Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

Design of a FAIR digital data health infrastructure in Africa for COVID-19 reporting and research.

The limited volume of COVID-19 data from Africa raises concerns for global genome research, which requires a diversity of genotypes for accurate disease prediction, including on the provenance of the new SARS-CoV-2 mutations. The Virus Outbreak Data Network (VODAN)-Africa studied the possibility of increasing the production of clinical data, finding concerns about data ownership, and the limited use of health data for quality treatment at point of care. To address this, VODAN Africa developed an architecture to record clinical health data and research data collected on the incidence of COVID-19, producing these as human- and machine-readable data objects in a distributed architecture of locally governed, linked, human- and machine-readable data. This architecture supports analytics at the point of care and-through data visiting, across facilities-for generic analytics. An algorithm was run across FAIR Data Points to visit the distributed data and produce aggregate findings. The FAIR data architecture is deployed in Uganda, Ethiopia, Liberia, Nigeria, Kenya, Somalia, Tanzania, Zimbabwe, and Tunisia.

Enhancing poly-γ-glutamic acid production in Bacillus amyloliquefaciens by introducing the glutamate synthesis features from Corynebacterium glutamicum.

BACKGROUND: Poly-γ-glutamic acid (γ-PGA) is a valuable polymer with glutamate as its sole precursor. Enhancement of the intracellular glutamate synthesis is a very important strategy for the improvement of γ-PGA production, especially for those glutamate-independent γ-PGA producing strains. Corynebacterium glutamicum has long been used for industrial glutamate production and it exhibits some unique features for glutamate synthesis; therefore introduction of these metabolic characters into the γ-PGA producing strain might lead to increased intracellular glutamate availability, and thus ultimate γ-PGA production. RESULTS: In this study, the unique glutamate synthesis features from C. glutamicum was introduced into the glutamate-independent γ-PGA producing Bacillus amyloliquefaciens NK-1 strain. After introducing the energy-saving NADPH-dependent glutamate dehydrogenase (NADPH-GDH) pathway, the NK-1 (pHT315-gdh) strain showed slightly increase (by 9.1%) in γ-PGA production. Moreover, an optimized metabolic toggle switch for controlling the expression of ɑ-oxoglutarate dehydrogenase complex (ODHC) was introduced into the NK-1 strain, because it was previously shown that the ODHC in C. glutamicum was completely inhibited when glutamate was actively produced. The obtained NK-PO1 (pHT01-xylR) strain showed 66.2% higher γ-PGA production than the NK-1 strain. However, the further combination of these two strategies (introducing both NADPH-GDH pathway and the metabolic toggle switch) did not lead to further increase of γ-PGA production but rather the resultant γ-PGA production was even lower than that in the NK-1 strain. CONCLUSIONS: We proposed new metabolic engineering strategies to improve the γ-PGA production in B. amyloliquefaciens. The NK-1 (pHT315-gdh) strain with the introduction of NADPH-GDH pathway showed 9.1% improvement in γ-PGA production. The NK-PO1 (pHT01-xylR) strain with the introduction of a metabolic toggle switch for controlling the expression of ODHC showed 66.2% higher γ-PGA production than the NK-1 strain. This work proposed a new strategy for improving the target product in microbial cell factories.

Mutations in genes encoding antibiotic substances increase the synthesis of poly-γ-glutamic acid in Bacillus amyloliquefaciens LL3.

Poly-γ-glutamic acid (γ-PGA) is an important natural biopolymer that is used widely in fields of foods, medicine, cosmetics, and agriculture. Several B. amyloliquefaciens LL3 mutants were constructed to improve γ-PGA synthesis via single or multiple marker-less in-frame deletions of four gene clusters (itu, bae, srf, and fen) encoding antibiotic substances. γ-PGA synthesis by the Δsrf mutant showed a slight increase (4.1 g/L) compared with that of the wild-type strain (3.3 g/L). The ΔituΔsrf mutant showed increased γ-PGA yield from 3.3 to 4.5 g/L, with an increase of 36.4%. The γ-PGA yield of the ΔituΔsrfΔfen and ΔituΔsrfΔfenΔbae mutants did not show a further increase. The four gene clusters' roles in swarming motility and biofilm formation were also studied. The Δsrf and Δbae mutant strains were both significantly defective in swarming, indicating that bacillaene and surfactin are involved in swarming motility of B. amyloliquefaciens LL3. Furthermore, Δsrf and Δitu mutant strains were obviously defective in biofilm formation; therefore, iturin and surfactin must play important roles in biofilm formation in B. amyloliquefaciens LL3.

