Experimental validation of a novel method of dose accumulation for the rectum.

BACKGROUND: Dose-surface maps (DSMs) are an increasingly popular tool to evaluate spatial dose-outcome relationships for the rectum. Recently, DSM addition has been proposed as an alternative method of dose accumulation from deformable registration-based techniques. In this study, we performed the first experimental investigation of the accuracy at which DSM accumulation can capture the total dose delivered to a rectum's surface in the presence of inter-fraction motion. MATERIAL AND METHODS: A custom PVC rectum phantom capable of representing typical rectum inter-fraction motion and filling variations was constructed for this project. The phantom allowed for the placement of EBT3 film sheets on the representative rectum surface to measure rectum surface dose. A multi-fraction prostate VMAT treatment was designed and delivered to the phantom in a water tank for a variety of inter-fraction motion scenarios. DSMs for each fraction were calculated in two ways using CBCT images acquired during delivery and summed to produce accumulated DSMs. Accumulated DSMs were then compared to film measurements using gamma analysis (3%/2 mm criteria). Similarity of isodose clusters between films and DSMs was also investigated. RESULTS: Baseline agreement between film measurements and accumulated DSMs for a stationary rectum was 95.6%. Agreement between film and accumulated DSMs in the presence of different types of inter.-fraction motion was ≥92%, and isodose cluster mean distance to agreement was within 1.5 mm for most scenarios. Overall, DSM accumulation performed the best when using DSMs that accounted for changes in rectum path orientation. CONCLUSION: Dose accumulation performed with DSMs was found to accurately replicate total delivered dose to a rectum phantom in the presence of inter-fraction motion.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of renal cell carcinoma was published in 2019 with an update planned for 2021. It was therefore decided by both the ESMO and the Singapore Society of Oncology (SSO) to convene a special, virtual guidelines meeting in May 2021 to adapt the ESMO 2019 guidelines to take into account the ethnic differences associated with the treatment of renal cell carcinomas in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with renal cell carcinoma representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma.

The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

Video education to improve recognition of common benign and malignant cutaneous lesions and skin cancer prevention in the public.

OBJECTIVE: Although dermatologists strive to provide patient education on sun protection and skin cancer, approximately 90% of Americans have limited health literacy skills. Little has been written about the means to best teach all levels of learners to recognize common benign and malignant skin lesions. Earlier work found that with advancing age, adults were less able to identify concerning lesions, thus underscoring the need for accessible education. METHODS: We showed subjects a brief video (7th grade level) about common cutaneous growths, reducing the risk of skin cancer, and the importance of early detection. Subjects were asked about their skin cancer history, educational format preference, and the perceived impact of the video. Comprehension of symptoms of skin cancer and the benefits of sunscreen use and the ability to identify a melanoma, nevus, angioma, and seborrheic keratosis were also assessed. RESULTS: Of the 156 subjects, mean age 52.7 years (range, 18-88 years), 31% had a history of skin cancer. A total of 98.7% found the video to be helpful; 92% preferred having a video as part of their teaching versus 9% who preferred written materials alone, 99% knew that a new or changing lesion could signal skin cancer, and 100% correctly answered that wearing sunscreen is protective. Subjects correctly identified lesions as melanoma (99%), benign mole (97%), angiomas (96%), and seborrheic keratosis (91%). There was a nominal trend toward higher scores in people who preferred video learning, had no history of skin cancer, and were older than 60 years of age. CONCLUSION: In this study, we found that a brief, plain-language video was effective at conveying understandable content to help subjects learn to identify common cancerous and benign skin growths while also teaching them strategies to protect against skin cancer.

ALGEBRA: ALgorithm for the heterogeneous dosimetry based on GEANT4 for BRAchytherapy.

