Phase II Study of Concurrent Capecitabine and External Beam Radiotherapy for Pain Control of Bone Metastases of Breast Cancer Origin

Background

Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer.

Methodology/Principal Findings

Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m² twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%).

Conclusions/Significance

External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01784393","term_id":"NCT01784393"}}NCT01784393{"type":"clinical-trial","attrs":{"text":"NCT01784393","term_id":"NCT01784393"}}NCT01784393     

Evaluation of helmet and goggle designs by modeling non-penetrating projectile impacts

Despite the progress in developing personal combat-protective gear, eye and brain injuries are still widely common and carry fatal or long-term repercussions. The complex nature of the cranial tissues suggests that simple methods (e.g. crash-dummies) for testing the effectiveness of personal protective gear against non-penetrating impacts are both expensive and ineffective, and there are ethical issues in using animal or cadavers. The present work presents a versatile testing framework for quantitatively evaluating protective performances of head and eye combat-protective gear, against non-penetrating impacts. The biomimetic finite element (FE) head model that was developed provides realistic representation of cranial structure and tissue properties. Simulated crash impact results were validated against a former cadaveric study and by using a crash-phantom developed in our lab. The model was then fitted with various helmet and goggle designs onto which a non-penetrating ballistic impact was applied. Example data show that reduction of the elastic and shear moduli by 30% and 80% respectively of the helmet outer Kevlar-29 layer, lowered intracranial pressures by 20%. Our modeling suggests that the level of stresses that develop in brain tissues, which ultimately cause the brain damage, cannot be predicted solely by the properties of the helmet/goggle materials. We further found that a reduced contact area between goggles and face is a key factor in reducing the mechanical loads transmitted to the optic nerve and eye balls following an impact. Overall, this work demonstrates the simplicity, flexibility and usefulness for development, evaluation, and testing of combat-protective equipment using computational modeling.

• Highlights

• A finite element head model was developed for testing head gear.

• Reduced helmet’s outer layer elastic and shear moduli lowered intracranial stresses.

• Gear material properties could not fully predict impact-related stress in the brain.

• Reduced goggles-face contact lowered transmitted loads to the optic nerve and eyes.

     

The A locus that controls anthocyanin accumulation in pepper encodes a MYB transcription factor homologous to Anthocyanin2 of Petunia

Pepper plants containing the dominant A gene accumulate anthocyanin pigments in the foliage, flower and immature fruit. We previously mapped A to pepper chromosome 10 in the F₂ progeny of a cross between 5226 (purple-fruited) and PI 159234 (green-fruited) to a region that corresponds, in tomato, to the location of Petunia anthocyanin 2 (An2), a regulator of anthocyanin biosynthesis. This suggested that A encodes a homologue of Petunia An2. Using the sequences of An2 and a corresponding tomato expressed sequence tag, we isolated a pepper cDNA orthologous to An2 that cosegregated with A. We subsequently determined the expression of A by Northern analysis, using RNA extracted from fruits, flowers and leaves of 5226 and PI 159234. In 5226, expression was detected in all stages of fruit development and in both flower and leaf. In contrast, A was not expressed in the sampled tissues in PI 159234. Genomic sequence comparison of A between green- and purple-fruited genotypes revealed no differences in the coding region, indicating that the lack of expression of A in the green genotypes can be attributed to variation in the promoter region. By analyzing the expression of the structural genes in the anthocyanin biosynthetic pathway in 5226 and PI 159234, it was determined that, similar to Petunia, the early genes in the pathway are regulated independently of A, while expression of the late genes is A-dependent.Communicated by R. Hagemann     

Novel applications of feather tip extracts from MDV-infected chickens; diagnosis of commercial broilers, whole genome separation by PFGE and synchronic mucosal infection

Marek's disease virus (MDV) productive replication occurs in the feather follicle epithelium and the feather tips are valuable both for research and disease diagnosis. Three novel applications of feather tip extracts are described now: (A). As a source of DNA for amplifying either MDV and/or ALV-J. In two clinical situations a marked advantage was obtained compared to blood and organs; in broiler breeder flocks with a mixed MDV and ALV-J infection, and in young broilers with neurological Marek's disease (MD). (B). Separation of the large ( approximately 200 kbp) MDV genome directly from the infected chickens. Using pulsed field gel electrophoresis, the DNA extracted from tumors or feather tips was separated and hybridized to a 132 bp tandem repeat MDV probe. Compared to 2/55 polymerase chain reaction (PCR) positive tumor samples, 15/61 feather tip extracts contained whole MDV genomes. (C). Experimental MDV infection was induced by the mucosal route by dripping feather tip extract to the eye and mouth of the bird. That attempted to reproduce the native infection process, however the use of extracts, instead of dry feather dust was a compromise, aimed to synchronize the infection. In one trial, tumors were induced 6 weeks after dripping day-old broilers, while in another, feather tips were PCR positive 16 days after dripping of 2-month-old layers.     

