Teri Melese

Open innovation networks between academia and industry: an imperative for breakthrough therapies.

Open innovation networks between academia and industry: an imperative for breakthrough therapies

Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: From bedside to bench and back.

The RASopathies are a group of genetic syndromes caused by germline mutations in genes that encode components of the Ras/mitogen‐activated protein kinase (MAPK) pathway. Some of these syndromes are neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardio‐facio‐cutaneous syndrome, LEOPARD syndrome and Legius syndrome. Their common underlying pathogenetic mechanism brings about significant overlap in phenotypic features and includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium “Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back” chronicle the timely and typical research symposium which brought together clinicians, basic scientists, physician‐scientists, advocate leaders, trainees, students and individuals with Ras syndromes and their families. The goals, to discuss basic science and clinical issues, to set forth a solid framework for future research, to direct translational applications towards therapy and to set forth best practices for individuals with RASopathies were successfully meet with a commitment to begin to move towards clinical trials.

Costello and cardio‐facio‐cutaneous syndromes: Moving toward clinical trials in RASopathies

The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen‐activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio‐facio‐cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well‐studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.

From genetics and genomics to drug discovery: yeast rises to the challenge

Yeast expands its role from eukaryotic genetics and genomics to drug discovery.

Distribution of three hexose derivatives across the pancreatic epithelium: Paracellular shunts or cellular passage?

It has been proposed that the pancreatic epithelium is permeable to three presumably passively distributed non-electrolytes, namely sucrose, inulin and mannitol, via paracellular shunts, and that the increased flux of sucrose and inulin seen during augmented digestive enzyme secretion is due to an increase in the permeability of these shunts. The present study considers this hypothesis by comparing the permeability of the epithelium to three different hexose derivatives, mannitol, inositol and 3-O-methyl-glucose, in both the unstimulated state and after the augmentation of protein secretion with a cholinergic drug. The epithelium was found to be more permeable to mannitol than to either inositol or 3-O-methyl-glucose. In the unstimulated state, the concentration of mannitol in ductal fluid at the steady state was approx. 54% of its concentration in the interstitium, as compared to 12% for inositol and 8% for 3-O-methyl-glucose. Cholinergic stimulation substantially increased the concentration of inositol and 3-O-methyl-glucose in secretion, but did not increase that of mannitol. The increase in the concentration of inositol occurred in the absence of an increase in its rate of transepithelial movement. Taken together, the results suggest that: (1) there is a substantial passage of mannitol through the cells of the epithelial layer, and (2) the increased concentration of inositol and 3-O-methyl-glucose in ductal fluid that occurs with stimulation is due to an increase in their efflux from secretory cells.