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The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina. Human-induced pluripotent stem cells (hiPSCs) can be utilised to generate an alternative disease model, the 3D retinal organoid, which contains all major retinal cell types including photoreceptors complete with cilial structures. These retinal organoids facilitate the study of disease mechanisms and potential therapies in a human-derived system. Three-dimensional retinal organoids are still a developing technology, and despite impressive progress, several limitations remain. This review will discuss the state of hiPSC-derived retinal organoid technology for accurately modelling prominent retinal ciliopathies related to genes, including RPGR, CEP290, MYO7A, and USH2A. Additionally, we will discuss the development of novel gene therapy approaches targeting retinal ciliopathies, including the delivery of large genes and gene-editing techniques. [ABSTRACT FROM AUTHOR]

The development of a stable human gut microbiota occurs within the first year of life. Many open questions remain about how microfloral species are influenced by the composition of milk, in particular its content of human milk oligosaccharides (HMOs). The objective is to investigate the effect of the human HMO glycome on bacterial symbiosis and competition, based on the glycoside hydrolase (GH) enzyme activities known to be present in microbial species. We extracted from UniProt a list of all bacterial species catalysing glycoside hydrolase activities (EC 3.2.1.-), cross-referencing with the BRENDA database, and obtained a set of taxonomic lineages and CAZy family data. A set of 13 documented enzyme activities was selected and modelled within an enzyme simulator according to a method described previously in the context of biosynthesis. A diverse population of experimentally observed HMOs was fed to the simulator, and the enzymes matching specific bacterial species were recorded, based on their appearance of individual enzymes in the UniProt dataset. Pairs of bacterial species were identified that possessed complementary enzyme profiles enabling the digestion of the HMO glycome, from which potential symbioses could be inferred. Conversely, bacterial species having similar GH enzyme profiles were considered likely to be in competition for the same set of dietary HMOs within the gut of the newborn. We generated a set of putative biodegradative networks from the simulator output, which provides a visualisation of the ability of organisms to digest HMO and mucin-type O-glycans. B. bifidum, B. longum and C. perfringens species were predicted to have the most diverse GH activity and therefore to excel in their ability to digest these substrates. The expected cooperative role of Bifidobacteriales contrasts with the surprising capacities of the pathogen. These findings indicate that potential pathogens may associate in human gut based on their shared glycoside hydrolase digestive apparatus, and which, in the event of colonisation, might result in dysbiosis. The methods described can readily be adapted to other enzyme categories and species as well as being easily fine-tuneable if new degrading enzymes are identified and require inclusion in the model. [ABSTRACT FROM AUTHOR]

Objective: This paper outlines the evolution of mental health rehabilitation in NSW, where allocation of health resources has repeatedly contradicted the policy intention to reorient services from inpatient to community-based services, leaving community rehabilitation the poor and disconnected cousin of inpatient services. The expanding role of community-managed organisations (CMOs) in psychosocial rehabilitation, the introduction of the National Disability Insurance Scheme (NDIS), and emerging service models have helped foster a maturing housing and social care environment, but present reality and the integration of health and social care services remains at a distance from best evidence practice. Conclusion: The challenge of the next decade of mental health reform is to embrace and consolidate greater service diversity and complexity. Understanding what factors influenced present reality is important in providing guardrails for the future, enabling the current wave of renewal and reinvestment in NSW to build on the strengths of past developments and steer a course around their weaknesses. [ABSTRACT FROM AUTHOR]

Windmountainite is relatively rare: aside from its occurrence at Wind Mountain, it is only reported (but not confirmed by quantitative chemical analysis) on Mindat.org (accessed June 2023) at the Aris phonolite intrusion in Windhoek, Namibia, where other palygorskite-group minerals have been found. Representative crystal-structure models of (A) palygorskite group, (B) amphibole supergroup, (C) sepiolite group, and (D) 2:1 phyllosilicates (mica group), illustrating the structural similarities between windmountainite (palygorskite group) to other minerals. WINDMOUNTAINITE, a hydrated ferric iron magnesium silicate Graph HT ht , was discovered by one of us (AMM) in material collected in 2012 from Wind Mountain, New Mexico (fig. 1). [Extracted from the article]