Task group 43 (TG43)-based dosimetry algorithms are efficient for brachytherapy dose calculation in water. However, human tissues have chemical compositions and densities different than water. Moreover, the mutual shielding effect of seeds on each other (interseed attenuation) is neglected in the TG43-based dosimetry platforms. The scientific community has expressed the need for an accurate dosimetry platform in brachytherapy. The purpose of this paper is to present ALGEBRA, a Monte Carlo platform for dosimetry in brachytherapy which is sufficiently fast and accurate for clinical and research purposes. ALGEBRA is based on the GEANT4 Monte Carlo code and is capable of handling the DICOM RT standard to recreate a virtual model of the treated site. Here, the performance of ALGEBRA is presented for the special case of LDR brachytherapy in permanent prostate and breast seed implants. However, the algorithm is also capable of handling other treatments such as HDR brachytherapy.

SU-E-J-208: Dosimetric Assessment of Treatment Using CBCT Images.

PURPOSE: To evaluate target coverage for five breast patients receiving boost treatment to the tumor bed by calculating the daily dose on cone beam computed tomography (CBCT) images and utilizing deformable image registration techniques. METHODS: The daily dose is calculated on pretreatment CBCT images using the same beam configuration as the original volumetric modulated arc therapy (VMAT) plan. Calculations were done with two different isocenter positions according to: (1) the initial patient setup and (2) the shifts applied for treatment based on CBCT verification. The daily doses are deformed and accumulated onto the planning CT using commercially available deformable image registration software. The dose distribution is compared to the original distribution and tumor and PTV coverage is evaluated for both situations (initial and shifted positions). The deformation accuracy is evaluated by calculating the change in centroid location and the Dice coefficient of deformed contours. RESULTS: The tumor bed is adequately covered regardless of the treatment position. The average dose received by 98% (D98) of the tumor bed volume differs from the original plan by +1.6% and -0.2% for the shifted and initial positions respectively. However, when dose is accumulated in the initial setup position PTV coverage is lost; the average D98 for the PTV changes by -15.8% and -26.9% for the shifted and initial positions respectively. The average change in centroid location is 0.43 mm and 1.53 mm for the left and right lung contour respectively. The Dice coefficient for the left and right lung is 0.94 and 0.95 respectively. CONCLUSIONS: The margins used to define the PTV are sufficient to ensure tumor bed coverage for the given positioning variability. We are also confident in the deformation used to deform and accumulate dose based on deformed contour comparison. Hardware provided by MIM Software Inc.

ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin.

The ATP-binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL-C level, in a gene-dose-dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL-C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.

Monte Carlo study of LDR seed dosimetry with an application in a clinical brachytherapy breast implant.

A Monte Carlo (MC) study was carried out to evaluate the effects of the interseed attenuation and the tissue composition for two models of 125I low dose rate (LDR) brachytherapy seeds (Medi-Physics 6711, IBt InterSource) in a permanent breast implant. The effect of the tissue composition was investigated because the breast localization presents heterogeneities such as glandular and adipose tissue surrounded by air, lungs, and ribs. The absolute MC dose calculations were benchmarked by comparison to the absolute dose obtained from experimental results. Before modeling a clinical case of an implant in heterogeneous breast, the effects of the tissue composition and the interseed attenuation were studied in homogeneous phantoms. To investigate the tissue composition effect, the dose along the transverse axis of the two seed models were calculated and compared in different materials. For each seed model, three seeds sharing the same transverse axis were simulated to evaluate the interseed effect in water as a function of the distance from the seed. A clinical study of a permanent breast 125I implant for a single patient was carried out using four dose calculation techniques: (1) A TG-43 based calculation, (2) a full MC simulation with realistic tissues and seed models, (3) a MC simulation in water and modeled seeds, and (4) a MC simulation without modeling the seed geometry but with realistic tissues. In the latter, a phase space file corresponding to the particles emitted from the external surface of the seed is used at each seed location. The results were compared by calculating the relevant clinical metrics V85, V100, and V200 for this kind of treatment in the target. D90 and D50 were also determined to evaluate the differences in dose and compare the results to the studies published for permanent prostate seed implants in literature. The experimental results are in agreement with the MC absolute doses (within 5% for EBT Gafchromic film and within 7% for TLD-100). Important differences between the dose along the transverse axis of the seed in water and in adipose tissue are obtained (10% at 3.5 cm). The comparisons between the full MC and the TG-43 calculations show that there are no significant differences for V85 and V100. For V200, 8.4% difference is found coming mainly from the tissue composition effect. Larger differences (about 10.5% for the model 6711 seed and about 13% for the InterSource125) are determined for D90 and D50. These differences depend on the composition of the breast tissue modeled in the simulation. A variation in percentage by mass of the mammary gland and adipose tissue can cause important differences in the clinical dose metrics V200, D90, and D50. Even if the authors can conclude that clinically, the differences in V85, V100, and V200 are acceptable in comparison to the large variation in dose in the treated volume, this work demonstrates that the development of a MC treatment planning system for LDR brachytherapy will improve the dose determination in the treated region and consequently the dose-outcome relationship, especially for the skin toxicity.