Ecological Consequences of Clonal Integration in Plants.

Clonal plants are widespread throughout the plant kingdom and dominate in diverse habitats. Spatiotemporal heterogeneity of environment is pervasive at multiple scales, even at scales relevant to individual plants. Clonal integration refers to resource translocation and information communication among the ramets of clonal plants. Due to clonal integration, clonal plant species possess a series of peculiar attributes: plasticity in response to local and non-local conditions, labor division with organ specialization for acquiring locally abundant resources, foraging behavior by selective placement of ramets in resource-rich microhabitats, and avoidance of intraclonal competition. Clonal integration has very profound ecological consequences for clonal plants. It allows them to efficiently cope with environmental heterogeneity, by alleviating local resource shortages, buffering environmental stresses and disturbances, influencing competitive ability, increasing invasiveness, and altering species composition and invasibility at the community level. In this paper, we present a comprehensive review of research on the ecological consequences of plant clonal integration based on a large body of literature. We also attempt to propose perspectives for future research.

Roles of Clonal Integration in both Heterogeneous and Homogeneous Habitats.

Many studies have shown that clonal integration can promote the performance of clonal plants in heterogeneous habitats, but the roles of clonal integration in both heterogeneous and homogeneous habitats were rarely studied simultaneously. Ramet pairs of Alternanthera philoxeroides (Mart.) Griseb were placed in two habitats either heterogeneous or homogeneous in soil nutrient availability, with stolon connections left intact or severed. Total biomass, total length of stolons, and number of new ramets of distal (relatively young) ramets located in low-nutrient environments were significantly greater when the distal ramets were connected to than when they were disconnected from proximal (relatively old) ramets located in high-nutrient environments. Total length of stolons of proximal ramets growing in low-nutrient environments was significantly higher when the proximal ramets were connected to than when they were disconnected from the distal ramets growing in high-nutrient environments, but stolon connection did not affect total biomass or number of new ramets of the proximal ramets. Stolon severing also did not affect the growth of the whole ramet pairs in heterogeneous environments. In homogeneous high-nutrient environments stolon severing promoted the growth of the proximal ramets and the ramet pairs, but in homogeneous low-nutrient environments it did not affect the growth of the proximal or distal ramets. Hence, for A. philoxeroides, clonal fragmentation appears to be more advantageous than clonal integration in resource-rich homogeneous habitats, and clonal integration becomes beneficial in heterogeneous habitats. Our study contributes to revealing roles of clonal integration in both heterogeneous and homogeneous habitats and expansion patterns of invasive clonal plants such as A. philoxeroides in multifarious habitats.

Biomass Allocation of Stoloniferous and Rhizomatous Plant in Response to Resource Availability: A Phylogenetic Meta-Analysis.

Resource allocation to different functions is central in life-history theory. Plasticity of functional traits allows clonal plants to regulate their resource allocation to meet changing environments. In this study, biomass allocation traits of clonal plants were categorized into absolute biomass for vegetative growth vs. for reproduction, and their relative ratios based on a data set including 115 species and derived from 139 published literatures. We examined general pattern of biomass allocation of clonal plants in response to availabilities of resource (e.g., light, nutrients, and water) using phylogenetic meta-analysis. We also tested whether the pattern differed among clonal organ types (stolon vs. rhizome). Overall, we found that stoloniferous plants were more sensitive to light intensity than rhizomatous plants, preferentially allocating biomass to vegetative growth, aboveground part and clonal reproduction under shaded conditions. Under nutrient- and water-poor condition, rhizomatous plants were constrained more by ontogeny than by resource availability, preferentially allocating biomass to belowground part. Biomass allocation between belowground and aboveground part of clonal plants generally supported the optimal allocation theory. No general pattern of trade-off was found between growth and reproduction, and neither between sexual and clonal reproduction. Using phylogenetic meta-analysis can avoid possible confounding effects of phylogeny on the results. Our results shown the optimal allocation theory explained a general trend, which the clonal plants are able to plastically regulate their biomass allocation, to cope with changing resource availability, at least in stoloniferous and rhizomatous plants.

Are fiducial markers useful surrogates when using respiratory gating to reduce motion of gastroesophageal junction tumors?