An alternative excited-state proton transfer pathway in green fluorescent protein variant S205V

Wild-type green fluorescent protein (wt-GFP) has a prominent absorbance band centered at approximately 395 nm, attributed to the neutral chromophore form. The green emission arising upon excitation of this band results from excited-state proton transfer (ESPT) from the chromophore hydroxyl, through a hydrogen-bond network proposed to consist of a water molecule and Ser205, to Glu222. Although evidence for Glu222 as a terminal proton acceptor has already been obtained, no evidence for the participation of Ser205 in the proton transfer process exists. To examine the role of Ser205 in the proton transfer, we mutated Ser205 to valine. However, the derived GFP variant S205V, upon excitation at 400 nm, still produces green fluorescence. Time-resolved emission spectroscopy suggests that ESPT contributes to the green fluorescence, and that the proton transfer takes place approximately 30 times more slowly than in wt-GFP. The crystal structure of S205V reveals rearrangement of Glu222 and Thr203, forming a new hydrogen-bonding network. We propose this network to be an alternative ESPT pathway with distinctive features that explain the significantly slowed rate of proton transfer. In support of this proposal, the double mutant S205V/T203V is shown to be a novel blue fluorescent protein containing a tyrosine-based chromophore, yet is incapable of ESPT. The results have implications for the detailed mechanism of ESPT and the photocycle of wt-GFP, in particular for the structures of spectroscopically identified intermediates in the cycle.     

Toll-like receptors modulate adult hippocampal neurogenesis

Neurogenesis - the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCalpha/beta-dependent activation of the NF-kappaB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.     

A vestige of a prebiotic bonding machine is functioning within the contemporary ribosome

Based on the presumed capability of a prebiotic pocket-like entity to accommodate substrates whose stereochemistry enables the creation of chemical bonds, it is suggested that a universal symmetrical region identified within all contemporary ribosomes originated from an entity that we term the 'proto-ribosome'. This 'proto-ribosome' could have evolved from an earlier machine that was capable of performing essential tasks in the RNA world, called here the 'pre-proto-ribosome', which was adapted for producing proteins.     

Active anthocyanin degradation in <Emphasis Type="Italic">Brunfelsia calycina</Emphasis> (yesterday–today–tomorrow) flowers

Anthocyanins are the largest group of plant pigments responsible for colors ranging from red to violet and blue. The biosynthesis of anthocyanins, as part of the larger phenylpropanoid pathway, has been characterized in great detail. In contrast to the detailed molecular knowledge available on anthocyanin synthesis, very little is known about the stability and catabolism of anthocyanins in plants. In this study we present a preliminary characterization of active in planta degradation of anthocyanins, requiring novel mRNA and protein synthesis, in Brunfelsia calycina flowers. Brunfelsia is a unique system for this study, since the decrease in pigment concentration in its flowers (from dark purple to white) is extreme and rapid, and occurs at a specific and well-defined stage of flower development. Treatment of detached flowers with protein and mRNA synthesis inhibitors, at specific stages of flower development, prevented degradation. In addition, treatment of detached flowers with cytokinins delayed senescence without changing the rate of anthocyanin degradation, suggesting that degradation of anthocyanins is not part of the general senescence process of the flowers but rather a distinctive and specific pathway. Based on studies on anthocyanin degradation in wine and juices, peroxidases are reasonable candidates for the in vivo degradation. A significant increase in peroxidase activity was shown to correlate in time with the rate of anthocyanin degradation. An additional indication that oxidative enzymes are involved in the process is the fact that treatment of flowers with reducing agents, such as DTT and glutathione, caused inhibition of degradation. This study represents the first step in the elucidation of the molecular mechanism behind in vivo anthocyanin degradation in plants.     

Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells

Heparanase is a heparan sulfate-degrading endoglycosidase expressed by mature monocytes and myeloid cells, but not by immature hematopoietic progenitors. Heparanase gene expression is upregulated during differentiation of immature myeloid cells. PML-RARalpha and PLZF-RARalpha fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression. AML-Eto, a translocation product associated with AML FAB M2, also downregulates heparanase gene expression. The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA. We found that retinoic acid that dissociates PML-RARalpha from the DNA, and which is used to treat acute promyelocytic leukemia patients, restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line. The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid-treated acute promyelocytic leukemia patient. Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML-Eto fusion gene product in M2 type AML. In summary, we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells.