Summary
Background
A short‐term course of pegylated‐interferon (Peg‐IFN), or a long‐term treatment with a third generation nucleot(s)ide analogue (NUC), of chronic hepatitis B (CHB) infection ...achieves viral suppression and may prevent disease progression. Owing to different mechanisms of action of the two regimens, a Peg‐IFN and NUC combination treatment may be an attractive approach to enhance the off‐treatment rates of virological and serological response.
Aim
To review the literature on combinations of Peg‐IFN plus NUC, including the simultaneous initiation of Peg‐IFN and NUC in naïve patients; an ‘add‐on’ combination, where Peg‐IFN is started at variable times after the beginning of NUC; or a ‘switch‐to’ strategy usually from NUC to Peg‐IFN.
Methods
We performed a PubMed literature search using the following terms individually or in combination: NUC, hepatitis B virus, chronic hepatitis, interferon, pegylated‐interferon, nucleos(t)ide analogues, entecavir, tenofovir. English‐language articles published up to December 2015, as well as conference proceedings from international meetings were reviewed. References from selected papers were reviewed and used if relevant.
Results
While combination and NUC pre‐treatment failed to increase HBsAg clearance rates, more promising results were achieved in patients under long‐term effective NUC therapy.
Conclusion
While Peg‐IFN and nucleos(t)ide analogue combination therapy should not be recommended currently, the addition of or the switch to Peg‐IFN in nucleos(t)ide analogue‐treated patients with chronic hepatitis B infection may be useful option.
Degenerative processes of the intervertebral disc (IVD) and cartilaginous endplate lead to chronic spine pathologies. Several studies speculated on the intrinsic regenerative capacity of degenerated ...IVD related to the presence of local mesenchymal progenitors. However, a complete characterisation of the resident IVD cell populations, particularly that isolated from the endplate, is lacking. The purpose of the present study was to characterise the gene expression profiles of human nucleus pulposus (NPCs), annulus fibrosus (AFCs) and endplate (EPCs) cells, setting the basis for future studies aimed at identifying the most promising cells for regenerative purposes. Cells isolated from NP, AF and EP were analysed after in vitro expansion for their stemness ability, immunophenotype and gene profiles by large-scale microarray analysis. The three cell populations shared a similar clonogenic, adipogenic and osteogenic potential, as well as an immunophenotype with a pattern resembling that of mesenchymal stem cells. NPCs maintained the greatest chondrogenic potential and shared with EPCs the loss of proliferation capability during expansion. The largest number of selectively highly expressed stemness, chondrogenic/tissue-specific and surface genes was found in AFCs, thus representing the most promising source of tissue-specific expanded cells for the treatment of IVD degeneration.
Aliment Pharmacol Ther 2011; 34: 353–362
Summary
Background Transient elastography has gained popularity to stage liver fibrosis in chronic viral hepatitis, however, diagnostic cut‐offs for severe ...fibrosis in chronic hepatitis B are poorly defined.
Aim To evaluate an algorithm with two distinct cut‐offs for positive and negative prediction of significant fibrosis and cirrhosis in chronic hepatitis B patients.
Methods Two cohorts of treatment‐naïve patients with chronic hepatitis B (125 training and 92 validations) were consecutively and concurrently examined by percutaneous liver biopsy and transient elastography. Fibrosis was staged by Metavir (significant fibrosis = F ≥ 2; cirrhosis = F4) in ≥2 cm long liver tissue cores.
Results A >13.1 kPa positive and a ≤9.4 kPa negative cut‐off for cirrhosis had a >90% sensitivity and specificity, with an accuracy of 94%. The corresponding cut‐offs for F ≥ 2 were >9.4 and ≤6.2 kPa, thus classifying 56% of patients with an overall accuracy of 90%. In the validation cohort, F4 and F ≥ 2 were predicted by the above transient elastography cut‐offs with an overall accuracy >90%. In 165 patients with higher than upper limit of normal transaminase activity the dual cut‐off algorithm of transient elastography was as accurate as in the 52 patients with normal alanine aminotransferase values in the prediction and exclusion of cirrhosis, only.
Conclusions A dual cut‐off algorithm allowed for correctly classifying both significant fibrosis and cirrhosis in the majority of the patients with chronic hepatitis B, independent of alanine aminotransferase values, thus reducing the need for liver biopsy investigations.
