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Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12‐18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β‐radioimmunotherapy (RIT) with the 90Y‐labeled anti‐FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α‐RIT with OTSA101 labeled with the α‐emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac‐labeled OTSA101 to SYO‐1 synovial sarcoma cells was comparable to that of the imaging agent 111In‐labeled OTSA101. Biodistribution studies showed high uptake in SYO‐1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac‐labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y‐labeled OTSA101. 90Y‐ and 225Ac‐labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac‐labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac‐labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y‐labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment‐related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac‐labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO‐1. RIT with 225Ac‐labeled OTSA101 is a promising therapeutic option for synovial sarcoma. FZD10‐targeted alpha‐radioimmunotherapy with 225Ac‐labeled OTSA101 provided a high radiation dose to tumors and achieved 60% complete response in the synovial sarcoma mouse model SYO‐1. This is the best outcome among FZD10‐targeted therapy to date. Our alpha‐radioimmunotherapy would provide an additional therapeutic option to synovial sarcoma patients that do not show a good response to conventional therapy.

Proton therapy dose is affected by relative biological effectiveness differently than X-ray therapies. The current clinically accepted weighting factor is 1.1 at all positions along the depth–dose profile. However, the relative biological effectiveness correlates with the linear energy transfer, cell or tissue type, and the dose per fraction causing variation of relative biological effectiveness along the depth–dose profile. In this article, we present a simple relative biological effectiveness-weighted treatment planning risk assessment algorithm in 2-dimensions and compare the results with those derived using the standard relative biological effectiveness of 1.1. The isodose distribution profiles for beams were accomplished using matrices that represent coplanar intersecting beams. These matrices were combined and contoured using MATLAB to achieve the distribution of dose. There are some important differences in dose distribution between the dose profiles resulting from the use of relative biological effectiveness = 1.1 and the empirically derived depth-dependent values of relative biological effectiveness. Significant hot spots of up to twice the intended dose are indicated in some beam configurations. This simple and rapid risk analysis could quickly evaluate the safety of various dose delivery schema.

Astronauts beyond the Earth's orbit are exposed to high-energy cosmic-ray nuclei with high values of linear energy transfer (LET), resulting in much more biological damage than from x-rays or γ-rays and may result in mutations and cancer induction. The relative biological effectiveness of these nuclei depends on the LET, rising to as high as ≈50 at LET values of ≈100-200 keV/μm. An endpoint of concern is germ cell mutations passed on to offspring, arising from exposure to these nuclei. A vertebrate model for germ cell mutation is Medaka fish (Oryzias latipes). We exposed wild type males to doses of 1 GeV per nucleon Fe nuclei or to 290 MeV per nucleon C nuclei. They were mated to females with recessive mutations at five-color loci. The transparent embryos from >100 days of mating (representing exposed sperm, spermatids, or spermatogonia) were observed so as to detect dominant lethal mutations and total color mutations, even though the embryos might not hatch. The relative number of mutant embryos as a function of dose were compared with those induced by γ-rays. The relative biological effectiveness values for dominant lethal mutations and total color mutations for exposed sperm and spermatids were 1.3-2.1 for exposure to C nuclei and 1.5-3.0 for exposure to Fe nuclei. (The spermatogonial data were uncertain.) These low values, and the negligible number of viable mutations, compared with those for mutations in somatic cells and for neoplastic transformation, indicate that germ cell mutations arising from exposures to cosmic ray nuclei are not a significant hazard to astronauts.

Both cell lethality and neoplastic transformation were assessed for C3H10Tl/2 cells exposed to neutrons with energies from 0.040 to 13.7 MeV. Monoenergetic neutrons with energies from 0.23 to 13.7 MeV and two neutron energy spectra with average energies of 0.040 and 0.070 MeV were produced with a Van de Graaff accelerator at the Radiological Research Accelerator Facility (RARAF) in the Center for Radiological Research of Columbia University. For determination of relative biological effectiveness (RBE), cells were exposed to 250 kVp X rays. With exposures to 250 kVp X rays, both cell survival and radiationinduced oncogenic transformation were curvilinear. Irradiation of cells with neutrons at all energies resulted in linear responses as a function of dose for both biological endpoints. Results indicate a complex relationship between RBEm and neutron energy. For both survival and transformation, RBEm was greatest for cells exposed to 0.35 MeV neutrons. RBEm was significantly less at energies above or below 0.35 MeV. These results are consistent with microdosimetric expectation. These results are also compatible with current assessments of neutron radiation weighting factors for radiation protection purposes. Based on calculations of dose-averaged LET, 0.35 MeV neutrons have the greatest LET and therefore would be expected to be more biologically effective than neutrons of greater or lesser energies.

