Urinary Analysis of FGFR3 and TERT Gene Mutations Enhances Performance of Cxbladder Tests and Improves Patient Risk Stratification.

PURPOSE: Cxbladder tests are urinary biomarker tests for detection of urothelial carcinoma. We developed enhanced Cxbladder tests that incorporate DNA analysis of 6 single nucleotide polymorphisms for the FGFR3 and TERT genes, in addition to the current 5 mRNA biomarkers and clinical risk factors. MATERIALS AND METHODS: Two multicenter, prospective studies were undertaken in: (1) U.S. patients with gross hematuria aged ≥18 years and (2) Singaporean patients with gross hematuria or microhematuria aged >21 years. All patients provided a midstream urine sample and underwent cystoscopy. Samples were retrospectively analyzed using enhanced Cxbladder-Triage (risk stratifies patients), enhanced Cxbladder-Detect (risk stratifies patients and detects positive patients), and the combination enhanced Cxbladder-Triage × Cxbladder-Detect. RESULTS: In the pooled cohort (N=804; gross hematuria: n=484, microhematuria: n=320), enhanced Cxbladder-Detect had a sensitivity of 97% (95% CI 89%-100%), specificity of 90% (95% CI 88%-92%), and negative predictive value of 99.7% (95% CI 99%-100%) for detection of urothelial carcinoma. Overall, 83% of patients were enhanced Cxbladder-Detect-negative (ie, needed no further work-up). Of 133 enhanced Cxbladder-Detect-positive patients, 59 had a confirmed tumor, of which 19 were low-grade noninvasive papillary carcinoma or papillary urothelial neoplasm of low malignant potential. In total, 40 tumors were high-grade Ta, T1-T4, Tis, including concomitant carcinoma in situ. Of the 74 patients with normal cystoscopy, 41 were positive by single nucleotide polymorphism analysis. Enhanced Cxbladder-Triage and enhanced Cxbladder-Detect had significantly better specificity than the first-generation Cxbladder tests (P < .001). CONCLUSIONS: This study in ethnically diverse patients with hematuria showed the analytical validity of the enhanced Cxbladder tests.

Five-year outcomes of an anterior mesh kit for severe pelvic organ prolapse in women.

AIMS: The Elevate™ Anterior mesh was designed to correct anterior vaginal wall defects by providing level 1 and 2 support via a single incision and transvaginal approach. This study aimed to examine the objective and subjective outcomes following prolapse repair using the Elevate™ Anterior mesh kit. METHODS: A retrospective case series review of 270 patients with Baden-Walker Grades 3 or 4 anterior compartment prolapse who underwent the Elevate™ Anterior mesh kit was undertaken. Operative complications were recorded with follow-up intervals arranged at 1, 6, 12, 24, 36, 48 and 60 months. A standardized questionnaire directed at urinary, pain and recurrence symptoms was used at each follow-up visit. Pelvic examinations were performed at each follow-up visit to assess for objective cure and for detection of complications. The primary outcome was to assess the cure rate defined as anterior vaginal wall prolapse ≤ Grade 1. RESULTS: The follow-up rate was 28.9%. Subjective and objective cure rates at 60 months were 100% and 96.2%, respectively. Ten (3.7%) intraoperative complications were recorded. At 60 months, three (3.8%) patients complained of de novo stress/urge urinary incontinence. One patient had dyspareunia at 6 months postsurgery which resolved by the end of 1 year. Prolapse recurrences in the anterior compartment was 3.8% at the end of 5 years. Mesh exposure into the vagina occurred in three patients. CONCLUSIONS: In conclusion, our experience with the Elevate™ Anterior mesh kit had promising subjective and objective outcomes with high patient satisfaction rates.

Roles of Plant Growth-Promoting Rhizobacteria (PGPR) in Stimulating Salinity Stress Defense in Plants: A Review.

