Role of RASSF1A promoter methylation in the pathogenesis of hepatocellular carcinoma: a meta-analysis of 21 cohort studies

We carried out the current meta-analysis aiming to comprehensively assess the potential role of RASSF1A aberrant promoter methylation in the pathogenesis of hepatocellular carcinoma (HCC). A range of electronic databases were searched: Web of Science (1945–2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966–2013), EMBASE (1980–2013), CINAHL (1982–2013) and the Chinese Biomedical Database (CBM) (1982–2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude risk difference (RD) with their 95 % confidence interval (95 % CI) was calculated. In the present meta-analysis, 21 clinical cohort studies with a total of 1,205 HCC patients were included. The results of our meta-analysis illustrated that the frequency of RASSF1A promoter methylation in cancer tissues were significantly higher than those of normal, adjacent and benign tissues (cancer tissues vs. normal tissues: RD = 0.63, 95 % CI 0.53–0.73, P < 0.001; cancer tissues vs. adjacent tissues: RD = 0.43, 95 % CI 0.33–0.53, P < 0.001; cancer tissues vs. benign tissues: RD = 0.48, 95 % CI 038–0.58, P < 0.001; respectively). Further subgroup by ethnicity demonstrated that RASSF1A aberrant promoter methylation was correlated with the pathogenesis of HCC among both Asians and Caucasians (all P < 0.05). The current meta-analysis suggests that RASSF1A aberrant promoter methylation may be implicated in the pathogenesis of HCC. Thus, detection of RASSF1A promoter methylation may be a helpful and valuable biomarker for diagnosis and prognosis of HCC.     

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies

BACKGROUND: Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited. METHODS: We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies. RESULTS: In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]). CONCLUSIONS: Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.     

Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis

Background

This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations.

Methods

The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models.

Results

A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31).

Conclusions

This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

     

MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma

In our in-depth analysis carried out by the Illumina Solexa massive parallel signature sequencing, microRNA-99a (miR-99a) was found to be the sixth abundant microRNA in the miRNome of normal human liver but was markedly down-regulated in hepatocellular carcinoma (HCC). Compelling evidence has suggested the important roles of microRNAs in HCC development. However, the biological function of miR-99a deregulation in HCC remains unknown. In this study, we found that miR-99a was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-99a expression in HCC tissues significantly correlated with shorter survival of HCC patients, and miR-99a was identified to be an independent predictor for the prognosis of HCC patients. Furthermore, restoration of miR-99a dramatically suppressed HCC cell growth in vitro by inducing the G(1) phase cell cycle arrest. Intratumoral injection of cholesterol-conjugated miR-99a mimics significantly inhibited tumor growth and reduced the α-fetoprotein level in HCC-bearing nude mice. Insulin-like growth factor 1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) were further characterized as the direct targets of miR-99a. Furthermore, protein levels of IGF-1R and mTOR were found to be inversely correlated with miR-99a expression in HCC tissues. miR-99a mimics inhibited IGF-1R and mTOR pathways and subsequently suppressed expression of cell cycle-related proteins, including cyclin D1 in HCC cells. Conclusively, miR-99a expression was frequently down-regulated in HCC tissues and correlates with the prognosis of HCC patients, thus proposing miR-99a as a prospective prognosis predictor of HCC. miR-99a suppresses HCC growth by inducing cell cycle arrest, suggesting miR-99a as potential tumor suppressor for HCC therapeutics.     

Epidermal growth factor gene polymorphism and risk of hepatocellular carcinoma: a meta-analysis

Background

Hepatocarcinogenesis is a complex process that may be influenced by many factors, including polymorphism in the epidermal growth factor (EGF) gene. Previous work suggests an association between the EGF 61*A/G polymorphism (rs4444903) and susceptibility to hepatocellular carcinoma (HCC), but the results have been inconsistent. Therefore, we performed a meta-analysis of several studies covering a large population to address this controversy.

Methods

PubMed, EMBASE, Google Scholar and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between EGF 61*A/G polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

Eight studies were chosen in this meta-analysis, involving 1,304 HCC cases (1135 Chinese, 44 Caucasian and 125 mixed) and 2,613 controls (1638 Chinese, 77 Caucasian and 898 mixed). The EGF 61*G allele was significantly associated with increased risk of HCC based on allelic contrast (OR = 1.29, 95% CI = 1.16–1.44, p<0.001), homozygote comparison (OR = 1.79, 95% CI = 1.39–2.29, p<0.001) and a recessive genetic model (OR = 1.34, 95% CI = 1.16–1.54, p<0.001), while patients carrying the EGF 61*A/A genotype had significantly lower risk of HCC than those with the G/A or G/G genotype (A/A vs. G/A+G/G, OR = 0.66, 95% CI = 0.53–0.83, p<0.001).

