Validation of the Concept of a Common Typical Time of Disease Duration for Hepatocellular Carcinoma Patients Using the Fisher Information Processing of Tumor Imaging Results Combined With Network Phenotyping Strategy Quantification of Individual Patient Clinical Profile Patterns.

A primary goal of current clinical cancer research is the identification of prognostic tumor subtypes. It is increasingly clear that tumor growth depends on both internal tumor factors, and factors that are external to the tumor, such as microenvironment. We recently showed that parameter values alone are less important than the patterns of all patient parameters together for the identification of prognostic subtypes and have identified a network phenotyping strategy method to quantitatively describe the dependency of the tumor on the environment, to characterize hepatocellular carcinoma (HCC) subtypes.

Evaluation of total hepatocellular cancer lifespan, including both clinically evident and preclinical development, using combined network phenotyping strategy and fisher information analysis.

We previously showed that for hepatocellular cancer (HCC) prognostication, disease parameters need to be considered within a total personal clinical context. This requires preserving the coherence of data values, observed simultaneously for each patient during baseline diagnostic evaluation. Application of the Network Phenotyping Strategy (NPS) provided quantitative descriptors of these patient coherences.

Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters.

Previous work has shown that two general processes contribute to hepatocellular cancer (HCC) prognosis: liver damage, monitored by indices such as blood bilirubin, prothrombin time (PT), and aspartate aminostransferase (AST); and tumor biology, monitored by indices such as tumor size, tumor number, presence of portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. These processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient.

Macro- and micro-environmental factors in clinical hepatocellular cancer.

We previously developed a network phenotyping strategy (NPS), a graph theory-based transformation of clinical practice data, for recognition of two primary subgroups of hepatocellular cancer (HCC), called S and L, which differed significantly in their tumor masses. In the current study, we have independently validated this result on 641 HCC patients from another continent. We identified the same HCC subgroups with mean tumor masses 9 cm x n (S) and 22 cm x n (L), P<10(-14).

A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon.

Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP).

Phenotypic Categorization and Profiles of Small and Large Hepatocellular Carcinomas.

We used a database of 4139 Taiwanese HCC patients to take a new approach (Network Phenotyping Strategy) to HCC subset identification. Individual parameters for liver function tests, complete blood count, portal vein thrombosis, AFP levels and clinical demographics of age, gender, hepatitis or alcohol consumption, were considered within the whole context of complete relationships, being networked with all other parameter levels in the entire cohort. We identified 4 multi-parameter patterns for one tumor phenotype of patients and a separate 5 multi-parameter patterns to characterize another tumor phenotype of patterns.

Thrombocytopenia in relation to tumor size in patients with hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) size at diagnosis is important in management. Without screening programs, tumor size at diagnosis is heterogeneous.

Aims: To examine the clinical parameters related to tumor size.

Small hepatocellular carcinomas and thrombocytopenia.

Background: Clinical phenotypes of small and large hepatocellular carcinomas (HCCs) are not well characterized.

Aim: To evaluate the characteristics of small HCCs diagnosed by screening.

Method: A cohort of 430 small HCCs that were diagnosed through screening, were dichotomized according to a size of ≤ 3 cm or >3 cm maximum tumor diameter and compared for radiological and blood-test parameters.

Small hepatocellular carcinoma in Chinese patients.

Background/aims: Physicians aim to either prevent HCC by treating the underlying cause or to diagnose it at its earliest, clinically-observable stages by surveillance, for maximal treatment benefit. Surveillance depends predominantly on radiological screening and less satisfactorily on AFP blood tests. We previously examined a large cohort of unresectable HCC patients and found some useful, statistically-significant, prognostic factors.

Small HCCs identified by screening.

Background: Survival in HCC depends on diagnosis at early tumor stage, best achieved through surveillance radiology. There is also a need for complementary serum tests.

Methods: We evaluated baseline liver function parameters from a cohort of 231 HCC patients who were diagnosed by surveillance.

Significance of increased serum GGTP levels in HCC patients.

A large dataset of patients with biopsy-proven and unresectable HCC who were prospectively followed from diagnosis till death, was examined for the prognostic significance of serum GGTP levels. Their survival-ordered baseline clinical parameter data was examined. Two cohorts of patients with both low AFP and bilirubin levels were identified, who had serum GGTP levels with an increasing trend with increasing AFP levels.

Low alpha-fetoprotein hepatocellular carcinoma.

Background And Aim: A large proportion of hepatocellular carcinoma (HCC) patients do not secrete elevated levels of the tumor marker alpha-fetoprotein (AFP). There is little published guide to prognostic features of this patient subset.

