The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase ßTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

Type 1 diabetes development requires both CD4+ and CD8+ T cells and can be reversed by non-depleting antibodies targeting both T cell populations.

Type 1 diabetes development in NOD mice appears to require both CD4(+) and CD8(+) T cells. However, there are some situations where it has been suggested that either CD4(+) or CD8(+) T cells are able to mediate diabetes in the absence of the other population. In the case of transgenic mice, this may reflect the numbers of antigen-specific T cells able to access the pancreas and recruit other cell types such as macrophages leading to a release of high concentrations of damaging cytokines. Previous studies examining the requirement for CD8(+) T cells have used antibodies specific for CD8alpha. It is known that CD8alpha is expressed not only on alphabeta T cells, but also on other cell types, including a DC population that may be critical for presenting islet antigen in the pancreatic draining lymph nodes. Therefore, we have re-examined the need for both CD4(+) and CD8(+) T cell populations in diabetes development in NOD mice using an antibody to CD8beta. Our studies indicate that by using highly purified populations of T cells and antibodies specific for CD8(+) T cells, there is indeed a need for both cell types. In accordance with some other reports, we found that CD4(+) T cells appeared to be able to access the pancreas more readily than CD8(+) T cells. Despite the ability of CD4(+) T cells to recruit CD11b class II positive cells, diabetes did not develop in the absence of CD8(+) T cells. These studies support the observation that CD8(+) T cells may be final effector cells. As both T cell populations are clearly implicated in diabetes development, we have used a combination of non-depleting antibodies to target both CD4-positive and CD8-positive cells and found that this antibody combination was able to reverse diabetes onset in NOD mice as effectively as anti-CD3 antibodies.

Patients with chronic pancreatitis have islet progenitor cells in their ducts, but reversal of overt diabetes in NOD mice by anti-CD3 shows no evidence for islet regeneration.

Monoclonal antibodies to T-cell coreceptors have been shown to tolerise autoreactive T-cells and prevent or even reverse autoimmune pathology. In type 1 diabetes, there is a loss of insulin-secreting beta-cells, and a cure for type 1 diabetes would require not only tolerance induction but also recovery of the functional beta-cell mass. Although we have previously shown that diabetic mice have increased numbers of ductal progenitors in the pancreas, there is no evidence of any increase of insulin-secreting cells in the ducts. In contrast, in the adult human pancreas of patients with chronic pancreatitis, we can demonstrate, in the ducts, increased numbers of insulin-containing cells, as well as cells containing other endocrine and exocrine markers. There are also significantly increased numbers of cells expressing the homeodomain protein, pancreatic duodenal homeobox-1. Anti-CD3 has been shown to reverse overt diabetes in NOD mice; thus, we have used this model to ask whether monoclonal antibody-mediated inhibition of ongoing beta-cell destruction enables islet regeneration to occur. We find no evidence that such monoclonal antibody therapy results in either regeneration of insulin-secreting beta-cells or of increased proliferation of islet beta-cells.

A study of the molecular properties of water in hydrated mannitol.

An understanding of the properties of water in hydrated saccharides and saccharide derivatives is relevant to a number of pharmaceutical processes, including wet granulation. This study uses a range of physical measurement techniques [viz. nuclear magnetic resonance spectroscopy (NMR), dielectric relaxation spectroscopy (DRS), near infrared spectroscopy (NIR), and differential scanning calorimetry (DSC)] to analyze the molecular properties of water in hydrated mannitol (containing up to 0.45 g water per gram of dry sample). The resulting measurements show a correlation between the different techniques, in that each technique shows two transitions (h(t1) and h(t2)) in the properties of the hydrated material (at water contents of approximately 0.1 g/g and 0.25-0.3 g/g, respectively). It is suggested that h(t1) and h(t2) mark the appearance of a second and a third population of water and that these transitions are due to different stages of microdissolution of the solid. Evidence is presented that shows that this second population of water undergoes a thermodynamic phase transition close to 0 degrees C, and therefore the material must contain some water that is behaving like free water. The significance of the transitions (h(t1) and h(t2)) and the mobility of water (above and below these transitions) are yet to be established for mixtures of sugars and other materials. However, it is probable that this information will contribute to our understanding of the how these types of materials are processed (e.g., during the wet granulation process) and how drugs maintain their stability during processes that involve the significant hydration of a powder blend.