Progenitor cell expansion: an important source of hepatocyte regeneration in chronic hepatitis

BACKGROUND/AIMS: Progenitor cell activation with subsequent maturation to hepatocytes and cells of the biliary lineage has been demonstrated in a variety of chronic liver diseases but the kinetics and magnitude of the progenitor cell response has not been adequately studied in detail in chronic hepatitis. We undertook this study to evaluate factors responsible for the progenitor cell/ductular response and further dissect the role of disease grade and stage as determinants of hepatocellular differentiation of bipotential progenitor cells in chronic hepatitis. METHODS: Cytokeratin 7 (and 19) stained biopsies from patients with chronic hepatitis C (n = 47), hepatitis B (n = 20), and autoimmune hepatitis (n = 20) were studied. Ploidy analysis and proliferation indices were evaluated in a subset of cases. RESULTS: Ductular reactions were present in the majority of cases (97%), appeared early in disease, and correlated with disease activity, while progenitor cell derived hepatocyes appeared later in disease and their extent correlated with disease stage. Proliferation indices of all cell types correlated with disease activity. CONCLUSIONS: Progenitor cell derived hepatocytes accrue in chronic hepatitis, possibly related to native hepatocellular dysfunction. However, the fate of these hepatocytes is unclear.     

Review of experimental attempts of islet allotransplantation in rodents:Parameters involved and viability of the procedure

The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords "rodent islet transplantation" to review. We included studies that involved allotransplantation experiments with rodents’ islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of isletdonors and advance the treatment options for type 1 diabetes.     

The main indications and techniques for vascular exclusion of the liver

BACKGROUND: The purpose of vascular clamping during the course of liver resection is to reduce bleeding and subsequent complications. AIM: To show both step-by-step surgical techniques for vascular exclusion of the liver and their indications. METHODS: It is described the following techniques: clamping of the hepatic pedicle, "Pringle" maneuver; intermittent clamping of the hepatic pedicle; intermittent vascular exclusion of the liver, without vena cava clamping, and hepatic vascular exclusion with vena cava clamping. Also metabolic and homodynamic consequences as well as the technical failure of the application of each of them are discussed. CONCLUSIONS: The choice of technique to use for clamping during hepatectomy depends on the surgeon's judgment. Dogmatic or systematic attitude, is prejudiciable for the patient and liver surgeon must be able to use all kinds of clamping.     

Association of Depression and Anxiety on Quality of Life, Treatment Adherence, and Prognosis in Patients with Advanced Non-small Cell Lung Cancer

Background

Symptoms of depression and anxiety are common in patients with lung cancer and may produce an impact on both health-related quality of life (HRQL) and survival. The aim of the present study was to evaluate the association of depression and anxiety on HRQL, treatment adherence, and prognosis in patients with non-small cell lung cancer (NSCLC).

Methods

This is a prospective study of patients with stage IIIB or IV NSCLC. Depression and anxiety were measured using the hospital anxiety and depression scale, the International Neuropsychiatric Interview, and the HRQL with the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Instruments were applied before treatment and repeated at 3 and 6 months. Lack of treatment adherence was considered as patients who stopped going to their consultation appointments.

Results

A total of 82 patients were included. At the initial evaluation, depression and anxiety were found in 32.9 and 34.1 % of patients, respectively. Depression was associated with feminine gender (p = 0.034) and poor performance status (p = 0.048). Depression and anxiety showed an association with HRQL. Patients with depression showed median overall survival of 6.8 months, whereas that for nondepressed patients was 14 months (hazard ratio [HR], 1.9; 95 % confidence interval (95 % CI), 1.03–3.7; p = 0.042). The 58 % of patients with depression had poor treatment adherence versus 42 % of patients without depression (p = 0.004).

Conclusions

Depression and anxiety were present in one-third of patients with recently diagnosed NSCLC. Depression and anxiety were associated with decreased HRQL scales, and depression was independently associated with treatment adherence and with poor prognosis.     

