RB +/− individuals develop retinoblastoma and, subsequently, many other tumors. The Rb relatives p107 and p130 protect the tumor-resistant Rb−/− mouse retina. Determining the mechanism underlying this tumor suppressor function may expose novel strategies to block Rb-pathway cancers. p107/p130 are best known as E2f inhibitors, but here we implicate E2f-independent Cdk2 inhibition as the critical p107 tumor suppressor function in vivo. Like p107 loss, deleting p27 or inactivating its Cdk inhibitor (CKI) function (p27CK−) cooperated with Rb loss to induce retinoblastoma. Genetically, p107 behaved like a CKI because inactivating Rb and one allele each of p27 and p107 was tumorigenic. While Rb loss induced canonical E2f targets, unexpectedly p107 loss did not further induce these genes but instead caused post-transcriptional Skp2-induction and Cdk2 activation. Strikingly, Cdk2 activity correlated with tumor penetrance across all the retinoblastoma models. Therefore, Rb restrains E2f, but p107 inhibits cross-talk to Cdk. While removing either E2f2 or E2f3 genes had little effect, removing only one E2f1 allele blocked tumorigenesis. More importantly, exposing retinoblastoma-prone fetuses to small molecule E2f or Cdk inhibitors for merely one week dramatically inhibited subsequent tumorigenesis in adult mice. Protection was achieved without disrupting normal proliferation. Thus, exquisite sensitivity of the cell-of-origin to E2f and Cdk activity can be exploited to prevent Rb pathway-induced cancer in vivo without perturbing normal cell division. These data suggest that E2f inhibitors, never before tested in vivo, or Cdk inhibitors, largely disappointing as therapeutics, may be effective preventive agents.

BackgroundSTAT1 and IRF1 collaborate to induce interferon-γ (IFNγ) stimulated genes (ISGs), but the extent to which they act alone or together is unclear. The effect of single nucleotide polymorphisms (SNPs) on in vivo binding is also largely unknown.ResultsWe show that IRF1 binds at proximal or distant ISG sites twice as often as STAT1, increasing to sixfold at the MHC class I locus. STAT1 almost always bound with IRF1, while most IRF1 binding events were isolated. Dual binding sites at remote or proximal enhancers distinguished ISGs that were responsive to IFNγ versus cell-specific resistant ISGs, which showed fewer and mainly single binding events. Surprisingly, inducibility in one cell type predicted ISG-responsiveness in other cells. Several dbSNPs overlapped with STAT1 and IRF1 binding motifs, and we developed methodology to rapidly assess their effects. We show that in silico prediction of SNP effects accurately reflects altered binding both in vitro and in vivo.ConclusionsThese data reveal broad cooperation between STAT1 and IRF1, explain cell type specific differences in ISG-responsiveness, and identify genetic variants that may participate in the pathogenesis of immune disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s12867-017-0084-1) contains supplementary material, which is available to authorized users.

Microorganisms have long been used in the production of a variety of foods, alcoholic beverages, additives, and supplements due to their cost effectiveness and environmental advantages. Solid‐state fermentation (SSF) reproduces the natural microbiological process that can be utilized in a controlled way to produce the desired product. In the present study, modulation of phenolic compounds, antioxidant potential, and mineral content during SSF of three lentil cultivars, namely, HM‐1, LL‐931, and Sapna, were explored. The total phenolic content (TPC) for 6th day Aspergillus‐fermented lentil (AFL) flour increased by 79.2% for cv. HM‐1, 78.8% for cv. LL‐931, and 122.8% for cv. Sapna. High‐performance liquid chromatography (HPLC) results also showed that SSF not only improved the phenolic content of lentil cultivars but also resulted in the formation of some new phenolic compounds (resorcinol and cinnamic acid). The condensed tannin content, DPPH (2,2‐diphenyl‐1‐picrylhydrazyl) inhibition activity, hydroxyl free radical scavenging activity, reducing power activity, and total antioxidant capacity of aqueous ethanolic extracts from all AFLs also increased significantly (p ≤ 0.05) up to 6th day of fermentation. Mineral content differed significantly (p ≤ 0.05), with AFL extracts exhibiting higher mineral content than their unfermented counterparts. Among different minerals, Cu content of all AFL extracts was the highest with an increase of 46.4% to 60.0% upon fermentation. All minerals showed a significant (p ≤ 0.05) increase in their concentrations upon fermentation except for K in which the increase was less than 0.1%. However, in vitro bioavailability of iron and zinc was significantly (p ≤ 0.05) higher in AFL as compared with their unfermented counterparts, with the highest level being observed on the 6th day of fermentation. Thus, biotransformed lentils could be utilized in the preparation of functional foods and novel nutraceuticals for their health‐promoting properties.

Squamous cell carcinoma (SCC) of urinary tract is a rarely encountered tumor. The incidence of this tumor is 1.4 per cent of all renal malignancies (1). We present a case of 52 years male with squamous cell carcinoma of renal pelvis, presenting as chronic pyelonephritis transforming the kidney into non-functioning multicystic cavitatory mass without any renal calculi. The case highlights the rarity of tumor in absence of calculi or any other predisposing factor. Moreover, histology of resected specimen detected features of SCC giving importance to careful and exhaustive assessment of specimen and of histologic sections, when there is no suspicion of malignancy clinically.