Sci-Sat AM(2): Brachy-08: Monte Carlo calculations of 192Ir high dose rate brachytherapy treatment plans using CT and cone beam CT images.

The feasibility of using cone beam computed tomography (CBCT) images for Monte Carlo (MC) brachytherapy dose calculations has been investigated. To evaluate the effects of tissue heterogeneities and finite patient dimensions for 192Ir high dose rate treatment, CT-based MC calculations for breast and head and neck cases were first performed using the PTRAN_CT photon transport code. PTRAN_CT is an accelerated MC code specifically designed for patient-specific dose calculations. Muscles and adipose tissues, which are nearly indistinguishable in CBCT images, are found to cause minimal dose perturbations at 192Ir energies compared to water. The proximity of the tumor to the skin, however, will have an observable impact on the dose up to a few percent. Therefore, for CBCT calculations, a reasonable assignment of material and density values to the patient voxel geometry, with a good delineation of the skin and bony structures, will suffice for MC dose calculations. A CBCT-based calculation for an actual treatment plan with the tumor close to the cheek was performed. The results were compared to TG43 calculations to quantify the dose differences in the target and critical structures. Since the dose delivered to the tumor is mostly primary dose, deviations are found mostly in the organs at risk where scatter contribution becomes more significant. This study shows that for HDR brachytherapy applications, CBCT-based MC calculations is a feasible option despite inferior image quality and larger uncertainties in the Hounsfield Units compared to CT images. Research supported by Nucletron BV.

Sci-Sat AM(2): Brachy-05: Dosimetry effects of the TG-43 approximations for two iodine seeds in LDR brachytherapy.

PURPOSES: This work consists of studying the interseed and tissue composition effects for two model iodine seeds: the IBt Interseed-125 and the 6711 model seed. MATERIALS & METHODS: Three seeds were modeled with the MCNP MC code in a water sphere to evaluate the interseed effect. The dose calculated at different distances from the centre was compared to the dose summed when the seeds were simulated separately. The tissue composition effect was studied calculating the radial dose function for different tissues. Before carrying out post-implant studies, the absolute dose calculated by MC was compared to experiment results: with LiF TLDs in an acrylic breast phantom and with an EBT Gafchromic film placed in a water tank. Afterwards, the TG-43 approximation effects were studied for a prostate and breast post-implant. RESULTS AND DISCUSSION: The interseed effect study shows that this effect is more important for model 6711 (15%) than for IBt (10%) due to the silver rod in 6711. For both seed models the variations of the radial dose function as a function of the tissue composition are quasi similar. The absolute dose comparisons between MC calculations and experiments give good agreement (inferior to 3% in general). For the prostate and breast post-implant studies, a 10% difference between MC calculations and the TG-43 is found for both models of seeds. CONCLUSION: This study shows that the differences in dose distributions between TG43 and MC are quite similar for the two models of seeds and are about 10% for the studied post-implant treatments.

Sci-Sat AM(2): Brachy-04: Spectral and dosimetric study of the Xoft electronic brachytherapy system.