To date, soil salinity becomes a huge obstacle for food production worldwide since salt stress is one of the major factors limiting agricultural productivity. It is estimated that a significant loss of crops (20-50%) would be due to drought and salinity. To embark upon this harsh situation, numerous strategies such as plant breeding, plant genetic engineering, and a large variety of agricultural practices including the applications of plant growth-promoting rhizobacteria (PGPR) and seed biopriming technique have been developed to improve plant defense system against salt stress, resulting in higher crop yields to meet human's increasing food demand in the future. In the present review, we update and discuss the advantageous roles of beneficial PGPR as green bioinoculants in mitigating the burden of high saline conditions on morphological parameters and on physio-biochemical attributes of plant crops via diverse mechanisms. In addition, the applications of PGPR as a useful tool in seed biopriming technique are also updated and discussed since this approach exhibits promising potentials in improving seed vigor, rapid seed germination, and seedling growth uniformity. Furthermore, the controversial findings regarding the fluctuation of antioxidants and osmolytes in PGPR-treated plants are also pointed out and discussed.

Improved clinical outcome and biomarkers in adults with papulopustular rosacea treated with doxycycline modified-release capsules in a randomized trial.

BACKGROUND: Patients with rosacea have increased amounts of cathelicidin and protease activity but their usefulness as disease biomarkers is unclear. OBJECTIVE: We sought to evaluate the effect of doxycycline treatment on cathelicidin expression, protease activity, and clinical response in rosacea. METHODS: In all, 170 adults with papulopustular rosacea were treated for 12 weeks with doxycycline 40-mg modified-release capsules or placebo in a multicenter, randomized, double-blind, placebo-controlled study. Clinical response was compared with cathelicidin and protease activity in stratum corneum samples obtained by tape strip and in skin biopsy specimens obtained from a random subset of patients. RESULTS: Treatment with doxycycline significantly reduced inflammatory lesions and improved investigator global assessment scores compared with placebo. Cathelicidin expression and protein levels decreased over the course of 12 weeks in patients treated with doxycycline. Low levels of protease activity and cathelicidin expression at 12 weeks correlated with treatment success. Low protease activity at baseline was a predictor of clinical response in the doxycycline treatment group. LIMITATIONS: Healthy control subjects were not studied. CONCLUSIONS: Improved clinical outcome correlated with reduced cathelicidin and protease activity, supporting both the mechanism of doxycycline and the potential of these molecules as biomarkers for rosacea.

Conversion of Escherichia coli into Mixotrophic CO2 Assimilation with Malate and Hydrogen Based on Recombinant Expression of 2-Oxoglutarate:Ferredoxin Oxidoreductase Using Adaptive Laboratory Evolution.

We report the mixotrophic growth of Escherichia coli based on recombinant 2-oxoglutarate:ferredoxin oxidoreductase (OGOR) to assimilate CO2 using malate as an auxiliary carbon source and hydrogen as an energy source. We employ a long-term (~184 days) two-stage adaptive evolution to convert heterotrophic E. coli into mixotrophic E. coli. In the first stage of evolution with serine, diauxic growth emerges as a prominent feature. At the end of the second stage of evolution with malate, the strain exhibits mixotrophy with CO2 as an essential substrate for growth. We expect this work will open new possibilities in the utilization of OGOR for microbial CO2 assimilation and future hydrogen-based electro-microbial conversion.

Valorization of soybean pulp for sustainable α-ketoisocaproate production using engineered Bacillus subtilis whole-cell biocatalyst.

