The role of aldo-keto reductase 1C3 (AKR1C3)-mediated prostaglandin D2 (PGD2) metabolism in keloids.

Keloids are progressively expanding scars, mostly prevalent in individuals of African descent. Previous data identified increased mast cell number and activation state in keloids suggesting a role in disease progression. The major eicosanoid secreted by mast cells is prostaglandin D2 (PGD2), a relatively unstable pro-inflammatory mediator which can be spontaneously converted to 15-deoxy-(Delta12,14)-prostaglandin J2(15d-PGJ2) or enzymatically metabolized to 9α,11ß-PGF2 by aldo-keto reductase 1C3 (AKR1C3). In this work, we investigated the possible role of PGD2 and its metabolites in keloids using CRL1762 keloid fibroblasts (KF) and immunohistochemical staining. Our data suggested approximately 3-fold increase of tryptase-positive mast cell count in keloids compared with normal skin. Furthermore, AKR1C3 was overexpressed in the fibrotic area of keloids while relatively weak staining detected in normal skin. Metabolism of PGD2 to 9α,11ß-PGF2 by both, KF and normal fibroblasts, was dependent on AKR1C3 as this reaction was attenuated in the presence of the AKR1C3 inhibitor, 2'-hydroxyflavanone, or in cells with decreased AKR1C3 expression. 15d-PGJ2, but not the other tested PGs, inhibited KF proliferation, attenuated KF-mediated collagen gel contraction and increased caspase-3 activation. In addition, treatment with 15d-PGJ2 activated P38-MAPK, induced reactive oxygen species and upregulated superoxide dismutase-1 (SOD-1). Finally, inhibition of P38-MAPK further augmented 15d-PGJ2-induced caspase-3 cleavage and attenuated its effect on SOD-1 transcription. This work suggests that localized dual inhibition of AKR1C3 and P38-MAPK may inhibit keloid progression. Inhibiting AKR1C3 activity may generate oxidative environment due to redirection of PGD2 metabolism towards 15d-PGJ2 while inhibition of P38-MAPK will sensitize keloid cells to ROS-induced apoptosis.

Malate dehydrogenase: a story of diverse evolutionary radiation.

Malate dehydrogenase (MDH) is a ubiquitous enzyme involved in cellular respiration across all domains of life. MDH's ubiquity allows it to act as an excellent model for considering the history of life and how the rise of aerobic respiration and eukaryogenesis influenced this evolutionary process. Here, we present the diversity of the MDH family of enzymes across bacteria, archaea, and eukarya, the relationship between MDH and lactate dehydrogenase (LDH) in the formation of a protein superfamily, and the connections between MDH and endosymbiosis in the formation of mitochondria and chloroplasts. The development of novel and powerful DNA sequencing techniques has challenged some of the conventional wisdom underlying MDH evolution and suggests a history dominated by gene duplication, horizontal gene transfer, and cryptic endosymbiosis events and adaptation to a diverse range of environments across all domains of life over evolutionary time. The data also suggest a superfamily of proteins that do not share high levels of sequential similarity but yet retain strong conservation of core function via key amino acid residues and secondary structural components. As DNA sequencing and 'big data' analysis techniques continue to improve in the life sciences, it is likely that the story of MDH will continue to refine as more examples of superfamily diversity are recovered from nature and analyzed.

The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-based chemotherapy and radiation therapy for rectal cancer.

PURPOSE: A direct relationship between the volume of small bowel irradiated and the degree of acute small bowel toxicity experienced during concurrent 5-fluorouracil (5-FU)-based chemoradiotherapy for rectal carcinoma is well recognized but poorly quantified. This study uses three-dimensional treatment-planning tools to more precisely quantify this dose-volume relationship. METHODS AND MATERIALS: Forty patients receiving concurrent 5-FU-based chemotherapy and pelvic irradiation for rectal carcinoma had treatment-planning CT scans with small bowel contrast. A median isocentric dose of 50.4 Gy was delivered using a posterior-anterior and opposed lateral field arrangement. Bowel exclusion techniques were routinely used, including prone treatment position on a vacuum bag cradle to allow anterior displacement of the abdominal contents and bladder distension. Individual loops of small bowel were contoured on each slice of the planning CT scan, and a small bowel dose-volume histogram was generated for the initial pelvis field receiving 45 Gy. The volume of small bowel receiving each dose between 5 and 40 Gy was recorded at 5-Gy intervals. RESULTS: Ten patients (25%) experienced Common Toxicity Criteria Grade 3+ acute small bowel toxicity. A highly statistically significant association between the development of Grade 3+ acute small bowel toxicity and the volume of small bowel irradiated was found at each dose level. Specific dose-volume threshold levels were found, below which no Grade 3+ toxicity occurred and above which 50-60% of patients developed Grade 3+ toxicity. The volume of small bowel receiving at least 15 Gy (V15) was strongly associated with the degree of toxicity. Univariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicity. CONCLUSIONS: A strong dose-volume relationship exists for the development of Grade 3+ acute small bowel toxicity in patients receiving concurrent 5-FU-based chemoradiotherapy for rectal carcinoma.