"Good enough solutions" and the genetics of complex diseases

In this Emerging Science Review, we discuss a systems genetics strategy, which we call gene module association study (GMAS), as a novel approach complementing genome-wide association studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly. The first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high-throughput) data from the population to construct gene coexpression networks. Coexpression analysis typically groups 20 000 genes into 20 to 30 modules containing tens to hundreds of genes, whose aggregate behavior can be represented by the module's "eigengene." The third step is to correlate expression patterns with phenotype, as in GWAS, only applied to eigengenes instead of single nucleotide polymorphisms. The goal of the GMAS approach is to identify groups of coregulated genes that explain complex traits from a systems perspective. From an evolutionary standpoint, we hypothesize that variability in eigengene patterns reflects the "good enough solution" concept, that biological systems are sufficiently complex so that many possible combinations of the same elements (in this case eigengenes) can produce an equivalent output, that is, a "good enough solution" to accomplish normal biological functions. However, when faced with environmental stresses, some "good enough solutions" adapt better than others, explaining individual variability to disease and drug susceptibility. If validated, GMAS may imply that common polygenic diseases are related as much to group interactions between normal genes, as to multiple gene mutations.     

Endovascular therapy of spontaneous aortocaval fistulae associated with abdominal aortic aneurysms

We report a case of an abdominal aortic aneurysm (AAA) associated with an aortocaval fistula managed with endovascular techniques. The patient had a known AAA, and on the latest computed follow-up tomographic scan, evidence of fistulization between the aorta and the vena cava was suggested, which was later corroborated by standard contrast angiography. His comorbidities precluded an open repair, and this prompted consideration for an endovascular intervention. Successful exclusion of the AAA was performed, with no evidence of endoleaks or persistence of the fistula. The endovascular approach provides an efficacious alternative to traditional methods for repair of an aortocaval fistula, which is especially important in elderly patients with several comorbidities.     

Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial

Background

C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib.

Methods

Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437.

Results

Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p?=?0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p?=?0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p?=?0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p?=?0.021) and OS (HR 0.31; p?=?0.006) in all and EGFR mutated patients.

Conclusions

A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.

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Impregnated netting slows infestation by Triatoma infestans

We used sentinel animal enclosures to measure the rate of infestation by the Chagas disease vector, Triatoma infestans, in an urban community of Arequipa, Peru, and to evaluate the effect of deltamethrin-impregnated netting on that rate. Impregnated netting decreased the rate of infestation of sentinel enclosures (rate ratio, 0.23; 95% confidence interval, 0.13-0.38; P < 0.001), controlling for the density of surrounding vector populations and the distance of these to the sentinel enclosures. Most migrant insects were early-stage nymphs, which are less likely to carry the parasitic agent of Chagas disease, Trypanosoma cruzi. Spread of the vector in the city therefore likely precedes spread of the parasite. Netting was particularly effective against adult insects and late-stage nymphs; taking into account population structure, netting decreased the reproductive value of migrant populations from 443.6 to 40.5. Impregnated netting can slow the spread of T. infestans and is a potentially valuable tool in the control of Chagas disease.     

Genome-Wide Association Study for Age-Related Hearing Loss (AHL) in the Mouse: A Meta-Analysis

Age-related hearing loss (AHL) is characterized by a symmetric sensorineural hearing loss primarily in high frequencies and individuals have different levels of susceptibility to AHL. Heritability studies have shown that the sources of this variance are both genetic and environmental, with approximately half of the variance attributable to hereditary factors as reported by Huag and Tang (Eur Arch Otorhinolaryngol 267(8):1179–1191, 2010). Only a limited number of large-scale association studies for AHL have been undertaken in humans, to date. An alternate and complementary approach to these human studies is through the use of mouse models. Advantages of mouse models include that the environment can be more carefully controlled, measurements can be replicated in genetically identical animals, and the proportion of the variability explained by genetic variation is increased. Complex traits in mouse strains have been shown to have higher heritability and genetic loci often have stronger effects on the trait compared to humans. Motivated by these advantages, we have performed the first genome-wide association study of its kind in the mouse by combining several data sets in a meta-analysis to identify loci associated with age-related hearing loss. We identified five genome-wide significant loci (<10⁻⁶). One of these loci confirmed a previously identified locus (ahl8) on distal chromosome 11 and greatly narrowed the candidate region. Specifically, the most significant associated SNP is located 450 kb upstream of Fscn2. These data confirm the utility of this approach and provide new high-resolution mapping information about variation within the mouse genome associated with hearing loss.