Lung cancer is the most common cause of cancer death worldwide. Surgical resection has played a major role in the treatment of non-small-cell lung cancer (NSCLC); however, the disease is often detected in a progressive and inoperable form. Surgical resection may also be impossible for early-stage NSCLC due to medical conditions, such as pulmonary or cardiovascular disease and old age. Radiotherapy plays an important role for these patients. Proton-beam therapy is a particle radiotherapy with an excellent dose localization that permits treatment of lung cancer by administering a high dose to the tumor while minimizing damage to the surrounding normal tissues. Thus, proton beams are increasingly being used for lung cancer. In this context, the authors review the current knowledge on proton-beam therapy for the treatment of NSCLC.

Epidemiological studies of Japanese atomic bomb survivors indicate that the risk of cancer from radiation exposure is higher in individuals who are relatively young at the time of exposure, with women facing a more significant risk compared to men. However, this type of data is limited for other radiation types, such as particle radiations. Low linear energy transfer (LET) carbon ions are a type of particle radiation to which humans may be exposed as cosmic radiation during long-duration space missions and as radiation passing through healthy tissue during carbon ion radiotherapy. This raises concerns about the risk of late complications, including cancer development. To address these issues, we examined the lifespan of mice after exposure to γ rays or low-LET carbon-ion beams, assessed the effects of sex and age at the time of exposure, and calculated the RBE. Male and female B6C3F1 mice of various ages (embryonic days 3, 13, and 17, and postnatal weeks 1, 3, 7, and 15) were whole-body irradiated a single time with 137 Cs γ rays (662 keV) or 290-MeV/u monoenergetic carbon ions (LET, ~ 13 keV/µm), and their lifespan was analyzed. For both γ rays and carbon ions, the hazard ratio for mortality increased in a dose-dependent manner, was higher for females than for males, and peaked at 1 week of age at the time of exposure. The RBE of low-LET carbon ions for lifespan shortening was 0.9–1.8 for females and 1.2–2.0 for males, regardless of the age at exposure. Thus, the risk associated with low-LET carbon ion exposure varied with age and sex, but RBE did not. These findings provide essential data for assessing the impacts of low-LET carbon ion exposure.

For tumor therapy with light ions and for experimental aspects in particle radiobiology the relative biological effectiveness (RBE) is an important quantity to describe the increased effectiveness of particle radiation. By establishing and analysing a database of ion and photon cell survival data, some remarkable properties of RBE-related quantities were observed. The database consists of 855 in vitro cell survival experiments after ion and photon irradiation. The experiments comprise curves obtained in different labs, using different ion species, different irradiation modalities, the whole range of accessible energies and linear energy transfers (LETs) and various cell types. Each survival curve has been parameterized using the linear-quadratic (LQ) model. The photon parameters, α and β, appear to be slightly anti-correlated, which might point toward an underlying biological mechanism. The RBE values derived from the survival curves support the known dependence of RBE on LET, on particle species and dose. A positive correlation of RBE with the ratio α/β of the photon LQ parameters is found at low doses, which unexpectedly changes to a negative correlation at high doses. Furthermore, we investigated the course of the β coefficient of the LQ model with increasing LET, finding typically a slight initial increase and a final falloff to zero. The observed fluctuations in RBE values of comparable experiments resemble overall RBE uncertainties, which is of relevance for treatment planning. The database can also be used for extensive testing of RBE models. We thus compare simulations with the local effect model to achieve this goal.