The disposal of soybean pulp (okara) (∼14 M tons annually) represents a global concern. α-ketoisocaproate (KIC) is an intrinsic l-leucine metabolite boosting mammalian muscle growth and has great potential in animal husbandry. However, the use of pure l-leucine (5000 USD/kg) for KIC (22 USD/kg) bioproduction is cost-prohibitive in practice, while okara rich in l-leucine (10%) could serve as an economical alternative. Following the concept of a circular bioeconomy, we managed to develop a cost-efficient platform to valorize okara into KIC. In this study, proteolytic Bacillus subtilis strain 168 capable of utilizing okara as a comprehensive substrate was employed as the whole-cell biocatalyst for KIC bioproduction. First, we elucidated the function of genes involved in KIC downstream metabolism in strain 168, including those encoding 2-oxoisovalerate dehydrogenase (bkdAA), 2-oxoisovalerate decarboxylase (bkdAB), enoyl-CoA hydratase (fadB), and bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (fadN). Among those KIC downstream metabolizing mutants of strain 168, the 2-oxoisovalerate decarboxylase gene knockout strain (ΔbkdAB) was found to have a better accumulation of KIC. To further improve the KIC yield, a soluble l-amino acid deaminase (LAAD) from Proteus vulgaris was heterologously expressed in the ΔbkdAB strain and a ∼50% conversion of total l-leucine contained in okara was catalyzed into KIC, along with a ∼50% reduction of CO2 emission compared to the wild-type cultures. Altogether, this renovated biocatalytic system provides an alternative platform to valorize okara for producing value-added chemicals in an eco-friendly manner.

A domain in the herpes simplex virus 1 triplex protein VP23 is essential for closure of capsid shells into icosahedral structures.

VP23 is a key component of the triplex structure. The triplex, which is unique to herpesviruses, is a complex of three proteins, two molecules of VP23 which interact with a single molecule of VP19C. This structure is important for shell accretion and stability of the protein coat. Previous studies utilized a random transposition mutagenesis approach to identify functional domains of the triplex proteins. In this study, we expand on those findings to determine the key amino acids of VP23 that are required for triplex formation. Using alanine-scanning mutagenesis, we have made mutations in 79 of 318 residues of the VP23 polypeptide. These mutations were screened for function both in the yeast two-hybrid assay for interaction with VP19C and in a genetic complementation assay for the ability to support the replication of a VP23 null mutant virus. These assays identified a number of amino acids that, when altered, abolish VP23 function. Abrogation of virus assembly by a single-amino-acid change bodes well for future development of small-molecule inhibitors of this process. In addition, a number of mutations which localized to a C-terminal region of VP23 (amino acids 205 to 241) were still able to interact with VP19C but were lethal for virus replication when introduced into the herpes simplex virus 1 (HSV-1) KOS genome. The phenotype of many of these mutant viruses was the accumulation of large open capsid shells. This is the first demonstration of capsid shell accumulation in the presence of a lethal VP23 mutation. These data thus identify a new domain of VP23 that is required for or regulates capsid shell closure during virus assembly.

A multicenter, randomized, vehicle-controlled phase 2 study of blue light photodynamic therapy with aminolevulinic acid HCl 20% topical solution for the treatment of actinic keratoses on the upper extremities: the effect of occlusion during the drug incubation period.

BACKGROUND: Photodynamic therapy (PDT) with aminolevulinic acid (ALA) has been shown to be safe and effective in the treatment of actinic keratoses (AKs) of the face and scalp. A recent small study has suggested that ALA-PDT can be effective for AKs of the dorsal hands/forearms. However, studies designed to provide sufficient statistical power to test this hypothesis are lacking in the literature. OBJECTIVES: To determine and compare the safety and efficacy of blue light ALA-PDT vs blue light placebo vehicle (VEH) in the treatment of AKs of the upper extremities and to evaluate the effect of occlusion after application of ALA vs VEH. METHODS: ALA or VEH was applied to both dorsal hands/forearms for the 3-hour incubation period before blue light treatment (10 J/ cm2). One extremity of each subject was covered with occlusive dressing during the incubation period. Treatment was repeated at week 8 if any AK lesions remained. RESULTS: The median AK lesion clearance rate at week 12 was 88.7% for extremities treated with occluded ALA (ALA+OCC), 70.0% for extremities treated with nonoccluded ALA, 16.7% for extremities treated with occluded VEH (VEH+OCC), and 5.6% for extremities treated with nonoccluded VEH (P<.0001). ALA+OCC resulted in a significantly higher clearance rate compared with the nonoccluded extremity at weeks 8 (P=.0006) and 12 (P=.0029). Thirty-four percent (12/35) of extremities treated with ALA+OCC had complete clearance of lesions at week 12 compared with 0% (0/35) of extremities treated with VEH+OCC (P=.0002). The safety pro!le in this study is consistent with previously reported side effects of the therapy. CONCLUSION: Blue light ALA-PDT following a 3-hour incubation appears efficacious for AK clearance of the upper extremities. Incubation using an occlusive dressing significantly increases the efficacy of the procedure and also increases the incidence and severity of some acute inflammatory side effects of PDT.