Conclusion

The 61*G polymorphism in EGF is a risk factor for hepatocarcinogenesis while the EGF 61*A allele is a protective factor. Further large and well-designed studies are needed to confirm this conclusion.     

Association between shift work and risk of type 2 diabetes mellitus: a systematic review and dose-response meta-analysis of observational studies

ABSTRACT

To evaluate the association between shift work and risk of type 2 diabetes mellitus, we searched PubMed, EMBASE and Web of Science from their inception to June 8, 2019. Observational studies examining the relationship between shift work and type 2 diabetes were included. Subgroup analyses were conducted to explore whether specific characteristics would affect the relationship. A dose-response relationship was estimated by using generalized least squares trend regression. Finally, twelve cohort studies and nine cross-sectional studies were included (inter-rater agreement, k = 0.96). The result of meta-analysis indicated that shift work was associated with an increased risk of type 2 diabetes (relative risk = 1.10, 95% confidence interval = 1.05–1.14). Subgroup analyses demonstrated that female shift workers have increased risk of type 2 diabetes while male not observed, health care workers showed the highest risk compared with civil servants and manual workers, and night shift and rotating shift were associated with an increased risk of type 2 diabetes. Dose-response meta-analysis based on three cohorts among female workers indicated that there might be a positive association between duration of shift work and the risk of type 2 diabetes. In conclusion, shift work is positively associated with an increased risk of type 2 diabetes. Among female workers, with the years of exposure to shift work prolonged, the risk of type 2 diabetes might increase accordingly. In the future, more studies are needed to confirm the results of dose-response analysis.     

Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women

Background

Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains unclear. Therefore, we aimed to evaluate this association in two cohorts of US women.

Methods and Findings

We followed 69,269 women aged 42–67 in Nurses'' Health Study I (NHS I, 1988–2008), and 107,915 women aged 25–42 in NHS II (1989–2007) without diabetes, cardiovascular disease, and cancer at baseline. Participants were asked how long they had worked rotating night shifts (defined as at least three nights/month in addition to days and evenings in that month) at baseline. This information was updated every 2–4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. We documented 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases during the 18–20 years of follow-up. In the Cox proportional models adjusted for diabetes risk factors, duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios (95% confidence intervals) for participants with 1–2, 3–9, 10–19, and ≥20 years of shift work were 1.05 (1.00–1.11), 1.20 (1.14–1.26), 1.40 (1.30–1.51), and 1.58 (1.43–1.74, p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03 (0.98–1.08), 1.06 (1.01–1.11), 1.10 (1.02–1.18), and 1.24 (1.13–1.37, p-value for trend <0.001).

Conclusions

Our results suggest that an extended period of rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight. Proper screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes. Please see later in the article for the Editors'' Summary     

The role of glycation in aging and diabetes mellitus

One of the hypotheses trying to explain the process of aging is the idea of glycation of proteins. This reaction, also called the Maillard or browning reaction, may explain age-related symptoms such as cataract, atherosclerosis and modification of collagen-containing tissues. Diabetics, which posses elevated blood sugar levels, show signs of accelerated aging exposing similar complications. The Maillard reaction, which occurs on a large scale in vivo, may play a key role in the initiation of these symptoms.     

Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies

Objective

Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

Research Design and Methods

Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

Results

The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10⁻¹⁸). Substantial heterogeneity was present (I² = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10⁻⁴), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10⁻¹³), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10⁻⁵). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

Conclusions

A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.     

Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis

Background

Although insulin analogues are commonly prescribed for the management of diabetes mellitus, there is uncertainty regarding their optimal use. We conducted meta-analyses to compare the outcomes of insulin analogues with conventional insulins in the treatment of type 1, type 2 and gestational diabetes.

Methods

We updated 2 earlier systematic reviews of the efficacy and safety of rapid-and long-acting insulin analogues. We searched electronic databases, conference proceedings and “grey literature” up to April 2007 to identify randomized controlled trials that compared insulin analogues with conventional insulins. Study populations of interest were people with type 1 and type 2 diabetes (adult and pediatric) and women with gestational diabetes.

