Practical considerations in reducing swallowing dysfunction following concurrent chemoradiotherapy with intensity-modulated radiotherapy for head and neck cancer.

Data have emerged that the addition of concurrent chemotherapy to radiation can lead to swallowing dysfunction that may have an impact on patient quality of life and lead to significant morbidities such as poor nutritional status, enteral feeding tube dependence, and aspiration pneumonia. Although intensity-modulated radiation therapy (IMRT) for head and neck cancer was initially developed to spare the parotid gland to reduce xerostomia, attention has recently focused on its utility to selectively decrease radiation dose to specified anatomic structures responsible for a functional swallow. Recent reports have proposed a variety of dose thresholds or constraints to these swallowing-related structures, which may guide IMRT planning with the aim of reducing dysphagia. This critical review of the current literature assesses the feasibility of IMRT to maintain swallowing function and appraises the various dosimetric parameters that have been proposed to help minimize long-term dysphagia.

Enteropathy-associated T cell lymphoma presenting with acute abdominal syndrome: a case report and review of literature.

INTRODUCTION: Enteropathy-associated T cell lymphoma (EATL) is a rare peripheral non-Hodgkin's T cell lymphoma originating from intraepithelial T lymphocytes of the intestines. In general, this condition has a poor prognosis. A common initial presentation of this cancer which is a small intestinal perforation necessitating emergency surgery is of interest to practicing surgeons. The diagnosis is rarely made prior to pathological examination. METHODS: We report a case of a 39-year-old African American man who presented with acute abdomen and was found to have a deep necrotic ulcer of the jejunum during exploratory laparotomy. RESULTS: Pathological examination and laboratory results demonstrated EATL, type 2, which is not associated with celiac disease. A review of the literature on EATL is also presented.

Directed evolution to re-adapt a co-evolved network within an enzyme.

We have previously used targeted active-site saturation mutagenesis to identify a number of transketolase single mutants that improved activity towards either glycolaldehyde (GA), or the non-natural substrate propionaldehyde (PA). Here, all attempts to recombine the singles into double mutants led to unexpected losses of specific activity towards both substrates. A typical trade-off occurred between soluble expression levels and specific activity for all single mutants, but many double mutants decreased both properties more severely suggesting a critical loss of protein stability or native folding. Statistical coupling analysis (SCA) of a large multiple sequence alignment revealed a network of nine co-evolved residues that affected all but one double mutant. Such networks maintain important functional properties such as activity, specificity, folding, stability, and solubility and may be rapidly disrupted by introducing one or more non-naturally occurring mutations. To identify variants of this network that would accept and improve upon our best D469 mutants for activity towards PA, we created a library of random single, double and triple mutants across seven of the co-evolved residues, combining our D469 variants with only naturally occurring mutations at the remaining sites. A triple mutant cluster at D469, E498 and R520 was found to behave synergistically for the specific activity towards PA. Protein expression was severely reduced by E498D and improved by R520Q, yet variants containing both mutations led to improved specific activity and enzyme expression, but with loss of solubility and the formation of inclusion bodies. D469S and R520Q combined synergistically to improve k(cat) 20-fold for PA, more than for any previous transketolase mutant. R520Q also doubled the specific activity of the previously identified D469T to create our most active transketolase mutant to date. Our results show that recombining active-site mutants obtained by saturation mutagenesis can rapidly destabilise critical networks of co-evolved residues, whereas beneficial single mutants can be retained and improved upon by randomly recombining them with natural variants at other positions in the network.