The Axxent developed by Xoft Inc. is a miniature x-ray tube capable of generating a 50 kVp x-ray spectrum with dose-rates suitable for HDR applications. Results of spectral measurements compared with Geant4 Monte Carlo simulations have been published. This study is a continuation of previous work with shifting emphasis towards dosimetric characterization of the miniature x-ray tube. Dose distributions using EBT Gafchromic films agree to within 10 % of Geant4 results. In addition, TG-43 parameters can be calculated. However, consideration should be given to the biological effectiveness of the spectrum at different depths. Spectral measurements show significant beam hardening with 1st HVL increasing from 0.55 to 1.20 mm Al after 11.50 mm of water filtration. This effect may be attributed to the significant loss of low energy characteristic photons. Furthermore, the degree of beam hardening is dependent of the material, with 1st HVLs of 1.20 and 1.03 mm Al after 11.50 mm of water and Lucite respectively. The biological effect is quantified by calculating the number of single and double strand breaks. The number of strand breaks for the 50 kVp x-ray spectrum is similar to that of I-125 radiation.

Primary care physician attitudes concerning follow-up of abnormal test results and ambulatory decision support systems.

OBJECTIVES: Failures to follow-up abnormal test results are common in ambulatory care. Information systems could assist providers with abnormal test result tracking, yet little is known about primary care providers attitudes toward outpatient decision support systems. METHODS: A cross-sectional survey of 216 primary care physicians (PCPs) that utilize a single electronic medical record (EMR) without computer-based clinical decision support. RESULTS: The overall response rate was 65% (140/216). Less than one-third of the respondents were satisfied with their current system to manage abnormal laboratory, radiographs, Pap smear, or mammograms results. Only 15% of providers were satisfied with their system to notify patients of abnormal results. Over 90% of respondents felt automated systems to track abnormal test results would be useful. Seventy-nine percent of our respondents believed that they could comply better with guidelines through electronic clinical reminders. CONCLUSIONS: Most PCPs were not satisfied with their methods for tracking abnormal results. Respondents believed that clinical decision support systems (CDSS) would be useful and could improve their ability to track abnormal results.

Scanned continuous wave CO2 laser resurfacing: a closer look at the different scanning modes.

BACKGROUND: The immediate effects of CO2 laser resurfacing include tissue ablation and residual thermal damage. These laser-tissue interactions are shaped by parameters including fluence, dwell time, and number of passes. OBJECTIVE: To assess the vaporization depth and residual thermal damage following use of the "superficial" or "deep" scanning modes of a 40 W continuous wave CO2 laser using both frozen and paraffin sections. METHODS: Fourteen subjects were divided into two groups for test treatments in the right preauricular area with two passes of the laser. The "superficial" mode parameters were 10 mm2 scan, 200 mm lens, power 36 W, scan time 0.24 seconds, dwell time 0.22 msec, and fluence 5.5 J/cm2. The "deep" mode settings were 9 mm2 scan, 200 mm lens, power 18 W, scan time 0.64 seconds, dwell time 0.28 msec, and fluence 7.0 J/cm2. The deep mode has a greater pattern density than the superficial mode and also has a double pattern of exposure. Biopsies encompassing equal areas of treated and untreated skin were taken immediately postoperatively and processed with both frozen and paraffin-embedded techniques. RESULTS: Vaporization depth was similar in both scanning modes and by both tissue-processing techniques. On frozen sections, residual thermal damage was 20% greater in the deep mode than the superficial mode, but this was not a statistically significant difference. There was no significant difference between the two modes in the depth of thermal injury on paraffin sections. CONCLUSION: In keeping with theoretical expectations, vaporization depth was similar in both treatment groups. No significant difference in residual thermal damage could be demonstrated between the two modes. However, the results on frozen sections suggest that residual thermal damage may be greater in the deep mode than in the superficial mode. In addition, frozen sections may be more sensitive than paraffin sections in the detection of residual thermal damage following laser resurfacing.