Impact of breathing motion on whole breast radiotherapy: a dosimetric analysis using active breathing control.

PURPOSE: The active breathing control (ABC) apparatus was used to quantify the effect of breathing motion on whole breast radiotherapy (RT) with standard wedges and intensity-modulated RT (IMRT). METHODS AND MATERIALS: Ten patients with early-stage breast cancer underwent routine free-breathing (FB) CT simulations for whole breast RT. An ABC apparatus was used to obtain two additional CT scans with the breath held at the end of normal inhalation and normal exhalation. The FB scan was used to develop both a standard treatment plan using wedged coplanar tangents and an IMRT plan using multiple static multileaf collimator segments. To simulate breathing, each plan was copied and applied to the normal inhalation and normal exhalation CT scans. RESULTS: The medial field border (defined by a radiopaque catheter) for the normal inhalation and normal exhalation scans moved an average of 0.6 cm anteriorly and 0.3 cm posteriorly compared with the FB position, respectively. The corresponding movement of the lateral field border was an average of 0.4 cm anteriorly and 0.2 cm posteriorly compared with the FB position. For both the wedged and the IMRT techniques, the dose delivered to breast tissue, biopsy cavity, and ipsilateral lung was similar for each of the three CT scan positions. However, the internal mammary node dose varied significantly with breathing. CONCLUSIONS: The dose delivered to breast using standard wedges or step-and-shoot IMRT is relatively insensitive to the effects of breast motion during normal breathing. However, an appreciable portion of the internal mammary nodes are irradiated during normal inhalation, contributing to the uncertainty in the analysis of the efficacy of internal mammary nodal RT in breast treatment.

Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT).

PURPOSE: We present a novel three-dimensional conformal radiation therapy (3D-CRT) technique to treat the lumpectomy cavity, plus a 1.5-cm margin, in patients with early-stage breast cancer and study its clinical feasibility. METHODS AND MATERIALS: A 3D-CRT technique for partial-breast irradiation was developed using archived CT scans from 7 patients who underwent an active breathing control study. The clinical feasibility of this technique was then assessed in 9 patients who were prospectively enrolled on an Investigational Review Board-approved protocol of partial-breast irradiation. The prescribed dose was 34 Gy in 5 patients and 38.5 Gy in 4 patients, delivered in 10 fractions twice daily over 5 consecutive days. The impact of both breathing motion and patient setup uncertainty on clinical target volume (CTV) coverage was studied, and an appropriate CTV-to-PTV (planning target volume) margin was calculated. RESULTS: By adding a CTV-to-PTV "breathing-only" margin of 5 mm, 98%-100% of the CTV remained covered by the 95% isodose surface at the extremes of normal inhalation and normal exhalation. The "total" CTV-to-PTV margin employed to accommodate organ motion and setup error (10 mm) was found to be sufficient to accommodate the observed uncertainty in the delivery precision. Patient tolerance was excellent, and acute toxicity was minimal. No skin changes were noted during treatment, and at the initial 4-8-week follow-up visit, only mild localized hyperpigmentation and/or erythema was observed. No instances of symptomatic radiation pneumonitis have occurred. CONCLUSIONS: Accelerated partial-breast irradiation using 3D-CRT is technically feasible, and acute toxicity to date has been minimal. A CTV-to-PTV margin of 10 mm seems to provide coverage for most patients. However, more patients and additional studies will be needed to validate the accuracy of this margin, and longer follow-up will be needed to assess acute and chronic toxicity, tumor control, and cosmetic results.

A nursing tool for adherence and recovery in psychosis: a pilot study.

Clients with psychotic disorders are at great risk for relapse and rehospitalization. This risk is magnified by poor adherence to medications, as well as refusal to accept optimal treatment planning, including more beneficial atypical medications. Adherence can be even more compromised because of clients' poor insight into these illnesses and their inability to recognize the potential for recovery that exists when taking medications as prescribed. This poor insight makes effective collaboration in treatment more difficult and is an exceptionally troubling impediment to successful treatment. Currently, there are few effective strategies to improve insight into psychosis. We have developed the Levels of Recovery from Psychotic Disorders Scale (LORS) as a teaching tool. It is designed to identify strengths and weaknesses in insight in order to provide the basis for an intervention to enhance and promote change. This article reviews the relevant literature on adherence and insight in this population of clients with psychotic disorders. It also reviews a pilot study comparing the LORS to the BASIS-32. The findings provide the basis for future studies using the LORS to enhance insight, adherence, and recovery.