Results

We included 68 randomized controlled trials in the analysis of rapid-acting insulin analogues and 49 in the analysis of long-acting insulin analogues. Most of the studies were of short to medium duration and of low quality. In terms of hemoglobin A_1c, we found minimal differences between rapid-acting insulin analogues and regular human insulin in adults with type 1 diabetes (weighted mean difference for insulin lispro: –0.09%, 95% confidence interval [CI] –0.16% to –0.02%; for insulin aspart: –0.13%, 95% CI –0.20% to –0.07%). We observed similar outcomes among patients with type 2 diabetes (weighted mean difference for insulin lispro: –0.03%, 95% CI –0.12% to –0.06%; for insulin aspart: –0.09%, 95% CI –0.21% to 0.04%). Differences between long-acting insulin analogues and neutral protamine Hagedorn insulin in terms of hemoglobin A_1c were marginal among adults with type 1 diabetes (weighted mean difference for insulin glargine: –0.11%, 95% CI –0.21% to –0.02%; for insulin detemir: –0.06%, 95% CI –0.13% to 0.02%) and among adults with type 2 diabetes (weighted mean difference for insulin glargine: –0.05%, 95% CI –0.13% to 0.04%; for insulin detemir: 0.13%, 95% CI 0.03% to 0.22%). Benefits in terms of reduced hypoglycemia were inconsistent. There were insufficient data to determine whether insulin analogues are better than conventional insulins in reducing long-term diabetes-related complications or death.

Interpretation

Rapid-and long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycemic control or reduced hypoglycemia. Long-term, high-quality studies are needed to determine whether insulin analogues reduce the risk of long-term complications of diabetes.Diabetes mellitus is associated with serious long-term complications and premature death.¹ Data from the Health Canada National Diabetes Surveillance System indicate that, in 2004/05, diabetes was diagnosed in about 5.5% (1.8 million) of Canadians aged 20 years and older.² Because the disease goes undetected in many cases, the true prevalence may approach 1.9 million.³Tight glycemic control, to maintain a hemoglobin A_1c concentration of 7.0% or less, is recommended for all patients with diabetes to reduce the risk of long-term complications such as cardiovascular-related death, retinopathy and nephropathy.⁴ Insulin is indicated for all patients with type 1 diabetes and for patients with type 2 diabetes if adequate glycemic control cannot be achieved through exercise, diet or oral antidiabetic therapy.⁴Conventional insulins include regular human insulin and intermediate-acting neutral protamine Hagedorn insulin. However, these agents do not replicate the pattern of basal and postprandial endogenous secretion of insulin. Insulin analogues are modified human insulins developed to address this limitation.⁵ The rapid-acting insulin analogues insulin lispro, insulin aspart and insulin glulisine are marketed in Canada as bolus insulins; the long-acting agents insulin glargine and insulin detemir are marketed as basal insulins.⁶Systematic reviews of the insulin analogues have been published previously.^7–10 However, through our comprehensive search of the literature, we did not identify any reviews of long-acting insulin analogues in the management of type 1 diabetes or gestational diabetes. In this article, we provide an up-to-date, comprehensive systematic review and meta-analysis of outcomes associated with the use of rapid-and long-acting insulin analogues in type 1 and type 2 diabetes (adult and pediatric patients) and gestational diabetes. Detailed methods and complete results are reported elsewhere.^11,12     

The association between serum selenium and gestational diabetes mellitus: A systematic review and meta-analysis

BackgroundResults of the studies about association between serum selenium concentration and gestational hyperglycemia are inconsistent. Some studies have demonstrated that women with gestational diabetes mellitus (GDM) have lower Se concentrations while contrary results are reported in other studies.AimThe aim of this study is to compare the serum Se concentration in women with GDM and normoglycemic pregnant women via a systematic review and meta-analysis.MethodsA computerized literature search on four databases (PubMed, Cochrane register of control trials, Scopus and Google scholar) was performed from inception through August 2013. Necessary data were extracted and random effects model was used to conduct the meta-analysis.ResultsSix observational studies (containing 147 women with GDM and 360 normoglycemic pregnant women) were found, which had compared serum Se concentration in women suffering from GDM with normal pregnant ones. Our meta-analysis revealed that serum Se concentration was lower in women with GDM compared to normoglycemic pregnant women (Hedges = −1.34; 95% CI: −2.33 to −0.36; P < 0.01). Stratified meta-analysis demonstrated that concentration of Se in the sera of women with GDM was lower than normal pregnant women both in second and third trimesters, but the result was not significant in second trimester (second trimester: Hedges = −0.68; 95% CI: −1.60−0.25; P = 0.15, third trimester: Hedges = −2.81; 95% CI: −5.21 to −0.42; P < 0.05). It was also demonstrated that serum Se status was lower in pregnant women with impaired glucose tolerance (IGT) compared to normoglycemic pregnant women (Hedges = −0.85; 95% CI: −1.18 to −0.52).ConclusionThe available evidences suggest that serum Se concentration is significantly lower in pregnant women with gestational hyperglycemia compared to normal pregnant women.     