BACKGROUND: Radiation therapy (RT) is an integral component of the management of gastroesophageal junction (GEJ) tumors. We evaluated the use of implanted radiopaque fiducials as tumor surrogates to allow for more focal delivery of RT to these mobile tumors when using respiratory gating (RG) to reduce motion. MATERIAL AND METHODS: We analyzed four-dimensional computed tomography scans of 20 GEJ patients treated with RG and assessed correlation between tumor and implanted fiducial motion over the whole respiratory cycle and within a clinically realistic gate around end-exhalation. We evaluated fiducial motion concordance in 11 patients with multiple fiducials. RESULTS: Gating reduced anterior-posterior (AP) and superior-inferior (SI) mean tumor and fiducial motions by over 50%. Fiducials and primary tumor motions were moderately correlated: R(2) for AP and SI linear fits to the entire group were 0.54 and 0.68, respectively, but the correlation had strong inter-patient variation. For all patients with multiple fiducials, relative in-gate displacements were below 3 mm; results were similar for eight of 11 patients over the whole cycle. CONCLUSION: Implanted fiducial and gross tumor volume (GTV) motions correlate well but the correlation is patient-specific and may be dependent on the location of the fiducials with respect to the GTV.

Plant Clonal Integration Mediates the Horizontal Redistribution of Soil Resources, Benefiting Neighboring Plants.

Resources such as water taken up by plants can be released into soils through hydraulic redistribution and can also be translocated by clonal integration within a plant clonal network. We hypothesized that the resources from one (donor) microsite could be translocated within a clonal network, released into different (recipient) microsites and subsequently used by neighbor plants in the recipient microsite. To test these hypotheses, we conducted two experiments in which connected and disconnected ramet pairs of Potentilla anserina were grown under both homogeneous and heterogeneous water regimes, with seedlings of Artemisia ordosica as neighbors. The isotopes [(15)N] and deuterium were used to trace the translocation of nitrogen and water, respectively, within the clonal network. The water and nitrogen taken up by P. anserina ramets in the donor microsite were translocated into the connected ramets in the recipient microsites. Most notably, portions of the translocated water and nitrogen were released into the recipient microsite and were used by the neighboring A. ordosica, which increased growth of the neighboring A. ordosica significantly. Therefore, our hypotheses were supported, and plant clonal integration mediated the horizontal hydraulic redistribution of resources, thus benefiting neighboring plants. Such a plant clonal integration-mediated resource redistribution in horizontal space may have substantial effects on the interspecific relations and composition of the community and consequently on ecosystem processes.

Higher transcription levels in ascorbic acid biosynthetic and recycling genes were associated with higher ascorbic acid accumulation in blueberry.

In our preliminary study, the ripe fruits of two highbush blueberry (Vaccinium corymbosum L.) cultivars, cv 'Berkeley' and cv 'Bluecrop', were found to contain different levels of ascorbic acid. However, factors responsible for these differences are still unknown. In the present study, ascorbic acid content in fruits was compared with expression profiles of ascorbic acid biosynthetic and recycling genes between 'Bluecrop' and 'Berkeley' cultivars. The results indicated that the l-galactose pathway was the predominant route of ascorbic acid biosynthesis in blueberry fruits. Moreover, higher expression levels of the ascorbic acid biosynthetic genes GME, GGP, and GLDH, as well as the recycling genes MDHAR and DHAR, were associated with higher ascorbic acid content in 'Bluecrop' compared with 'Berkeley', which indicated that a higher efficiency ascorbic acid biosynthesis and regeneration was likely to be responsible for the higher ascorbic acid accumulation in 'Bluecrop'.

Differential expression profiles of poplar MAP kinase kinases in response to abiotic stresses and plant hormones, and overexpression of PtMKK4 improves the drought tolerance of poplar.

Mitogen-activated protein kinase (MAPK) cascades are universal signal transduction modules that play essential roles in plant growth, development and stress response. MAPK kinases (MAPKKs), which link MAPKs and MAPKK kinases (MAPKKKs), are integral in mediating various stress responses in plants. However, to date few data about the roles of poplar MAPKKs in stress signal transduction are available. In this study, we performed a systemic analysis of poplar MAPKK gene family expression profiles in response to several abiotic stresses and stress-associated hormones. Furthermore, Populus trichocarpa MAPKK4 (PtMKK4) was chosen for functional characterization. Transgenic analysis showed that overexpression of the PtMKK4 gene remarkably enhanced drought stress tolerance in the transgenic poplar plants. The PtMKK4-overexpressing plants also exhibited much lower levels of H2O2 and higher antioxidant enzyme activity after exposure to drought stress compared to the wide type lines. Besides, some drought marker genes including PtP5CS, PtSUS3, PtLTP3 and PtDREB8 exhibited higher expression levels in the transgenic lines than in the wide type under drought conditions. This study provided valuable information for understanding the putative functions of poplar MAPKKs involved in important signaling pathways under different stress conditions.