Nausea, Vomiting, and Dyspepsia Following Solid Organ Abdominal Transplant.

Background and objective Multiple comorbidities may contribute to high readmission rates post-transplant procedures. In this study, we aimed to assess the rates and factors associated with hospital readmissions for dyspeptic symptoms among transplant patients. Methods This was a retrospective analysis of adult patients who underwent solid organ transplants at our institution. Pregnant patients or those patients with preexisting gastroparesis were excluded from the study. Readmissions associated with the International Classification of Diseases (ICD) codes for nausea/vomiting, weight loss, failure to thrive, abdominal pain, and/or bloating were included. Factors associated with 30-day and frequent readmissions (two or more) were explored. Results A total of 931 patients with solid organ transplants were included; 54% had undergone kidney transplants while 34% were liver transplants. Of note, 30% were readmitted within the first 30 days after discharge following transplant while 32.3% had frequent readmissions. A post-transplant upper endoscopy (EGD) was performed in 34% with food residue discovered in 19% suggesting gastroparesis. However, since only 22% of these patients had a gastric emptying study, only 6% were formally diagnosed with gastroparesis, which was independently associated with both 30-day [odds ratios (OR): 2.58, 95% confidence intervals (CI): 1.42-4.69] and frequent readmissions (OR: 6.71, 95% CI: 3.45-13.10). The presence of pre-transplant diabetes (35%) was significantly associated with a diagnosis of gastroparesis following transplant (OR: 5.17, 95% CI: 2.79-9.57). The use of belatacept (OR: 0.63, 95% CI: 0.42-0.94, p=0.023) was associated with a decrease in the odds of 30-day readmissions. Conclusion A significant number of patients were readmitted due to dyspeptic symptoms after solid organ transplants. Diabetes and gastroparesis were significantly associated with higher odds of readmissions while the use of belatacept appeared to be a protective factor.

Classification of ipsilateral breast tumor recurrences after breast conservation therapy can predict patient prognosis and facilitate treatment planning.

OBJECTIVE: To classify ipsilateral breast tumor recurrences (IBTR) as either new primary tumors (NP) or true local recurrence (TR). We utilized 2 different methods and compared sensitivities and specificities between them. Our goal was to determine whether distinguishing NP from TR had prognostic value. BACKGROUND: After breast-conservation therapy, IBTR may be classified into 2 distinct types (NP and TR). Studies have attempted to classify IBTR by using tumor location, histologic subtype, DNA flow cytometry data, or gene-expression profiling data. METHODS: A total of 447 (7.9%) of 5660 patients undergoing breast-conservation therapy from 1970 to 2005 experienced IBTR. Clinical data from 397 patients were available for review. We classified IBTRs as NP or TR on the basis of either tumor location and histologic subtype (method 1) or tumor location, histologic subtype, estrogen receptor status and human epidermal growth factor receptor 2 status (method 2). Kaplan-Meier curves and log-rank tests were used to evaluate overall and disease-specific survival differences between the 2 groups. Classification methods were validated by calculating sensitivity and specificity values using a Bayesian method. RESULTS: Of 397 patients, 196 (49.4%) were classified as NP by method 1 and 212 (53.4%) were classified as NP by method 2. The sensitivity and specificity values were 0.812 and 0.867 for method 1 and 0.870 and 0.800 for method 2, respectively. Regardless of method used, patients classified as NP developed contralateral breast carcinoma more often but had better 10-year overall and disease-specific survival rates than those classified as TR. Patients with TR were more likely to develop metastatic disease after IBTR. CONCLUSION: Ipsilateral breast tumor recurrences classified as TR and NP had clinically different features, suggesting that classifying IBTR may provide clinically significant data for the management of IBTR.