Directed modulation of the colonic bacteria to metabolize lactose effectively is a potentially useful approach to improve lactose digestion and tolerance. A randomized, double-blind, multisite placebo-controlled trial conducted in human subjects demonstrated that administration of a highly purified (>95%) short-chain galactooligosaccharide (GOS), designated “RP-G28,” significantly improved clinical outcomes for lactose digestion and tolerance. In these individuals, stool samples were collected pretreatment (day 0), after GOS treatment (day 36), and 30 d after GOS feeding stopped and consumption of dairy products was encouraged (day 66). In this study, changes in the fecal microbiome were investigated using 16S rRNA amplicon pyrosequencing and high-throughput quantitative PCR. At day 36, bifidobacterial populations were increased in 27 of 30 of GOS subjects (90%), demonstrating a bifidogenic response in vivo. Relative abundance of lactose-fermenting Bifidobacterium, Faecalibacterium, and Lactobacillus were significantly increased in response to GOS. When dairy was introduced into the diet, lactose-fermenting Roseburia species increased from day 36 to day 66. The results indicated a definitive change in the fecal microbiome of lactose-intolerant individuals, increasing the abundance of lactose-metabolizing bacteria that were responsive to dietary adaptation to GOS. This change correlated with clinical outcomes of improved lactose tolerance.

Understanding the origins and maintenance of biodiversity remains one of biology’s grand challenges. From theory and observational evidence, we know that variability in environmental conditions through time is likely critical to the coexistence of competing species. Nevertheless, experimental tests of fluctuation-driven coexistence are rare and have typically focused on just one of two potential mechanisms, the temporal storage effect, to the neglect of the theoretically equally plausible mechanism known as relative nonlinearity of competition. We combined experiments and simulations in a system of nectar yeasts to quantify the relative contribution of the two mechanisms to coexistence. Resource competition models parameterized from single-species assays predicted the outcomes of mixed-culture competition experiments with 83% accuracy. Model simulations revealed that both mechanisms have measurable effects on coexistence and that relative nonlinearity can be equal or greater in magnitude to the temporal storage effect. In addition, we show that their effect on coexistence can be both antagonistic and complementary. These results falsify the common assumption that relative nonlinearity is of negligible importance, and in doing so reveal the importance of testing coexistence mechanisms in combination.

Application of bioorganic fertilizers has been reported to improve crop yields and change soil bacterial community structure; however, little work has been done in apple orchard soils where the biological properties of the soils are being degraded due to long-term application of chemical fertilizers. In this study, we used Illumina-based sequencing approach to characterize the bacterial community in the 0–60-cm soil profile under different fertilizer regimes in the Loess Plateau. The experiment includes three treatments: (1) control without fertilization (CK); (2) application of chemical fertilizer (CF); and (3) application of bioorganic fertilizer and organic-inorganic mixed fertilizer (BOF). The results showed that the treatment BOF increased the apple yields by 114 and 67 % compared to the CK and CF treatments, respectively. The treatment BOF also increased the soil organic matter (SOM) by 22 and 16 % compared to the CK and CF treatments, respectively. The Illumina-based sequencing showed that Acidobacteria and Proteobacteria were the predominant phyla and Alphaproteobacteria and Gammaproteobacteria were the most abundant classes in the soil profile. The bacterial richness for ACE was increased after the addition of BOF. Compared to CK and CF treatments, BOF-treated soil revealed higher abundance of Proteobacteria, Alphaproteobacteria and Gammaproteobacteria, Rhizobiales, and Xanthomonadales while Acidobacteria, Gp7, Gp17, and Sphaerobacter were found in lower abundance throughout the soil profile. Bacterial community structure varied with soil depth under different fertilizer treatments, e.g., the bacterial richness, diversity, and the relative abundance of Verruccomicrobia, Candidatus Brocadiales, and Skermanella were decreased with the soil depth in all three treatments. Permutational multivariate analysis showed that the fertilizer regime was the major factor than soil depth in the variations of the bacterial community composition. Two groups, Lysobacter and Rhodospirillaceae, were found to be the significantly increased by the BOF addition and the genus Lysobacter may identify members of this group effective in biological control-based plant disease management and the members of family Rhodospirillaceae had an important role in fixing molecular nitrogen. These results strengthen the understanding of responses to the BOF and possible interactions within bacterial communities in soil that can be associated with disease suppression and the accumulation of carbon and nitrogen. The increase of apple yields after the application of BOF might be attributed to the fact that the application of BOF increased SOM, and soil total nitrogen, and changed the bacterial community by enriching Rhodospirillaceae, Alphaprotreobateria, and Proteobacteria.