Single negative colposcopy: is it enough to rule out high-grade disease?

It has been proposed that women who have a negative colposcopic examination or who have no cervical intraepithelial neoplasia (CIN) on colposcopic biopsy can be safely returned to routine screening with the next visit being three or five years later. We present data regarding 551 women who had colposcopy in Wales for a low-grade cytological abnormality and who were followed through Cervical Screening Wales for subsequent CIN. Of 436 women declared CIN free initially, 26 (6.0%) had high-grade CIN diagnosed on follow-up. We suggest that additional screening at an interval of less than three years should be offered to women with a negative colposcopy or a biopsy without CIN.     

The biochemical basis of metabolism in cancer cachexia.

Cancer cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass. It is the most common side effect of malignancy occurring in approximately one-half of untreated cancer patients. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of carbohydrate, lipid, and protein metabolism. This leads to a shorter survival time and a decreased response to therapy. Cachexia is often found before any signs or symptoms of the cancer. An uncertainty with cachexia is whether nutritional support is feeding the patient or the tumor. Often, cachexia is not responsive to simple nutritional interventions. Furthermore, appetite stimulants, cytokine inhibitors, and Cori cycle inhibitors have been used to treat cancer cachexia.     

Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.