60 years of development of the journal of integrative plant biology.

In celebration of JIPB's 60(th) anniversary, this paper summarizes and reviews the development process of the journal. To start, we offer our heartfelt thanks to JIPB's pioneer Editors-in-Chief who helped get the journal off the ground and make it successful. Academic achievement is the soul of academic journals, and this paper summarizes JIPB's course of academic development by analyzing it in four stages: the first two stages are mostly qualitative analyses, and the latter two stages are dedicated to quantitative analyses. Most-cited papers were statistically analyzed. Improvements in editing, publication, distribution and online accessibility--which are detailed in this paper--contribute to JIPB's sustainable development. In addition, JIPB's evaluation index and awards are provided with accompanying pictures. At the end of the paper, JIPB's milestones are listed chronologically. We believe that JIPB's development, from a national journal to an international one, parallels the development of the Chinese plant sciences.

Correction of motion artifacts in cone-beam CT using a patient-specific respiratory motion model.

PURPOSE: Respiratory motion adversely affects CBCT image quality and limits its localization accuracy for image-guided radiation treatment. Motion correction methods in CBCT have focused on the thorax because of its higher soft tissue contrast, whereas low-contrast tissue in abdomen remains a challenge. The authors report on a method to correct respiration-induced motion artifacts in 1 min CBCT scans that is applicable in both thorax and abdomen, using a motion model adapted to the patient from a respiration-correlated image set. METHODS: Model adaptation consists of nonrigid image registration that maps each image to a reference image in the respiration-correlated set, followed by a principal component analysis to reduce errors in the nonrigid registration. The model parametrizes the deformation field in terms of observed surrogate (diaphragm or implanted marker) position and motion (inhalation or exhalation) between the images. In the thorax, the model is obtained from the same CBCT images that are to be motion-corrected, whereas in the abdomen, the model uses respiration-correlated CT (RCCT) images acquired prior to the treatment session. The CBCT acquisition is a single 360 degrees rotation lasting 1 min, while simultaneously recording patient breathing. The approximately 600 projection images are sorted into six (in thorax) or ten (in abdomen) subsets and reconstructed to obtain a set of low-quality respiration-correlated RC-CBCT images. Application of the motion model deforms each of the RC-CBCT images to a chosen reference image in the set; combining all images yields a single high-quality CBCT image with reduced blurring and motion artifacts. Repeated application of the model with different reference images produces a series of motion-corrected CBCT images over the respiration cycle, for determining the motion extent of the tumor and nearby organs at risk. The authors also investigate a simpler correction method, which does not use PCA and correlates motion state with respiration phase, thus assuming repeatable breathing patterns. Comparison of contrast-to-noise ratios of pixel intensities within anatomical structures relative to surrounding background tissue provides a quantitative assessment of relative organ visibility. RESULTS: Evaluation in lung phantom, two patient cases in thorax and two in upper abdomen, shows that blurring and streaking artifacts are visibly reduced with motion correction. The boundaries of tumors in the thorax, liver, and kidneys are sharper and more discernible. Repeat application of the method in one thorax case, with reference images chosen at end expiration and end inspiration, indicates its feasibility for observing tumor motion extent. Phase-based motion correction without PCA reduces blurring less effectively; in addition, implanted markers appear broken up, indicating inconsistencies in the phase-based correction. In structures showing 1 cm or more motion excursion, PCA-based motion correction shows the highest contrast-to-noise ratios in the cases examined. CONCLUSIONS: Motion correction of CBCT is feasible and yields observable improvement in the thorax and abdomen. The PCA-based model is an important component: First, by reducing deformation errors caused by the nonrigid registration and second, by relating deformation to surrogate position rather than phase, thus accommodating breathing pattern changes between imaging sessions. The accuracy of the method requires confirmation in further patient studies.

Model-based estimation of ventricular deformation in the cat brain.

The estimation of ventricular deformation has important clinical implications related to neuro-structural disorders such as hydrocephalus. In this paper, a poroelastic model was used to represent deformation effects resulting from the ventricular system and was studied in 5 feline experiments. Chronic or acute hydrocephalus was induced by injection of kaolin into the cisterna magna or saline into the ventricles; a catheter was then inserted in the lateral ventricle to drain the fluid out of the brain. The measured displacement data which was extracted from pre-drainage and post-drainage MR images were incorporated into the model through the Adjoint Equations Method. The results indicate that the computational model of the brain and ventricular system captured 33% of the ventricle deformation on average and the model-predicted intraventricular pressure was accurate to 90% of the recorded value during the chronic hydrocephalus experiments.

Clonal integration affects growth, photosynthetic efficiency and biomass allocation, but not the competitive ability, of the alien invasive Alternanthera philoxeroides under severe stress.

BACKGROUND AND AIMS: Many notorious alien invasive plants are clonal, but little is known about some roles and aspects of clonal integration. Here, the hypothesis is tested that clonal integration affects growth, photosynthetic efficiency, biomass allocation and competitive ability of the exotic invasive weed Alternanthera philoxeroides (Amaranthaceae). METHODS: The apical parts of Alternanthera were grown either with or without the lawn grass Schedonorus phoenix (tall fescue) and their stolon connections to the basal parts grown without competitors were either severed or left intact. KEY RESULTS: Competition greatly reduced the maximum quantum yield of photosystem II (F(v)/F(m)) and growth (biomass, number of ramets and leaves, total stolon length and total leaf area) of the apical Alternanthera, but not the biomass of S. phoenix. Stolon connections significantly increased F(v)/F(m) and growth of Alternanthera. However, such effects on growth were smaller with than without competition and stolon connections did not alter the relative neighbour effect of Alternanthera. Stolon connections increased Alternanthera's biomass allocation to roots without competition, but decreased it with competition. CONCLUSIONS: Clonal integration contributed little to Alternanthera's competitive ability, but was very important for Alternanthera to explore open space. The results suggest that the invasiveness of Alternanthera may be closely related to clonal integration.

Large clones on cliff faces: expanding by rhizomes through crevices.

BACKGROUND AND AIMS: Large clones of rhizomatous plants are found in many habitats, but little is known about whether such clones also occur on cliff faces where environmental conditions are extremely harsh and heterogeneous. METHODS: Using molecular (intersimple sequence repeat, ISSR) markers, the genotypic composition of a cliff-face population of Oxyria sinensis in Sichuan, China, was investigated. KEY RESULTS: The 98 O. sinensis ramets sampled belonged to 12 different genotypes (clones). The three most frequent clones were represented with 45, 22 and 12 ramets, respectively; the remaining nine were represented with only one to five ramets. The three largest clones spanned at least 2.7 m in the vertical direction and 4.6-6.9 m in the horizontal direction on the cliff face. CONCLUSIONS: On the cliff face, large clones of O. sinensis are formed by rhizomes growing along the crevices. Expansion by rhizomes may help O. sinensis to exploit the patchy resources and support establishment and growth of new ramets. Moreover, rooted ramets connected by rhizomes may effectively reduce the susceptibility of O. sinensis to rock fall and erosion and thus greatly improve the chances for long-term survival. The multi-clone structure indicates that sexual reproduction is also important for the long-term persistence of O. sinensis populations on cliffs.

Data-guided brain deformation modeling: evaluation of a 3-D adjoint inversion method in porcine studies.

Biomechanical models of brain deformation are useful tools for estimating parenchymal shift that results during open cranial procedures. Intraoperative data is likely to improve model estimates, but incorporation of such data into the model is not trivial. This study tests the adjoint equations method (AEM) for data assimilation as a viable approach for integrating displacement data into a brain deformation model. AEM was applied to two porcine experiments. AEM-based estimates were compared both to measured displacement data [from computed tomography (CT) scans] and to model solutions obtained without the guidance of sparse data, which we term the best prior estimate (BPE). Additionally, the sensitivity of the AEM solution to inverse parameter selection was investigated. The results suggest that it is most important to estimate the size of the variance in the measurement error correctly, make the correlation length long and estimate displacement (over stress) boundary conditions. Application of AEM shows an average 33% improvement over BPE. This paper represents the first evidence of successful use of the AEM technique in three dimensions with experimental data validation. The guidelines established for selection of model parameters are starting points for further optimization of the method under clinical conditions.