Methods: We interrogated a large HCC database in which all patients had been followed until death, to examine which features might be prognostically useful.

HCC in young adults.

A large cohort of unresectable and untransplantable biopsy-proven HCC patients was rank-ordered for survival. Non-random clustering by age was noted, with 3 sub-cohorts of younger patients with survival in the range of 90-360 days. One sub-cohort had a predominance of females.

Network-based analysis of survival for unresectable hepatocellular carcinoma.

Primary hepatocellular cancer (HCC) classification systems are based on histopathology and radiology, yet clinical intuition and experience suggest that natural history and disease progression have distinctive clinical features, consistent with a cluster of homogeneous entities within a heterogeneous cohort. We built a rigorous, sequenced, graph-based strategy of network phenotyping analysis (NPA) to combine data smoothing to minimize stochasticity, multivariate analysis to identify ambiguity and prioritize key variables, and k-partite graphs to visualize coherence. In 890 unresectable HCC patients, we selected 13 baseline clinical variables.

Family networks of obesity and type 2 diabetes in rural Appalachia.

The prevalence of obesity and diabetes has been studied in adolescent and adult populations in poor, medically underserved rural Appalachia of West Virginia. A web-based questionnaire about obesity and diabetes was obtained in 989 family members of 210 Community Based Clinical Research (CBPR) trained adolescent members of a network of 18 science clubs, incorporating 142 families. After age-correction in < 20 years old, 50% of both adolescents and adults were obese.

Feasibility of adolescents to conduct community-based participatory research on obesity and diabetes in rural Appalachia.

Community-Based Participatory Research (CBPR) has been advocated to translate advances in health care sciences to the community. We describe a novel approach applied to obesity management and diabetes prevention. This takes advantage of a network of science clubs organized by the Health Sciences and Technology Academy (HSTA) for extracurricular activity of disadvantaged high school students in rural Appalachia.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study.

Objectives: 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point.

Results: We found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors.

HCC in older patients.

Background: Hepatocellular carcinoma (HCC) is a heterogeneous disease, with many poorly-defined prognostic patient subsets. Identification of discrete subsets will aid rational patient and treatment selection.

Methods: A database with 778 biopsy-proven, unresectable and untransplantable HCC patients who were followed from diagnosis till death was interrogated.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a case cohort study.

Background And Aims: A total of 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death.

Methods: Survival was the end-point for all analyses.

Results: We found in our overall analysis, that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated alpha-fetoprotein (AFP) or bilirubin or alkaline phosphatases were each statistically significant adverse prognostic factors.

Application of graph-based analysis of genomic sequence context for characterization of drug targets.

We show that analyzing individual genes of target proteins in terms of multiplicities of possible realizations of position-dependent thermodynamic states of their DNA molecules constitutes a new bioinformatics paradigm. It provides information that is unique and complementary to results of existing methods of sequence analysis. Using this graph-theory based approach, we developed informative and computationally immensely tractable tool to gain insight into intricate details of properties of drug targets.

Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers.

The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years.

WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization.

The induction of apoptosis by p53 in response to cellular stress is its most conserved function and crucial for p53 tumor suppression. We recently reported that p53 directly induces oligomerization of the BH1,2,3 effector protein Bak, leading to outer mitochondrial membrane permeabilization (OMMP) with release of apoptotic activator proteins. One important mechanism by which p53 achieves OMMP is by forming an inhibitory complex with the anti-apoptotic BclXL protein.

Rational design of DNA sequences for nanotechnology, microarrays and molecular computers using Eulerian graphs.

Nucleic acids are molecules of choice for both established and emerging nanoscale technologies. These technologies benefit from large functional densities of 'DNA processing elements' that can be readily manufactured. To achieve the desired functionality, polynucleotide sequences are currently designed by a process that involves tedious and laborious filtering of potential candidates against a series of requirements and parameters.

Efficient RNA interference depends on global context of the target sequence: quantitative analysis of silencing efficiency using Eulerian graph representation of siRNA.

Several aspects of gene silencing by small interfering RNA duplexes (siRNA) influence the efficiency of the silencing. They can be divided into two categories, one covering the cell-specific factors and the other covering molecular factors of the RNA interference (RNAi). A prerequisite for sequence-based siRNA design is that hybridization thermodynamics is the dominant factor.

p53 has a direct apoptogenic role at the mitochondria.

p53 induces apoptosis by target gene regulation and transcription-independent signaling. However, a mechanism for the latter was unknown. We recently reported that a fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells.