Characterization of the translocation-competent complex between the Helicobacter pylori oncogenic protein CagA and the accessory protein CagF.

CagA is a virulence factor that Helicobacter pylori inject into gastric epithelial cells through a type IV secretion system where it can cause gastric adenocarcinoma. Translocation is dependent on the presence of secretion signals found in both the N- and C-terminal domains of CagA and an interaction with the accessory protein CagF. However, the molecular basis of this essential protein-protein interaction is not fully understood. Herein we report, using isothermal titration calorimetry, that CagA forms a 1:1 complex with a monomer of CagF with nM affinity. Peptide arrays and isothermal titration calorimetry both show that CagF binds to all five domains of CagA, each with µM affinity. More specifically, a coiled coil domain and a C-terminal helix within CagF contacts domains II-III and domain IV of CagA, respectively. In vivo complementation assays of H. pylori with a double mutant, L36A/I39A, in the coiled coil region of CagF showed a severe weakening of the CagA-CagF interaction to such an extent that it was nearly undetectable. However, it had no apparent effect on CagA translocation. Deletion of the C-terminal helix of CagF also weakened the interaction with CagA but likewise had no effect on translocation. These results indicate that the CagA-CagF interface is distributed broadly across the molecular surfaces of these two proteins to provide maximal protection of the highly labile effector protein CagA.

Radiation Therapy for Benign Disease: Arteriovenous Malformations, Desmoid Tumor, Dupuytren Contracture, Graves Ophthalmopathy, Gynecomastia, Heterotopic Ossification, Histiocytosis.

Although the use of ionizing radiation in malignant conditions has been well established, its application in benign conditions has not been fully accepted and has been inadequately recognized by health care providers outside of radiation therapy. Most frequently, radiation therapy in these benign conditions is used along with other treatment modalities, such as surgery, in instances where the condition causes significant disability or could even lead to death. Radiation therapy can be helpful for inflammatory/proliferative disorders. This article discusses the current use of radiation therapy in some of the more common benign conditions.

Radiation Therapy for Benign Disease: Keloids, Macular Degeneration, Orbital Pseudotumor, Pterygium, Peyronie Disease, Trigeminal Neuralgia.

Although the use of ionizing radiation on malignant conditions has been well established, its application on benign conditions has not been fully accepted and has been inadequately recognized by health care providers outside of radiation therapy. Most frequently, radiation therapy in these benign conditions is used along with other treatment modalities, such as surgery, when the condition causes significant disability or could even lead to death. Radiation therapy can be helpful for inflammatory/proliferative disorders. This article discusses the present use of radiation therapy for some of the most common benign conditions.

Treatment and Outcomes of Primary Urethra Cancer.

BACKGROUND: Urethral cancer is a rare malignancy, representing <1% of all malignancies. Optimal management, due to its rarity, presents as a treatment dilemma for physicians. There is a lack of consensus regarding treatment as large randomized trials cannot be performed; thus, optimal management decisions rely on study of retrospective cases. This is a review of our institutional experience with urethral cancer treated with various treatment modalities. METHODS: A retrospective chart review was performed on 31 patients treated for primary cancer of the urethra from 1958 to 2008. The patients were stratified by sex, histologic type, stage, date of diagnosis, type of treatment, and last follow-up. Early stage cases were designated as Tis-T2N0M0 and advanced cases were designated as T3-4, N+ or M+. Analysis was performed based on clinical stage, treatment modalities and outcomes. RESULTS: Fourteen early stage cases and 17 advanced stage cases of urethral cancer were analyzed. The majority of early stage cases occurred in men (M:F=8:6) and the majority of advanced stage cases occurred in women (M:F=5:12). The most common histology was squamous cell carcinoma for both early and advanced stage cases. Surgery was the preferred modality of treatment for early stage cases (surgery used in 13 cases vs. chemo/radiotherapy used in 1 case) while for advanced cases, radiation ±chemotherapy was commonly used. Overall survival for this series was 45% at mean follow-up of 7 years. Eight of the 14 cases of early stage cancer remained disease free at last follow-up. Comparatively, only 5 of 17 with advanced cancers had no apparent disease at last follow-up. All but one of those patients were treated with combined modality therapy. CONCLUSIONS: Patients with early stage urethral cancers do well with single modality therapy, whereas patients who present with advanced cancers may benefit from combined modality therapy. More extensive study is required to recommend a particular treatment protocol. However, in this rare malignancy, institutional experiences provide the best evidence currently due to the lack of multi-institutional trials.

A Dosimetric Comparison of Intensity-Modulated Proton Therapy, Volumetric-Modulated Arc Therapy, and 4π Non-Coplanar Intensity-Modulated Radiation Therapy for a Patient with Parameningeal Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and manifests as two major histological subtypes: embryonal and alveolar. The five-year local failure rate for RMS at parameningeal sites (middle ear, mastoid region, nasal cavity, etc.) is around 17% despite multiple Intergroup Rhabdomyosarcoma Study Group (IRS) trials conducted to determine the optimal radiation treatment regimen. This case report explores the use of intensity-modulated proton therapy (IMPT) for a 10-year-old child who presented with left eye irritation, facial pain, and headaches and was found to have an alveolar parameningeal rhabdomyosarcoma. He received systemic therapy as well as radiation therapy to 5,640 cGy and 4,320 cGy over 24 fractions, prescribed for gross tumor extension and adjacent high-risk involved sites, respectively, via simultaneous integrated boost. Approximately two years following treatment, the patient has had no recurrence of his RMS with no distant metastases. In addition, his presenting symptom of left eye irritation has improved. His only side effect from radiation at this point is short stature, possibly due to growth hormone deficiency. The patient's IMPT plan was compared with volumetric-modulated arc therapy (VMAT) and 4π non-coplanar intensity-modulated radiation therapy (IMRT) plans, and comparisons of isodose lines show decreased dose to the distal brain tissue with preserved target conformality by IMPT. IMPT also allowed for increased sparing of the patient's retina, lens, and lacrimal gland. All radiation plans achieved conformal dose coverage to the planning/scanning target volumes, while the IMPT plan is potentially better at sparing the patient from developing long-term optic apparatus side effects and neurocognitive defects. In this case, IMPT is comparable, if not favorable, when long-term side effects can be reduced while maintaining dose conformality and local control.