Amplification of specific chromosomal regions assessed by fluorescent in situ hybridization on Pap smears to be added as screening tool for identifying women at risk of progressing to cervical cancer.

Cervical carcinoma is a frequent malignancy in developing countries despite being a preventable disease. For the first time, four screening tests were used simultaneously for identifying women with a risk of developing cervical cancer, to help clinicians and policy makers to implement the best strategy for reducing the burden of this disease. Women visiting a hospital in India were enrolled after institutional ethics clearance and informed consent. Visual inspection using acetic acid and Pap smear tests were performed on 2683 women, and 104 had abnormal cytology: atypical squamous cells of undetermined significance (n = 29), low-grade squamous intraepithelial lesion (n = 41), high-grade squamous intraepithelial lesion (n = 17), and squamous cell carcinoma (n = 17). These and 96 samples, with normal cytology, were subjected to high-risk human papilloma virus testing and fluorescent in situ hybridization evaluation. Women with abnormal cytology were followed for 5 years and evaluated with colposcopy-guided biopsy. Three accepted methods of screening and one novel fluorescent in situ hybridization assay were carried out in 200 cases. Cutoffs for fluorescent in situ hybridization were established. The screening methods had 88%-96% negative predictive value, while positive predictive value was low (20%) for visual inspection using acetic acid, 47% for fluorescent in situ hybridization, 56% for high-risk human papilloma virus, and 73% for combined high-risk human papilloma virus and fluorescent in situ hybridization. Combined high-risk human papilloma virus and fluorescent in situ hybridization had 94% sensitivity, specificity, and negative predictive value, suggesting that simultaneous screening with these two tests is appropriate for identifying women progressing to cervical cancer and not visual inspection using acetic acid, which has low positive predictive value and Pap cytology which requires to be repeated. Policy makers and clinicians can assess feasibility of incorporating this screening strategy to prevent cervical cancer.

Relevance of insulin-like growth factor 2 in the etiopathophysiology of diabetic nephropathy: possible roles of phosphatase and tensin homolog on chromosome 10 and secreted protein acidic and rich in cysteine as regulators of repair.

BACKGROUND: Diabetic nephropathy (DN) is a devastating complication of diabetes, the exact molecular pathophysiology of which is not well established. Hyperglycemia increases insulin-like growth factors (IGFs), especially IGF2, which acts via the IGF1 receptor present on renal cells. Elevated glucose levels damage the kidney, which is repaired by modulators such as secreted protein acidic and rich in cysteine (SPARC). Hence, it was hypothesized that IGF2 and SPARC may have an important role in the etiology of DN. METHODS: Human renal biopsies, histopathologically categorized as normal, early Type 2 diabetes mellitus (T2DM), or established DN, were analyzed for the localization and expression of IGF2, its negative regulator phosphatase and tensin homolog on chromosome 10 (PTEN), and SPARC. RESULTS: Expression of IGF2, PTEN, and SPARC was increased in renal biopsies from T2DM patients compared with normal samples. Although IGF2 protein was increased in biopsies from DN patients, PTEN and SPARC levels were decreased. Real-time reverse transcription-polymerase chain reaction indicated that transcript levels of IGF2 and PTEN were greater than those of ß-actin in all human renal biopsy samples. CONCLUSION: The results suggest the following molecular etiopathophysiology of DN: (i) hyperglycemia upregulates IGF2, which initiates PTEN, a regulator of IGF2 signaling; (ii) loss of this IGF2-PTEN feedback loop causes changes that are characteristic of DN; and (iii) lowered expression of the repair modulator SPARC results in the development and/or progression of DN. Hence, targeting relevant modulators, such as like IGF2, PTEN, and SPARC, may be important in the management of DN.