Genomic Organization of Zebrafish microRNAs

<p>Abstract</p> <p>Background</p> <p>microRNAs (miRNAs) are small (~22 nt) non-coding RNAs that regulate cell movement, specification, and development. Expression of miRNAs is highly regulated, both spatially and temporally. Based on direct cloning, sequence conservation, and predicted secondary structures, a large number of miRNAs have been identified in higher eukaryotic genomes but whether these RNAs are simply a subset of a much larger number of noncoding RNA families is unknown. This is especially true in zebrafish where genome sequencing and annotation is not yet complete.</p> <p>Results</p> <p>We analyzed the zebrafish genome to identify the number and location of proven and predicted miRNAs resulting in the identification of 35 new miRNAs. We then grouped all 415 zebrafish miRNAs into families based on seed sequence identity as a means to identify possible functional redundancy. Based on genomic location and expression analysis, we also identified those miRNAs that are likely to be encoded as part of polycistronic transcripts. Lastly, as a resource, we compiled existing zebrafish miRNA expression data and, where possible, listed all experimentally proven mRNA targets.</p> <p>Conclusion</p> <p>Current analysis indicates the zebrafish genome encodes 415 miRNAs which can be grouped into 44 families. The largest of these families (the miR-430 family) contains 72 members largely clustered in two main locations along chromosome 4. Thus far, most zebrafish miRNAs exhibit tissue specific patterns of expression.</p

The Value of the History and Physical for Patients with Newly Diagnosed Brain Metastases Considering Radiosurgery

Background: For patients with brain metastases, systemic disease burden has historically been accepted as a major determinant of overall survival (OS). However, less research has focused on specific history and physical findings made by clinicians and how such findings pertain to patient outcomes at a given time point. The aim of this study is to determine how the initial clinical assessment of patients with brain metastases, as part of the history and physical at the time of consultation, correlates with patient prognosis.Methods: We evaluated a prospective, multi-institutional database of 1523 brain metastases in 507 patients who were treated with radiosurgery (Gamma Knife or CyberKnife) from 2001-2014. Relevant history of present illness (HPI) and past medical history (PMH) variables included comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, and seizure history. Physical exam findings included a sensory exam, motor exam, and cognitive function. Univariate and multivariate Cox regression analyses were used to identify predictors of OS.Results: 294 patients were included in the final analysis with a median OS of 10.8 months (95% C.I., 7.8-13.7 months). On univariate analysis, significant HPI predictors of OS included age, primary diagnosis, performance status, extracranial metastases, systemic disease status, and history of surgery. Significant predictors of OS from the PMH included cardiac, vascular, and infectious comorbidities. On a physical exam, findings consistent with cognitive deficits were predictive of worse OS. However, motor deficits or changes in vision were not predictive of worse OS. In the multivariate Cox regression analysis, predictors of worse OS were primary diagnosis (p=0.002), ECOG performance status (OR 1.73, p<0.001), and presence of extracranial metastases (OR 1.22, p=0.009).Conclusion: Neurologic deficits and systemic comorbidities noted at presentation are not associated with worse overall prognosis for patients with brain metastases undergoing radiosurgery. When encountering new patients with brain metastases, the most informative patient-related characteristics that determine prognosis remain performance status, primary diagnosis, and extent of extracranial disease

PROCTITIS ONE WEEK AFTER STEREOTACTIC BODY RADIATION THERAPY FOR PROSTATE CANCER: IMPLICATIONS FOR CLINICAL TRIAL DESIGN

Background: Proctitis following prostate cancer radiation therapy is a primary determinant of quality of life (QOL). While previous studies have assessed acute rectal morbidity at 1 month after stereotactic body radiotherapy (SBRT), little data exist on the prevalence and severity of rectal morbidity within the first week following treatment. This study reports the acute bowel morbidity one week following prostate SBRT. Materials and methods: Between May 2013 and August 2014, 103 patients with clinically localized prostate cancer were treated with 35 to 36.25 Gy in five fractions using robotic SBRT delivered on a prospective clinical trial. Bowel toxicity was graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv.4). Bowel QOL was assessed using EPIC-26 questionnaire bowel domain at baseline, one week, one month, and three months. Time-dependent changes in bowel symptoms were statistically compared using the Wilcoxon signed-rank test. Clinically significant change was assessed by the minimally important difference (MID) in EPIC score. This was defined as a change of one-half standard deviation (SD) from the baseline score. Results: One hundred and three patients with a minimum of three months of follow-up were analyzed. The cumulative incidence of acute grade 2 GI toxicity was 23%. There were no acute ≥ grade 3 bowel toxicities. EPIC bowel summary scores maximally declined at 1 week after SBRT (-13.9, p<0.0001) before returning to baseline at three months after SBRT (+0.03, p=0.94). Prior to treatment, 4.9% of men reported that their bowel bother was a moderate to big problem. This increased to 28.4% (p<0.0001) one week after SBRT and returned to baseline at three months after SBRT (0.0%, p=0.66). Only the bowel summary and bowel bother score declines at 1 week met the MID threshold for clinically significant change. Conclusion: The rate and severity of acute proctitis following prostate SBRT peaked at one week after treatment and returned to baseline by 3 months. Toxicity assessment at one week can therefore minimize recall bias and should aid in the design of future clinical trials focused on accurately capturing and minimizing acute morbidity following SBRT

