GBM radiosensitizers: dead in the water…or just the beginning?

The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers. However, many of  the previous radiosensitizing strategies were not based on clear pre-clinical evidence, and in many cases blood-barrier penetration was not considered. Furthermore, DNA repair inhibitors have only recenly arrived in the clinic, and likely represent potent agents for glioma radiosensitization. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization

Seasonal changes in carbohydrate and mineral composition of overvigorous and devitalized Anab-e-Shahi grapevines in relation to uniruitiulness

Total carbohydrates in shoots, canes and old wood were higher in fruitful vines than in overvigorous or devitalized ones. The highest percentage of total carbohydrates was observed from December to February in all three types of vines. The minimum values for total carbohydrates in shoots of bearing vines were recorded in May. Total sugars were highest in bearing vines, followed by overvigorous and devitalized ones, respectively. Non-bearing (overvigorous and devitalized) vines had maximum sugar content in February, while bearing vines reached the maximum in January. Non-reducing sugars were practically absent in all vines from March to September. The first evidence of their presence was obtained in October.Nitrogen concentration was higher in overvigorous vines, followed by bearing and devitalized ones, respectively. Its level in devitalized vines was very low throughout the year. Also the nttrogen status of devitalized vineyard was very low, as observed in soil analysis. In bearing and overvigorous vines the percentage nitrogen was higher in shoots than in old wood. There was no significant difference in the phosphorus levels of bearing and overvigorous vines. Potassium level of overvigorous vines was slightly higher than that of bearing and devitalized vines.Overvigorous vines had low carbohydrates and very high ni,trogen, bearing vines had moderate carbohydrates and moderate nitrogen, while the devitalized vines had low carbohydrates and very low nitrogen level.Die jahreszeitlichen Veränderungen der Kohlenhydrat- und Mineralstoffzusammensetzung bei luxurierenden und kümmernden Anab-e-Shahi-Reben in Beziehung zu ihrer UnfruchtbarkeitDer Gesamtkohlenhydratgehalt in grünen Trieben, Tragruten und altem Holz war bei fruchttragenden Anab-e-Shahi-Reben größer als bei luxurierenden oder kümmernden Reben. Die höchste Konzentration der Gesamtkohlenhydrate wurde bei allen drei Rebtypen von Dezember bis Februar beobachtet; in den Trieben der traubentragenden Reben wurden im Mai die niedrigsten Werte festgestellt. Die Gesamtzuckerkonzentration nahm in der Reihenfolge fruchttragende, luxurierende, kümmernde Reben ab. Bei nicht-traubentragenden (luxurierenden und kümmernden) Reben war der Zuckergehalt im Februar am größten; traubentragende Reben erreichten ihr Zuckermaximum schon im Januar. Nichtreduzierende Zucker fehlten bei allen Reben von März bis September praktisch vollständig und waren erst von Oktober an nachzuweisen.Luxurierende Reben zeigten einen höheren Stickstoffgehalt als traubentragende und kümmernde Reben. Die letzteren wiesen das ganze Jahr über sehr niedrige Stickstoffkonzentrationen auf. Bodenanalysen ergaben, daß auch ihre Parzelle sehr schwach mit Stickstoff versorgt war. Bei fruchttragenden und luxurierenden Reben enthielten die grünen Triebe prozentual mehr Stickstoff als das alte Holz. Zwischen eiern Phosphorgehalt normaler und luxurierender Reben bestand kein signifikanter Unterschied. Bei den luxurierenden Reben war der Kaliumgehalt etwas höher als bei den traubentragenden und kümmernden Reben.Luxurierende Reben besaßen wenig Kohlenhydrate und sehr viel Stickstoff, traubentragende Reben wiesen mittlere Kohlenhydrat- und Stickstoffkonzentrationen auf, während die kümmernden Reben einen niedrigen Kohlenhydrat- und einen sehr geringen Stickstoffgehalt zeigten

A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases - An initial report.