Effects of microRNA-30a on migration,invasion and prognosis of hepatocellular carcinoma

The role of microRNA-30a (miR-30a) deregulation in tumor progression and its downstream signaling pathways remain unknown. Here we confirmed significant downregulation of miR-30a in hepatocellular carcinoma (HCC) tissues and cell lines compared with non-tumor counterparts. MiR-30a downregulation was significantly associated with worse disease-free survival (DFS) of HCC patients. Gain- and loss-of-function studies revealed that downregulation of miR-30a facilitated tumor cell migration, invasion and epithelial–mesenchymal transition (EMT). We identified SNAI1 as a direct target of miR-30a and demonstrated miR-30a as a novel regulator of EMT by targeting SNAI1, indicating its potential therapeutic value for reducing invasion and metastasis of HCC.     

The prognosis of acute and persistent low-back pain: a meta-analysis

Background:

Although low-back pain is a highly prevalent condition, its clinical course remains uncertain. Our main objective was to systematically review the literature on the clinical course of pain and disability in patients with acute and persistent low-back pain. Our secondary objective was to investigate whether pain and disability have similar courses.

Methods:

We performed a meta-analysis of inception cohort studies. We identified eligible studies by searching MEDLINE, Embase and CINAHL. We included prospective studies that enrolled an episode-inception cohort of patients with acute or persistent low-back pain and that measured pain, disability or recovery. Two independent reviewers extracted data and assessed methodologic quality. We used mixed models to determine pooled estimates of pain and disability over time.

Results:

Data from 33 discrete cohorts (11 166 participants) were included in the review. The variance-weighted mean pain score (out of a maximum score of 100) was 52 (95% CI 48–57) at baseline, 23 (95% CI 21–25) at 6 weeks, 12 (95% CI 9–15) at 26 weeks and 6 (95% CI 3–10) at 52 weeks after the onset of pain for cohorts with acute pain. Among cohorts with persistent pain, the variance-weighted mean pain score (out of 100) was 51 (95% CI 44–59) at baseline, 33 (95% CI 29–38) at 6 weeks, 26 (95% CI 20–33) at 26 weeks and 23 (95% CI 16–30) at 52 weeks after the onset of pain. The course of disability outcomes was similar to the time course of pain outcomes in the acute pain cohorts, but the pain outcomes were slightly worse than disability outcomes in the persistent pain cohorts.

Interpretation:

Patients who presented with acute or persistent low-back pain improved markedly in the first six weeks. After that time improvement slowed. Low to moderate levels of pain and disability were still present at one year, especially in the cohorts with persistent pain.Low-back pain is a highly prevalent condition associated with work absenteeism, disability and large health care costs; however, there is still disagreement about prognosis. For example, the European guidelines for the management of low-back pain states that 90% of patients with acute low-back pain recover in six weeks.¹ In contrast, some well-conducted cohort studies show a less optimistic picture, providing short-term estimates of recovery ranging from 39% to 76%.^2,3 This wide range of estimates of prognosis is likely explained by differences in cohorts and definitions used to define the onset or conclusion of an episode of low-back pain. Because very different definitions of recovery are often used, it is difficult to obtain pooled estimates of recovery rates. Instead, it might be more useful to describe the clinical course of low-back pain in terms of expected changes in pain or disability over time.A recent systematic review⁴ summarized the prognostic factors for persistent disabling low-back pain but did not describe the clinical course. The only meta-analysis to investigate the clinical course of acute low-back pain was published in 2003.⁵ This review concluded that both pain and disability improve rapidly within weeks (mean reduction of 58% of initial scores in the first month) and recurrences are common. A limitation of this review was that, although it retrieved 15 studies, only 5 were cohort studies; the remaining 10 were randomized controlled trials. Randomized trials often have narrow inclusion criteria and low rates of participation, which make them less suitable for inferring prognosis. The best design to describe the prognosis of a condition is a cohort study enrolling a representative sample of incident cases (i.e., by including patients at a similar early point in their condition).^6,7 Such studies are known as inception cohort studies. To the best of our knowledge, no review has yet investigated the clinical course of pain and disability among people with persistent low-back pain (subacute and chronic). Thus, the prognosis for people with persistent low-back pain is still uncertain.The aim of our study was to systematically review the clinical course of pain and disability in patients with acute and persistent low-back pain. We included only inception cohort studies. Our second aim was to investigate whether pain and disability have similar courses.     