Twinning-mediated anomalous alignment of rutile films revealed by synchrotron X-ray nanodiffraction.

Nanotwin structures in materials engender fascinating exotic properties. However, twinning usually alter the crystal orientation, resulting in random orientation and limited performances. Here, we report a well-aligned rutile TiO2 nanotwin film with superior preferential orientation than its isostructural substrate. By means of the synchrotron X-ray Laue nanodiffraction technique, the crystal orientation, twin boundaries, and deviatoric stresses of the film were quantitatively imaged at unprecedented spatial resolution to unravel the underlying mechanism of this anomalous alignment. Massive {101}-type rutile nanotwins were observed, and a crystallographic relationship of the heteroepitaxy was proposed. The rapid twinning and twin-controlled heteroepitaxy are responsible for the texture improvement. This work would open up opportunities for rational design of better twin-based functional materials, and implies the powerful capabilities of X-ray nanodiffraction technique for multidisciplinary applications.

Construction of engineered RuBisCO Kluyveromyces marxianus for a dual microbial bioethanol production system.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) genes play important roles in CO2 fixation and redox balancing in photosynthetic bacteria. In the present study, the kefir yeast Kluyveromyces marxianus 4G5 was used as host for the transformation of form I and form II RubisCO genes derived from the nonsulfur purple bacterium Rhodopseudomonas palustris using the Promoter-based Gene Assembly and Simultaneous Overexpression (PGASO) method. Hungateiclostridium thermocellum ATCC 27405, a well-known bacterium for its efficient solubilization of recalcitrant lignocellulosic biomass, was used to degrade Napier grass and rice straw to generate soluble fermentable sugars. The resultant Napier grass and rice straw broths were used as growth media for the engineered K. marxianus. In the dual microbial system, H. thermocellum degraded the biomass feedstock to produce both C5 and C6 sugars. As the bacterium only used hexose sugars, the remaining pentose sugars could be metabolized by K. marxianus to produce ethanol. The transformant RubisCO K. marxianus strains grew well in hydrolyzed Napier grass and rice straw broths and produced bioethanol more efficiently than the wild type. Therefore, these engineered K. marxianus strains could be used with H. thermocellum in a bacterium-yeast coculture system for ethanol production directly from biomass feedstocks.

Biodegradation of dioxins by Burkholderia cenocepacia strain 869T2: Role of 2-haloacid dehalogenase.

Dioxin compounds are persistent carcinogenic byproducts of anthropogenic activities such as waste combustion and other industrial activities. The ubiquitous distribution of dioxins is global concerns these days. Among of recent techniques, bioremediation, an eco-friendly and cost-effective technology, uses bacteria or fungi to detoxify in dioxins; however, not many bacteria can degrade the most toxic dioxin congener 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD). In this study, the endophytic bacterium Burkholderia cenocapacia 869T2 was capable of TCDD degradation by nearly 95 % after one-week of an aerobic incubation. Through transcriptomic analysis of the strain 869T2 at 6 -h and 12 -h TCDD exposure, a number of catabolic genes involved in dioxin metabolism were detected with high gene expressions in the presence of TCDD. The transcriptome data also indicated that B. cenocepacia strain 869T2 metabolized the dioxin compounds from an early phase (at 6 h) of the incubation, and the initial outline for a general dioxin degradation pathway were proposed. One of the catabolic genes, l-2-haloacid dehalogenase (2-HAD) was cloned to investigate its contribution in dioxin dehalogenation. By detecting the increasing concentration of chloride ions released from TCDD, our results indicated that the dehalogenase played a crucial role in dehalogenation of dioxin in the aerobic condition.

Pressure-dependent electronic structures in multiferroic DyMnO(3): A combined lifetime-broadening-suppressed x-ray absorption spectroscopy and ab initio electronic structure study.

Variations in the electronic structure and structural distortion in multiferroic DyMnO(3) were probed by synchrotron x-ray diffraction, lifetime-broadening-suppressed x-ray absorption spectroscopy (XAS), and ab initio electronic structure calculations. The refined x-ray diffraction data enabled an observation of a diminished local Jahn-Teller distortion of Mn sites within MnO(6) octahedra in DyMnO(3) on applying the hydrostatic pressure. The intensity of the white line in Mn K-edge x-ray absorption spectra of DyMnO(3) progressively increased with the increasing pressure. With the increasing hydrostatic pressure, the absorption threshold of an Mn K-edge spectra of DyMnO(3) shifted toward a greater energy, whereas the pre-edge line slightly shifted to a smaller energy. We provide the spectral evidence for the pressure-induced bandwidth broadening for manganites. The intensity enhancement of the white line in Mn K-edge spectra is attributed to a diminished Jahn-Teller distortion of MnO(6) octahedra in compressed DyMnO(3). A comparison of the pressure-dependent XAS spectra with the ab initio electronic structure calculations and full calculations of multiple scattering using the code FDMNES shows the satisfactory agreement between experimental and calculated Mn K-edge spectra.

Localization of herpes simplex virus type 1 UL37 in the Golgi complex requires UL36 but not capsid structures.

The herpes simplex virus type 1 (HSV-1) UL37 gene encodes a 120-kDa polypeptide which resides in the tegument structure of the virion and is important for morphogenesis. The goal of this study was to use green fluorescent protein (GFP) to follow the fate of UL37 within cells during the normal course of virus replication. GFP was inserted in frame at the C terminus of UL37 to generate a fluorescent-protein-tagged UL37 polypeptide. A virus designated K37eGFP, which replicated normally on Vero cells, was isolated and was shown to express the fusion polypeptide. When cells infected with this virus were examined by confocal microscopy, the fluorescence was observed to be predominantly cytoplasmic. As the infection progressed, fluorescence began to accumulate in a juxtanuclear structure. Mannosidase II and giantin were observed to colocalize with UL37eGFP at these structures, as judged by immunofluorescence assays. Therefore, UL37 traffics to the Golgi complex during infection. A VP26mRFP marker (red fluorescent protein fused to VP26) was recombined into K37eGFP, and when cells infected with this "dual-color" virus were examined, colocalization of the red (capsid) and green (UL37) fluorescence in the Golgi structure was observed. Null mutations in VP5 (DeltaVP5), which abolished capsid assembly, and in UL36 (Delta36) were recombined into the K37eGFP virus genome. In cells infected with K37eGFP/DeltaVP5, localization of UL37eGFP to the Golgi complex was similar to that for the parental virus (K37eGFP), indicating that trafficking of UL37eGFP to the Golgi complex did not require capsid structures. Confocal analysis of cells infected with K37eGFP/Delta36 showed that, in the absence of UL36, accumulation of UL37eGFP at the Golgi complex was not evident. This indicates an interaction between these two proteins that is important for localization of UL37 in the Golgi complex and thus possibly for cytoplasmic envelopment of the capsid. This is the first demonstration of a functional role for UL36:UL37 interaction in HSV-1-infected cells.

A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer.