Indications and treatment goals for SRS have changed since the publication of RTOG 90-05. We present initial retrospective outcomes from a new dose selection algorithm in use at our institution felt to be more contemporary with doses being used in the radiosurgery community today and report our local control and toxicity outcomes. This dose selection algorithm will be subject to a forthcoming prospective phase 2 trial.To evaluate safety and efficacy of an institutional dose selection algorithm in the treatment of brain metastases (BM) with single fraction radio-surgery (SRS).The medical records of 65 patients with ≤10 BM treated with GK at our institution between April 2012 and October 2012 were reviewed retrospectively. The prescription doses used in this study ranged from 16-22Gy and were based upon RTOG 90-05 guideline doses subsequently modified at our institution depending on lesion number, lesion volume, institutional experience and prior history of whole brain radiation therapy (WBRT). Primary endpoint was local recurrence (LR) with additional outcomes measured including distant intracranial recurrence (DIR), death without local recurrence (DWLR) and alive and disease free (ADF). Fine Gray competing risk analysis was used to examine factors affecting local recurrence.Median follow up was 8.9 months (range 1.0-29.6months) and 12 month overall survival was 37% (95% CI 24.9-49.1%). Overall local recurrence rate was 7.7%. On competing risks regression analysis, no variable was significantly associated with local recurrence, including previous whole brain radiotherapy (WBRT), (SHR 1.21 [95%CI 0.13-11.5], p=0.87 and radioresistant versus radiosensitive histology (SHR 0.51 [95% CI 0.06-7.73], p=0.55). No patient developed grade 3 or higher neurotoxicity at 12 months following GK.Initial local control and toxicity results from our institutional dose selection algorithm are reported here. Comparison of our results with RTOG 90-05 is difficult due to significant differences in the patient population and their treatments. The applicability of this algorithm merits further investigation across multiple centers for the purpose of treatment and clinical trial standardization in single fraction SRS and will be the subject of a forthcoming phase 2 prospective study within our own institution

Pseudo-analytic finite partition approach to temperature distribution problem in human limbs

ABSTRACT. Th

Asexuality: Classification and characterization

This is a post-print version of the article. The official published version can be obtaineed at the link below.The term “asexual” has been defined in many different ways and asexuality has received very little research attention. In a small qualitative study (N = 4), individuals who self-identified as asexual were interviewed to help formulate hypotheses for a larger study. The second larger study was an online survey drawn from a convenience sample designed to better characterize asexuality and to test predictors of asexual identity. A convenience sample of 1,146 individuals (N = 41 self-identified asexual) completed online questionnaires assessing sexual history, sexual inhibition and excitation, sexual desire, and an open-response questionnaire concerning asexual identity. Asexuals reported significantly less desire for sex with a partner, lower sexual arousability, and lower sexual excitation but did not differ consistently from non-asexuals in their sexual inhibition scores or their desire to masturbate. Content analyses supported the idea that low sexual desire is the primary feature predicting asexual identity

A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial

AbstractHematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell–replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.

Mutability and Importance of a Hypermutable Cell Subpopulation that Produces Stress-Induced Mutants in Escherichia coli

In bacterial, yeast, and human cells, stress-induced mutation mechanisms are induced in growth-limiting environments and produce non-adaptive and adaptive mutations. These mechanisms may accelerate evolution specifically when cells are maladapted to their environments, i.e., when they are are stressed. One mechanism of stress-induced mutagenesis in Escherichia coli occurs by error-prone DNA double-strand break (DSB) repair. This mechanism was linked previously to a differentiated subpopulation of cells with a transiently elevated mutation rate, a hypermutable cell subpopulation (HMS). The HMS could be important, producing essentially all stress-induced mutants. Alternatively, the HMS was proposed to produce only a minority of stress-induced mutants, i.e., it was proposed to be peripheral. We characterize three aspects of the HMS. First, using improved mutation-detection methods, we estimate the number of mutations per genome of HMS-derived cells and find that it is compatible with fitness after the HMS state. This implies that these mutants are not necessarily an evolutionary dead end, and could contribute to adaptive evolution. Second, we show that stress-induced Lac+ mutants, with and without evidence of descent from the HMS, have similar Lac+ mutation sequences. This provides evidence that HMS-descended and most stress-induced mutants form via a common mechanism. Third, mutation-stimulating DSBs introduced via I-SceI endonuclease in vivo do not promote Lac+ mutation independently of the HMS. This and the previous finding support the hypothesis that the HMS underlies most stress-induced mutants, not just a minority of them, i.e., it is important. We consider a model in which HMS differentiation is controlled by stress responses. Differentiation of an HMS potentially limits the risks of mutagenesis in cell clones

What are we measuring? A critique of range of motion methods currently in use for Dupuytren's disease and recommendations for practice

Background: Range of motion is the most frequently reported measure used in practice to evaluate outcomes. A goniometer is the most reliable tool to assess range of motion yet, the lack of consistency in reporting prevents comparison between studies. The aim of this study is to identify how range of motion is currently assessed and reported in Dupuytren’s disease literature. Following analysis recommendations for practice will be made to enable consistency in future studies for comparability. This paper highlights the variation in range of motion reporting in Dupuytren’s disease. Methods: A Participants, Intervention, Comparison, Outcomes and Study design format was used for the search strategy and search terms. Surgery, needle fasciotomy or collagenase injection for primary or recurrent Dupuytren’s disease in adults were included if outcomes were monitored using range of motion to record change. A literature search was performed in May 2013 using subject heading and free-text terms to also capture electronic publications ahead of print. In total 638 publications were identified and following screening 90 articles met the inclusion criteria. Data was extracted and entered onto a spreadsheet for analysis. A thematic analysis was carried out to establish any duplication, resulting in the final range of motion measures identified. Results: Range of motion measurement lacked clarity, with goniometry reportedly used in only 43 of the 90 studies, 16 stated the use of a range of motion protocol. A total of 24 different descriptors were identified describing range of motion in the 90 studies. While some studies reported active range of motion, others reported passive or were unclear. Eight of the 24 categories were identified through thematic analysis as possibly describing the same measure, ‘lack of joint extension’ and accounted for the most frequently used. Conclusions: Published studies lacked clarity in reporting range of motion, preventing data comparison and meta-analysis. Percentage change lacks context and without access to raw data, does not allow direct comparison of baseline characteristics. A clear description of what is being measured within each study was required. It is recommended that range of motion measuring and reporting for Dupuytren’s disease requires consistency to address issues that fall into 3 main categories:- Definition of terms Protocol statement Outcome reportin

Design and in vitro studies of a needle-type glucose sensor for subcutaneous monitoring

International audienceA new miniaturized glucose oxidase based needle-type glu¬ cose mlcrosensor has been developed for subcutaneous glu¬ cose monitoring. The sensor Is equivalent In shape and size to a 26-gauge needle (0.45-mm o.d.) and can be Implanted with ease without any Incision. The novel configuration greatly facilitates the deposition of enzyme and polymer films so that sensors with characteristics suitable for In vivo use (upper limit of linear range > 15 mM, response time 60%). The sensor response is largely Independent of ox¬ ygen tension In the normal physiological range. It also ex¬ hibits good selectivity against common interferences except for the exogenous drug acetaminophen

Covalent enzyme coupling on cellulose acetate membranes for glucose sensor development

International audienceMethods for immobilizing glucose oxidase (GOx) on cellulose acetate (CA) membranes are compared. The optimal method involves covalent coupling of bovine serum albumin (BSA) to CA membrane and a subsequent reaction of the membrane with GOx, which has previously been activated with an excess of p-benzoquinone. This coupling procedure is fairly reproducible and allows the preparation of thin membranes (5-20 µm) showing high surface activities (1-3 U/cm2) which are stable over a period of 1-3 months. Electrochemical and radiolabeling experiments show that enzyme inactivation as a result of immobilization is negligible. A good correlation between surface activity of membranes and their GOx load is observed