Multi-institutional Analysis of Vaginal Brachytherapy Alone for Women With Stage II Endometrial Carcinoma

PURPOSE: To investigate the survival endpoints in women with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer who received adjuvant vaginal brachytherapy (VBT) alone using multi-institutional pooled data. METHODS AND MATERIALS: We performed a multi-institutional analysis of surgically staged patients with FIGO stage II endometrioid-type endometrial cancer treated with VBT alone. Patient, tumor, and treatment characteristics were collected and analyzed. Univariable and multivariable frailty survival models were performed to assess clinicopathologic risk factors for recurrence and death. RESULTS: One hundred six patients were included (92 VBT alone and 14 VBT with chemotherapy) with median follow-up of 39.0 months. Pelvic node dissection was performed in 89.6% of patients. One hundred four patients (98.1%) and 2 patients (1.9%) had microscopic and macroscopic cervical stromal invasion, respectively. Grade 1 or 2 disease occurred in 88.6% of patients. For patients treated with VBT without chemotherapy, the 5-year estimates of vaginal failure, pelvic nodal failure, and distant metastases were 2.6%, 4.2%, and 7.2%, respectively. Five-year progression-free survival and overall survival were 74.0% and 76.2%, respectively. On univariable and multivariable models for progression-free survival, increasing age and lack of pelvic node resection were hazardous (P \u3c .05). CONCLUSIONS: Vaginal and pelvic failure rates were low in this selected population of stage II patients receiving adjuvant VBT without external beam radiation therapy. It is reasonable to consider adjuvant VBT alone in selected patients with grade 1 or 2 disease and microscopic cervical stromal invasion who underwent pelvic lymphadenectomy

Multi-institutional analysis of vaginal brachytherapy without external beam radiation therapy for stage II endometrial cancer patients.

Purpose/Objective(s): Vaginal brachytherapy (VBT) and external beam radiotherapy (EBRT) improve locoregional recurrence for Stage I endometrial cancer, and risk factors for recurrence have been previously described. Limited data exist for the use of VBT without EBRT for Stage II patients. The aim of this study is to perform a multi-institutional analysis of Stage II endometrial cancer patients treated with VBT alone without EBRT. Purpose/Objective(s): We analyzed patients with stage II endometrial cancer treated with VBT without EBRT at five institutions. All patients had cervical stromal invasion concordant with 2009 FIGO staging. Univariate and multivariable frailty survival models that allow for clustering of patients within their study site were performed to assess clinicopathologic risk factors for recurrence and death. Results: One hundred seven patients met inclusion criteria with median follow-up of 57.9 (95% CI: 51.5-70.4) months. Median age was 61 years (range 42-89 years). Endometrioid, serous (USC), clear cell (CCC), and carcinosarcoma (CS) histologies comprised 83.2%, 11.2%, 4.7%, and 0.9%, respectively. Lymphovascular invasion (LVI) was present in 36.2% of patients. Pelvic and para-aortic node dissections were performed in 87.8% and 54.2%, respectively. Chemotherapy was delivered in 28.2% of patients. Seventy-seven patients had endometrioid type treated with VBT only without chemotherapy. The crude rates of vaginal failure, non-vaginal pelvic failure, and distant metastasis were 2.6%, 3.9%, and 6.5%, respectively. Thirty patients had USC/CCC/CS histologies and/or were treated with chemotherapy. These patients had vaginal failure, non-vaginal pelvic failure, and distant metastasis of 0%, 10.0%, and 20.0%, respectively. For the entire cohort, the 3-year estimate of vaginal failure, non-vaginal pelvic failure, and distant metastasis was 2.2%, 7.2%, and 7.4%, respectively. On UVA for distant metastasis, grade 3 (compared to grade 1) trended toward hazardous with HR 5.59 (95% CI: 0.83-37.55, P =.08). Three-year survival for the entire cohort was 85.9%. On UVA for survival, USC histology was the greatest predictor of death with HR 2.78 (95% CI: 1.06-7.14, P =.03) compared to endometrioid type. There was no difference in survival between CCC and endometrioid type (P = 0.18). Presence of LVI trended toward increased risk of death with HR 2.16 (95% CI: 0.97-4.17, P = 0.06). On UVA and MVA, receipt of chemotherapy trended toward hazard for death (95% CI: 0.12-1.05, P = 0.06). Conclusion: This is the largest report of Stage II endometrial cancer patients treated with VBT without EBRT. Patients with Stage II endometrial cancer treated with VBT without EBRT, with favorable clinicopathologic features, have low rates of vaginal and pelvic failures. VBT without EBRT may be a reasonable adjuvant treatment option for appropriately selected patients. Patients with higher risk histologies, including those treated with chemotherapy, have a higher risk of pelvic and distant failure and require additional study for improved adjuvant therapy