptions toward WFH, and the pandemic. Results: One hundred fifteen (83%) employees completed the survey: 29 (74%) research, 62 (83%) clinicians, and 24 (100%) administrative personnel. Most were female (76%), 30-59 years old (88%), PRIM employees before May 2020 (89%), shared office space (52%), and had received either first or second dose of the COVID-19 vaccine (88%). Overall experience (86%) and emotional response (74%) with WFH were positive and not significantly different from 2020 (p = 0.128 and 0.782, respectively). Positive experience was associated with having adequate equipment (p = 0.002), perception of productivity (p = 0.002), financial advantage (p = 0.002), and time demands caring for dependents (p = 0.038). Clinicians reported less positive response (78%, p = 0.002) and less productivity (49%, p = 0.002) with WFH and higher level of stress (54%, p = 0.026) since COVID-19. Employees continued to support WFH permanently (79%) for two or more days/week (82%). There was continued increased emotional exhaustion (71%) similar to 2020 (p = 0.868), and being asked to work partially or completely from home permanently was favored by 64% versus 97% and 96% of clinicians, research, and administrative, respectively (p = 0.002). Conclusions: Support for WFH was sustained a year later and after three pandemic waves. These findings serve as a model for future rapid work transitions and can help elucidate factors associated with stress and emotional exhaustion in a new post-COVID-19 work environment.

Blood-based Migration Signature Biomarker Panel Discriminates Early Stage New Onset Diabetes related Pancreatic Ductal Adenocarcinoma from Type 2 Diabetes.

BACKGROUND AND AIMS: While type 2 diabetes is a well-known risk factor for pancreatic ductal adenocarcinoma (PDAC), PDAC-induced new-onset diabetes (PDAC-NOD) is a manifestation of underlying PDAC. In this study, we sought to identify potential blood-based biomarkers for distinguishing PDAC-NOD from type 2 diabetes (T2DM) without PDAC. MATERIALS AND METHODS: By ELISA analysis, a migration signature biomarker panel comprising tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FNIII-C) and CA 19-9 was analyzed in plasma samples from 50 PDAC-NOD and 50 T2DM controls. RESULTS: Both TFPI (area under the curve (AUC) 0.71) and TNC-FNIII-C (AUC 0.69) outperformed CA 19-9 (AUC 0.60) in distinguishing all stages of PDAC-NOD from T2DM controls. The combined panel showed an AUC of 0.82 (95% CI = 0.73-0.90) (p = 0.002). In the PDAC-NOD early stage II samples, the three biomarkers had an AUC of 0.84 (95% CI = 0.73-0.93) vs CA 19-9, AUC = 0.60, (95% CI = 0.45-0.73), which also improved significance (p = 0.0123). CONCLUSION: The migration signature panel adds significantly to CA 19-9 to discriminate PDAC-NOD from T2DM controls and warrants further validation for high-risk group stratification.

Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity.

Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related decline in telomere length observed in our population to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 3' flanking region of XRCC6 had significant effects on telomere length. At each bi-allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity (P < 0.003). The frequency of the minor allele was higher in long-lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not affect the association of SIRT1 with exceptional survival. The association of the same variant of SIRT1 with longevity was near significant (P < 0.07) in a second population. These results suggest a potential role of SIRT1 in linking telomere length and longevity. Given the differences between this gene and XRCC6, they point to the distinct impact that alternate pathways of telomere maintenance may have on aging and exceptional survival.

Glycopeptides with Sialyl Lewis Antigen in Serum Haptoglobin as Candidate Biomarkers for Nonalcoholic Steatohepatitis Hepatocellular Carcinoma Using a Higher-Energy Collision-Induced Dissociation Parallel Reaction Monitoring-Mass Spectrometry Method.

Nonalcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC) in the United States. Changes in N-glycosylation on specific glycosites of serum proteins have been investigated as potential markers for the early detection of NASH-related HCC. Herein, we report a glycopeptide with a Sialyl Lewis structure derived from serum haptoglobin (Hp) as a potential marker for NASH related HCCs among 95 patients with NASH, including 46 cirrhosis, 32 early-stage HCC, and 17 late-stage HCC. Hp immuno-isolated from patient serum was analyzed using LC-HCD-PRM-MS/MS followed by data analysis via Skyline software. Two glycopeptides involving site N184 and four glycopeptides involving site N241 were significantly changed in patients with HCC vs NASH cirrhosis (P < 0.05). The two-marker panel using N-glycopeptide N241_A4G4F2S4 showed the best performance for HCC detection when combined with α-fetoprotein (AFP), with an improved estimated area under the curve (AUC) = 0.898 (95% CI: 0.835, 0.951), compared to the AUC of 0.790(95% CI, 0.697 0.872) using AFP alone (P = 0.048). At 90% specificity, the combination of N241_A4G4F2S4 + AFP had an improved sensitivity of 63.3%, compared to the sensitivity of 52.3% using AFP alone. When using three markers, the panel of AFP + N241_A2G2F1S2 + N241_A4G4F2S4 yielded an estimated AUC of 0.928 (95% CI: 0.877, 0.970). Our findings indicated that N241_A4G4F2S4 may play an important role in distinguishing HCC from NASH cirrhosis.

PRM-MS Quantitative Analysis of Isomeric N-Glycopeptides Derived from Human Serum Haptoglobin of Patients with Cirrhosis and Hepatocellular Carcinoma.

Currently, surveillance strategies have inadequate performance for cirrhosis and early detection of hepatocellular carcinoma (HCC). The glycosylation of serum haptoglobin has shown to have significant differences between cirrhosis and HCC, thus can be used for diagnosis. We performed a comprehensive liquid chromatography-parallel reaction monitoring-mass spectrometry (LC-PRM-MS) approach, where a targeted parallel reaction monitoring (PRM) strategy was coupled to a powerful LC system, to study the site-specific isomerism of haptoglobin (Hp) extracted from cirrhosis and HCC patients. We found that our strategy was able to identify a large number of isomeric N-glycopeptides, mainly located in the Hp glycosylation site Asn207. Four N-glycopeptides were found to have significant changes in abundance between cirrhosis and HCC samples (p < 0.05). Strategic combinations of the significant N-glycopeptides, either with alpha-fetoprotein (AFP) or themselves, better estimate the areas under the curve (AUC) of their respective receiver operating characteristic (ROC) curves with respect to AFP. The combination of AFP with the isomeric sialylated fucosylated N-glycopeptides Asn207 + 5-6-1-2 and Asn207 + 5-6-1-3, resulted with an AUC value of 0.98, while the AUC value for AFP alone was 0.85. When comparing cirrhosis vs. early HCC, the isomeric N-glycopeptide Asn207 + 5-6-0-1 better estimated AUC with respect to AFP (AUCAFP = 0.81, and AUCAsn207 + 5-6-0-1 = 0.88, respectively).

MPSQ: a web tool for protein-state searching.

MPSQ (multi-protein-states query) is a web-based tool for the discovery of protein states (e.g. biological interactions, covalent modifications, cellular localizations). In particular, large sets of genes can be used to search for enriched state transition network maps (NMs) and features facilitating the interpretation of genomic-scale experiments such as microarrays. One NM collects all the catalogued states of a protein as well as the mutual transitions between the states. For the returned NM, graph visualization is provided for easy understanding and to guide further analysis.

A platform to standardize, store, and visualize proteomics experimental data.

With the development of functional genomics research, large-scale proteomics studies are now widespread, presenting significant challenges for data storage, exchange, and analysis. Here we present the Integrated Proteomics Exploring Database (IPED) as a platform for managing proteomics experimental data (both process and result data). IPED is based on the schema of the Proteome Experimental Data Repository (PEDRo), and complies with the General Proteomics Standard (GPS) drafted by the Proteomics Standards Committee of the Human Proteome Organization. In our work, we developed three components for the IPED platform: the IPED client editor, IPED server software, and IPED web interface. The client editor collects experimental data and generates an extensible markup language (XML) data file compliant with PEDRo and GPS; the server software parses the XML data file and loads information into a core database; and the web interface displays experimental results, to provide a convenient graphic representation of data. Given software convenience and data abundance, IPED is a powerful platform for data exchange and presents an important resource for the proteomics community. In its current release, IPED is available at http://www.biosino.org/iped2.

Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's Early Detection Research Network.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity. METHODS: The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository. RESULTS: The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis. CONCLUSIONS: The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy.