Alex Sobko
Sch-9 appears to be the Saccharomyces cerevisiae homolog of protein kinase B and S6 kinase and is involved in the control of numerous nutrient-sensitive processes, including regulation of cell size, cell cycle progression, and stress resistance. Sch-9 has also been implicated in the regulation of replicative and chronological life span. The availability of data from global studies of protein-protein interactions now makes it possible to predict and validate functional connections between Sch-9, its putative substrates, and other proteins. Sch-9 appears to be involved in control of biosynthetic and catabolic pathways. Thus, the analysis of Sch-9-associated proteins indicates that this kinase may be involved in regulation of protein synthesis. Sch-9 forms a complex with, and, presumably, phosphorylates starvation- and stress-induced protein kinase GCN2, which, in turn, phosphorylates translation initiation factor eIF2-alpha. Sch-9 also interacts with translation factors Arc1, Pab1 and prion-like protein Sup-35. Thus, Sch-9 may be part of the mechanism that relays availability of nutrients to utilization of glucose and to the rates of protein synthesis. One of the interesting outcomes of the proteome-wide analysis of protein-protein interactions in yeast is the finding that Sch-9 associates with Shp1, Cdc48, and Ufd1, which form a complex responsible for the recognition and targeting of ubiquitinated proteins to the proteasome for degradation. It is unknown and remains to be elucidated, whether mammalian paralogues of Sch-9 are also associated with the proteins involved in translation/ protein synthesis and proteasomal degradation.
RAY MD, Deo SVS, Luthra K, Mathur S, Anand P and Sharma A
The mainstay in the management of advanced epithelial ovarian cancer is platinum-based chemotherapy and complete cytoreductive surgery. Despite this, about two-thirds of patients have disease recurrence mostly within the peritoneal cavity. HIPEC (Hyperthermic Intraperitoneal Chemotherapy) is a modality that delivers cell-cycle non-specific chemotherapeutic agents along with heat 41°C to 43°C into the peritoneal cavity. HIPEC is done intra-operatively after achieving complete cytoreduction (which means after removal of all the tumor deposits more than 2.5 mm). Ovarian cancer is associated with the frequent finding of tumor-infiltrating lymphocytes in their tissue microenvironment. Especially studies have shown that ovarian cancer evades immune surveillance by higher expression of FOXP3 T cells. HIPEC has been used in the treatment of primary and recurrent tumors. In this review, we discuss how the significance of HIPEC on genetics and immunology of these patients with cancer have provided unique insights into the molecular and cellular basis of Treg cells. Studies of HIPEC and its association with Tregs cells should make it possible to increase the paucity of immuno- therapeutic modalities of most human cancer at an unprecedented level of molecular and cellular precision. The predictive, preventive, and therapeutic implications of these studies of HIPEC in relation to immunity in EOC may extend to patients with other peritoneal carcinomatosis.
Stocker A, Trojan A, Elfgen C, Hilbers ML, Moskovszky L and Varga Z
Purpose: Human epidermal growth factor-receptor-2 (HER2) is a membrane-tyrosine-kinase that is amplified/ overexpressed up to 20% in breast cancer. HER2 positive status is associated with faster disease progression, higher metastatic potential, and shorter disease-free / overall survival and also has emerged as an important therapeutic target in breast cancer. HER2 status can be determined by in situ-hybridization (ISH) or immunohistochemistry (IHC). Although the concordance rate between ISH and IHC is well-known, the prognostic power of both technologies if tested in parallel on the same tumor has not been studied extensively.
Methods: In this study we retrospectively analyzed a large HER2 positive breast cancer cohort tested both with fluorescence labelled ISH (FISH) and IHC in parallel on each case. We stratified HER2 positive results by FISH and IHC with long-term overall survival, five-year survival and metastases/recurrence rates. Positive HER2 status both FISH and IHC was available in 364 patients.
Results: The number of HER2 FISH-positive and FISH-negative patients was 342 and 22, respectively. The number of HER2 IHC 0/1+, IHC 2+, and IHC 3+ patients was 12, 42, and 310, respectively. Among the patients with IHC 3+ status,
288 were FISH-positive and 22 FISH-negative. HER2 status determined by FISH correlated with clinical outcomes (overall survival and with metastases/recurrence, P = 0.036, P = 0.039), whereas HER2 status determined by IHC did not.
Conclusion: Our results indicate that prognostic information in HER2 positive breast cancer also depends on the methodology of how positivity was determined. In our cohort, FISH was superior to IHC based positive HER2 status.