Cutaneous spectrum of coeliac disease.

Coeliac disease is characterized by gluten intolerance and immunologically mediated damage to small intestinal mucosa. Patients classically present with gastrointestinal symptoms including chronic diarrhoea, steatorrhoea, weight loss, anorexia and abdominal distension. In a substantial proportion of cases however, gastrointestinal symptoms are minor or absent, and cutaneous manifestations may provide an early clue to diagnosis. Early recognition of coeliac disease, with appropriate implementation of a gluten-free diet, may reduce the incidence of benign and malignant complications associated with this condition.

Circumferential fingernail.

We describe a Brazilian girl with a congenital circumferential nail on her left ring finger associated with other bony and soft tissue abnormalities of the affected limb. The tubular nail plate resembling a punch biopsy has been described as a circumferential nail, an extremely rare congenital malformation that can be associated with other congenital anomalies. In our review of the literature, there have only been two previous reports of this unusual condition affecting the fingernails.

Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies.

BACKGROUND: Previous studies defining the histopathologic features of patients with chronic idiopathic urticaria (CIU) were performed on wheals of uncertain duration and before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU. OBJECTIVE: We sought to determine the timing of the inflammatory infiltrate in the wheals of patients with CIU and to detect differences between patients with and without autoantibodies. METHODS: Immunohistochemistry was used to identify neutrophils (neutrophil elastase), T lymphocytes (CD3), and activated eosinophils (EG2) in biopsy specimens from uninvolved skin and wheals present for less than 4 hours and greater than 12 hours in 22 patients with CIU, as well as in biopsy specimens from the skin of 12 healthy control subjects. Patients were identified as having functional autoantibodies on the basis of their serum-evoked histamine release in vitro from the basophils of 2 healthy donors. RESULTS: EG2(+), neutrophil elastase+, and, to a lesser extent, CD3(+) cells were found in greater numbers in wheals undergoing biopsy at less than 4 and greater than 12 hours than in uninvolved skin (P <.05). Patients without autoantibodies (n = 12) had significantly more EG2(+) cells in wheals of greater than 12 hours' duration than patients with autoantibodies (n = 10; P =.02). There was no other difference between patients with and without autoantibodies in the cutaneous cellular infiltrate. CONCLUSION: Neutrophil and eosinophil accumulation occurs early in the evolution of a wheal in patients with CIU, but eosinophil activation may occur later or be more persistent in patients without autoantibodies.

The amino-terminal C/H1 domain of CREB binding protein mediates zta transcriptional activation of latent Epstein-Barr virus.

Latent Epstein-Barr virus (EBV) is maintained as a nucleosome-covered episome that can be transcriptionally activated by overexpression of the viral immediate-early protein, Zta. We show here that reactivation of latent EBV by Zta can be significantly enhanced by coexpression of the cellular coactivators CREB binding protein (CBP) and p300. A stable complex containing both Zta and CBP could be isolated from lytically stimulated, but not latently infected RAJI nuclear extracts. Zta-mediated viral reactivation and transcriptional activation were both significantly inhibited by coexpression of the E1A 12S protein but not by an N-terminal deletion mutation of E1A (E1ADelta2-36), which fails to bind CBP. Zta bound directly to two related cysteine- and histidine-rich domains of CBP, referred to as C/H1 and C/H3. These domains both interacted specifically with the transcriptional activation domain of Zta in an electrophoretic mobility shift assay. Interestingly, we found that the C/H3 domain was a potent dominant negative inhibitor of Zta transcriptional activation function. In contrast, an amino-terminal fragment containing the C/H1 domain was sufficient for coactivation of Zta transcription and viral reactivation function. Thus, CBP can stimulate the transcription of latent EBV in a histone acetyltransferase-independent manner mediated by the CBP amino-terminal C/H1-containing domain. We propose that CBP may regulate aspects of EBV latency and reactivation by integrating cellular signals mediated by competitive interactions between C/H1, C/H3, and the Zta activation domain.