Metastases have been widely thought to arise from rare, selected, mutation-bearing cells in the primary tumor. Recently, however, it has been proposed that breast tumors are imprinted ab initio with ...metastatic ability. Thus, there is a debate over whether 'phenotypic' disease progression is really associated with 'molecular' progression. We profiled 26 matched primary breast tumors and lymph node metastases and identified 270 probesets that could discriminate between the two categories. We then used an independent cohort of breast tumors (81 samples) and unmatched distant metastases (32 samples) to validate and refine this list down to a 126-probeset list. A representative subset of these genes was subjected to analysis by in situ hybridization, on a third independent cohort (57 primary breast tumors and matched lymph node metastases). This not only confirmed the expression profile data, but also allowed us to establish the cellular origin of the signals. One-third of the analysed representative genes (4 of 11) were expressed by the epithelial component. The four epithelial genes alone were able to discriminate primary breast tumors from their metastases. Finally, engineered alterations in the expression of two of the epithelial genes (SERPINB5 and LTF) modified cell motility in vitro, in accordance with a possible causal role in metastasis. Our results show that breast cancer metastases are molecularly distinct from their primary tumors.
Purpose
Chronic tendinopathy is a degenerative process causing pain and disability. Current treatments include biophysical therapies, such as pulsed electromagnetic fields (PEMF). The aim of this ...study was to compare, for the first time, the functional in vitro response of human tendon cells to different dosages of PEMF, varying in field intensity and duration and number of exposures.
Methods
Tendon cells, isolated from human semitendinosus and gracilis tendons (hTCs;
n
= 6), were exposed to different PEMF treatments (1.5 or 3 mT for 8 or 12 h, single or repeated treatments). Scleraxis (SCX), COL1A1, COL3A1 and vascular endothelial growth factor-A (VEGF-A) expression and cytokine production were assessed.
Results
None of the different dosages provoked apoptotic events. Proliferation of hTCs was enhanced by all treatments, whereas only 3 mT-PEMF treatment increased cell viability. However, the single 1.5 mT-PEMF treatment elicited the highest up-regulation of SCX, VEGF-A and COL1A1 expression, and it significantly reduced COL3A1 expression with respect to untreated cells. The treated hTCs showed a significantly higher release of IL-1β, IL-6, IL-10 and TGF-β. Interestingly, the repeated 1.5 mT-PEMF significantly further increased IL-10 production.
Conclusions
1.5 mT-PEMF treatment was able to give the best results in in vitro healthy human tendon cell culture. Although the clinical relevance is not direct, this investigation should be considered an attempt to clarify the effect of different PEMF protocols on tendon cells, in particular focusing on the potential applicability of this cell source for regenerative medicine purpose, both in surgical and in conservative treatment for tendon disorders.
Allogeneic hematopoietic SCT (HSCT) increases the risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) carriers but the incidence, risk factors and course of HBV ...reactivation after HSCT in HBsAg-negative/anti-hepatitis B core antigen (anti-HBc)-positive recipients are not well known. A total of 50 HBsAg-negative/anti-HBc-positive HSCT recipients with onco-hematological diseases, underwent sequential clinical and laboratory examinations, including serum HBsAg, during follow-up. Serum HBV DNA collected at HSCT was retrospectively amplified by a sensitive PCR assay. During 17 months of follow-up, six (12%) patients had seroreverted to HBsAg, 7-32 months after HSCT, with 1- and 5-year cumulative rates of 13 and 22%. HBsAg seroreversion was associated with serum HBeAg higher than 8 log₁₀ copies per ml HBV DNA and a 1.5 to 36 fold increase of serum alanine aminotransferase leading to HBeAg-positive chronic hepatitis B in all patients. Patients with chronic onco-hematological disease and long-lasting immunosuppression following HSCT had a higher risk of HBsAg seroreversion independently of serum HBV DNA levels at HSCT. HBsAg-negative/anti-HBc-positive HSCT recipients with chronic onco-hematological disease carry a significant risk of HBsAg seroreversion and HBeAg-positive chronic hepatitis B, independently of serum levels of HBV DNA at transplantation.
Summary
Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver ...biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis.
p63 is a developmentally regulated transcription factor related to p53. It is involved in the development of ectodermal tissues, including limb, skin and in general, multilayered epithelia. The ...ΔNp63α isoform is thought to play a ‘master’ role in the asymmetric division of epithelial cells. It is also involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. Our understanding of transcriptional networks controlled by p63 is limited, owing to the low number of bona fide targets. To screen for new targets, we employed chromatin immunoprecipitation from keratinocytes (KCs) coupled to the microarray technology, using both CpG islands and promoter arrays. The former revealed 96 loci, the latter yielded 85 additional genes. We tested 40 of these targets in several functional assays, including: (i) in vivo binding by p63 in primary KCs; (ii) expression analysis in differentiating HaCaT cells and in cells overexpressing ΔNp63α; (iii) promoter transactivation and (iv) immunostaining in normal tissues, confirming their regulation by p63. We discovered several new specific targets whose functional categorization links p63 to cell growth and differentiation.
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