Monocyte attachment to laminin in diabetes mellitus: The role of ATP

Monocyte-extracellular matrix interactions have been implicated in atherosclerosis pathophysiology. Laminin, the main basement membrane protein contains cell binding domains that can be cryptic, presented only after protein modification. In the present study we evaluated monocyte attachment to laminin-1 in the presence of ATP. Monocytes were derived from either healthy volunteers or patients with diabetes mellitus type II. For the estimation of monocyte attachment to laminin the myeloperoxidase assay was used. Monocytes derived from diabetic patients, showed an increased ability to attach to laminin (p = 0.0055). The presence of ATP increased the attachment of control monocytes to laminin (p = 0.0022). On the contrary, the presence of ATP did not affect the attachment of monocytes derived from diabetic patients to laminin. Our results indicate a modified interaction between monocytes and laminin-1 in diabetes mellitusKey words: monocytes, ATP, laminin-1, diabetes mellitus, attachment     

A meta-analysis of array-CGH studies implicates antiviral immunity pathways in the development of hepatocellular carcinoma

Background

The development and progression of hepatocellular carcinoma (HCC) is significantly correlated to the accumulation of genomic alterations. Array-based comparative genomic hybridization (array CGH) has been applied to a wide range of tumors including HCCs for the genome-wide high resolution screening of DNA copy number changes. However, the relevant chromosomal variations that play a central role in the development of HCC still are not fully elucidated.

Methods

In present study, in order to further characterize the copy number alterations (CNAs) important to HCC development, we conducted a meta-analysis of four published independent array-CGH datasets including total 159 samples.

Results

Eighty five significant gains (frequency ≥25%) were mostly mapped to five broad chromosomal regions including 1q, 6p, 8q, 17q and 20p, as well as two narrow regions 5p15.33 and 9q34.2-34.3. Eighty eight significant losses (frequency ≥25%) were most frequently present in 4q, 6q, 8p, 9p, 13q, 14q, 16q, and 17p. Significant correlations existed between chromosomal aberrations either located on the same chromosome or the different chromosomes. HCCs with different etiologies largely exhibited surprisingly similar profiles of chromosomal aberrations with only a few exceptions. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the genes affected by these chromosomal aberrations were significantly enriched in 31 canonical pathways with the highest enrichment observed for antiviral immunity pathways.

Conclusions

Taken together, our findings provide novel and important clues for the implications of antiviral immunity-related gene pathways in the pathogenesis and progression of HCC.     

Insulin use and weight maintenance in well-controlled type 2 diabetes: a prospective cohort study

Intensification of glycemic control is associated with weight gain, however, less is known about weight change during the maintenance phase of glycemic management. On the basis of current models of energy homeostasis, we hypothesize that insulin use will result in less weight gain than oral antidiabetic agents in patients with well-controlled diabetes. This is a prospective cohort nested within a randomized control trial at an academic clinic, with enrollment from June 2002 to January 2005. A total of 163 patients with type 2 diabetes were enrolled after obtaining glycemic control. Insulin use was assessed by self-report at baseline. Participants were weighed at baseline and five follow-up visits over 24 months. The weight change was compared between insulin users and noninsulin users. The average (s.d.) age was 55 (11), 44% are female and 21% are black. The median duration of diabetes was 5 (0.5-10) years. At baseline, 88 participants (54%) reported insulin use with an average of 69 (6) units/day. Baseline BMI in the insulin users was 35 (6) and 33 (6) in noninsulin patients. Over 24 months, noninsulin patients gained 2.3 additional kilograms compared with insulin users (2.8 kg (6.8) vs. 0.5 kg (6.5), P = 0.065). After adjusting for age, race, sex, baseline weight, intervention status, and change in A1C, insulin users had 2.5 kg less weight gain than noninsulin users (P = 0.033). Less weight gain was observed over 24 months in insulin-treated patients. Whether this effect may be due to central catabolic effects of insulin merits additional confirmatory study and mechanistic investigation.