BACKGROUND: CXCL12/CXCR4 signaling may be involved in tumor growth and angiogenesis, and homing of cancer cells to bone and other organs. Our purpose was to determine whether inhibition of CXCR4 with a peptide-based antagonist would reduce tumor growth and metastasis of breast cancer. METHODS: We used two mouse models of breast cancer. In the first model, 1 x 10(6) MDA-MB-231 breast cancer cells transfected with luciferase were implanted into the inguinal mammary fat pad to produce primary tumors. In the second model, 1 x 10(5) MDA-231-BSC12 cells were injected into the left cardiac ventricle to produce bone metastases. CTCE-9908, a peptide analog of CXCL12 that competitively binds to CXCR4, was used to test the effect of inhibiting CXCR4. Five mice from each mouse model were treated with CTCE-9908 (25 mg/kg, injected subcutaneously 5 d/wk). All mice were assessed weekly using bioluminescent imaging to quantify relative volumes of tumor burden. RESULTS: Bioluminescencent imaging showed that the mice treated with CTCE-9908 had significantly less primary tumor burden than the control mice. At 5 and 6 wk, the mice treated with CTCE-9908 had a 7-fold reduction and 5-fold reduction in primary tumor burden, respectively. Treatment with CTCE-9908 also significantly inhibited the rate of metastases compared with the control group. At 5 and 6 wk, the mice treated with CTCE-9908 demonstrated a 9-fold reduction and 20-fold reduction in metastatic tumor burden, respectively. CONCLUSION: Treatment with the CXCR4 antagonist CTCE-9908 significantly reduced metastasis as well as primary tumor growth in mouse models of breast cancer.

Better executive function is independently associated with full HIV suppression during combination therapy.

OBJECTIVE: HIV-associated neurocognitive impairment continues to be prevalent and clinically relevant. We examined the relationship between neurocognition and full plasma HIV RNA suppression among study participants over a 15-year period at a large research program. DESIGN/METHODS: We analyzed the combined prospective studies of the HIV Neurobehavioral Research Program at the University of California at San Diego. Participants were eligible for analysis if on three drug combination antiretroviral therapy with comprehensive neuropsychological testing results. Participants who reported recent nonadherence were excluded. The primary outcome was plasma HIV RNA of 50 copies/ml or less. Generalized estimating equation was used to assess for associations with full virologic suppression taking into account longitudinal visits. RESULTS: There were 1943 participants at baseline, of whom 69.4% had plasma HIV RNA of 50 copies/ml or less. Participants with full suppression were slightly older, less likely to abuse cocaine, and had significantly better executive function. Multivariate analysis with incorporation of longitudinal visits (total = 5555) confirmed current cocaine abuse to be strongly associated with lack of virologic suppression (odds ratio = 0.45, 95% confidence interval = 0.31-0.63). In contrast, increasing age, increasing years of HIV infection, and increasing executive function (odds ratio = 1.18 for T score change of 10, 95% confidence interval = 1.07-1.30) were associated with full virologic suppression. Lack of virologic suppression at baseline was associated with a significant subsequent decline in executive function. CONCLUSION: In a 15-year research cohort of almost 2000 HIV-infected individuals on combination antiretroviral therapy, better executive function was associated with full virologic suppression, possibly as a result rather than a cause.

Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer.

PURPOSE: To report the long-term results of a randomized radiotherapy dose escalation trial for prostate cancer. METHODS AND MATERIALS: From 1993 to 1998, a total of 301 patients with stage T1b to T3 prostate cancer were accrued to a randomized external beam dose escalation trial using 70 Gy versus 78 Gy. The median follow-up is now 8.7 years. Kaplan-Meier analysis was used to compute rates of prostate-specific antigen (PSA) failure (nadir + 2), clinical failure, distant metastasis, disease-specific, and overall survival as well as complication rates at 8 years post-treatment. RESULTS: For all patients, freedom from biochemical or clinical failure (FFF) was superior for the 78-Gy arm, 78%, as compared with 59% for the 70-Gy arm (p = 0.004, and an even greater benefit was seen in patients with initial PSA >10 ng/ml (78% vs. 39%, p = 0.001). The clinical failure rate was significantly reduced in the 78-Gy arm as well (7% vs. 15%, p = 0.014). Twice as many patients either died of prostate cancer or are currently alive with cancer in the 70-Gy arm. Gastrointestinal toxicity of grade 2 or greater occurred twice as often in the high dose patients (26% vs. 13%), although genitourinary toxicity of grade 2 or greater was less (13% vs. 8%) and not statistically significantly different. Dose-volume histogram analysis showed that the complication rate could be significantly decreased by reducing the amount of treated rectum. CONCLUSIONS: Modest escalation in radiotherapy dose improved freedom from biochemical and clinical progression with the largest benefit in prostate cancer patients with PSA >10 ng/ml.

ASTRO's 2007 core physics curriculum for radiation oncology residents.

In 2004, the American Society for Therapeutic Radiology and Oncology (ASTRO) published a curriculum for physics education. The document described a 54-hour course. In 2006, the committee reconvened to update the curriculum. The committee is composed of physicists and physicians from various residency program teaching institutions. Simultaneously, members have associations with the American Association of Physicists in Medicine, ASTRO, Association of Residents in Radiation Oncology, American Board of Radiology, and American College of Radiology. Representatives from the latter two organizations are key to provide feedback between the examining organizations and ASTRO. Subjects are based on Accreditation Council for Graduate Medical Education requirements (particles and hyperthermia), whereas the majority of subjects and appropriated hours/subject were developed by consensus. The new curriculum is 55 hours, containing new subjects, redistribution of subjects with updates, and reorganization of core topics. For each subject, learning objectives are provided, and for each lecture hour, a detailed outline of material to be covered is provided. Some changes include a decrease in basic radiologic physics, addition of informatics as a subject, increase in intensity-modulated radiotherapy, and migration of some brachytherapy hours to radiopharmaceuticals. The new curriculum was approved by the ASTRO board in late 2006. It is hoped that physicists will adopt the curriculum for structuring their didactic teaching program, and simultaneously, the American Board of Radiology, for its written examination. The American College of Radiology uses the ASTRO curriculum for their training examination topics. In addition to the curriculum, the committee added suggested references, a glossary, and a condensed version of lectures for a Postgraduate Year 2 resident physics orientation. To ensure continued commitment to a current and relevant curriculum, subject matter will be updated again in 2 years.

Comparison of outcomes for patients with unresectable, locally advanced non-small-cell lung cancer treated with induction chemotherapy followed by concurrent chemoradiation vs. concurrent chemoradiation alone.

PURPOSE: To retrospectively compare outcomes for patients with unresectable locally advanced non-small-cell lung cancer (NSCLC) treated at our institution with concurrent chemoradiation with or without induction chemotherapy. METHODS AND MATERIALS: We retrospectively analyzed 265 consecutive patients who received definitive treatment with three-dimensional conformal radiation and concurrent chemotherapy. Of these, 127 patients received induction chemotherapy before concurrent chemoradiation. RESULTS: The two groups of patients (with induction vs. without induction chemotherapy) were similar in age, performance status, weight loss, histology, grade, and stage. Patients who received induction chemotherapy had better overall survival (median, 1.9 vs. 1.4 years; 5-year rate, 25% vs. 12%; p < 0.001) and distant metastasis-free survival (5-year rate, 42% vs. 23%; p = 0.021). Locoregional control was not significantly different between the two groups. Multivariate analysis showed that induction chemotherapy was the most significant factor affecting overall survival, with a hazard ratio of 0.55 (95% confidence interval 0.40-0.75; p < 0.001). A planned subgroup analysis showed that induction chemotherapy was associated with a significant overall survival benefit for patients with adenocarcinoma or large-cell carcinoma (5-year rate, 24% vs. 8%; p = 0.003) but not for those with squamous cell carcinoma. A multivariate analysis of patients with adenocarcinoma or large-cell carcinoma confirmed that induction chemotherapy was the most significant factor associated with better overall survival, with a hazard ratio of 0.47 (95% confidence interval, 0.28-0.78; p = 0.003). CONCLUSION: Our retrospective analysis suggests that in combination with concurrent chemoradiation, induction chemotherapy may provide a small but significant survival benefit for patients with unresectable locally advanced adenocarcinoma or large-cell carcinoma of the lung.