The IUBMB enzyme classification system, available at the IUBMB ExplorEnz website, uses a four‐component number (the EC number) that identifies an enzyme in terms of reaction catalysed. There were originally six recognized groups of enzymes: Oxidoreductases (EC 1), Transferases (EC 2), Hydrolases (EC 3), Lyases (EC 4), Isomerases (EC 5) and Ligases (EC 6). Of these, the lyases, which are defined as 'enzymes that cleave C‐C, C‐O, C‐N and other bonds by means other than by hydrolysis or oxidation', present particular recognition and classification problems. Recently, a new class, the Translocases (EC 7), has been added, which incorporates enzymes that catalyse the movement of ions or molecules across membranes or their separation within membranes. A new subclass of the isomerases has also been included for those enzymes that alter the conformations of proteins and nucleic acids. Newly reported enzymes are being regularly added to the list after validation and where new information affects the classification of an existing entry, a new EC number is created, but the old one is not reused. [ABSTRACT FROM AUTHOR]

Purpose: Relating dose-volume histogram (DVH) information to patient outcomes is critical for outcomes research in radiation oncology, but this is statistically challenging. We performed this focused review of DVH toxicity studies to characterize current statistical approaches and determine the need for updated reporting recommendations. Methods and materials: We performed a focused MEDLINE search to identify studies published in 5 radiation oncology specialty journals that associated dosimetry with toxicity outcomes in humans receiving radiotherapy between 2015 and 2021. Elements abstracted from each manuscript included the study outcome, organs-at-risk (OARs) considered, DVH parameters analyzed, summary of the analytic approach, use of multivariable statistics, goodness-of-fit reporting, completeness of model reporting, assessment of multicollinearity, adjustment for multiple comparisons, and methods for dichotomizing variables. Each study was also assessed for sufficient reporting to allow for replication of results. Results: The MEDLINE search returned 2,300 studies for review and 325 met the inclusion criteria for the analysis. DVH variables were dichotomized using cut points in 154 (47.4%) studies. Logistic regression (55.4% of studies) was the most common statistical method used to relate DVH to toxicity outcomes, followed by Cox regression (20.6%) and linear regression (12.0%). Multivariable statistical tests were performed in 226 (69.5%) studies; of these, the possibility of multicollinearity was addressed in 47.8% and model goodness-of-fit were reported in 32.6%. The threshold for statistical significance was adjusted to account for multiple comparisons in 41 of 196 (17.1%) studies that included multiple statistical comparisons. Twenty-eight (8.6%) studies were classified as missing details necessary to reproduce the study results. Conclusions: Current practices of statistical reporting in DVH outcomes suggest that studies may be vulnerable to threats against internal and external validity. Recommendations for reporting are provided herein to guard against such threats and to promote cohesiveness among radiation oncology outcomes researchers. [ABSTRACT FROM AUTHOR]

Purpose: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all‐cause mortality. Materials and Methods: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4–L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid‐L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death. Results: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area. Conclusions: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa. This study strongly supports that body composition is related to mortality in men with localized prostate cancer. The inclusion of psoas area in the recursive partitioning analysis classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. [ABSTRACT FROM AUTHOR]

Tourmaline is an effective indicator mineral for porphyry Cu-Au-Mo exploration because the compositional and morphological features of tourmaline in such systems are distinct from those found in non-mineralized environments. The texture and chemistry of detrital tourmaline was investigated using local stream sediment samples in the vicinity of the Casino calc-alkalic porphyry Cu-Au-Mo deposit (Yukon, Canada) to identify prospective grains by comparing them to grains in bedrock samples from the deposit. Bulk stream sediment samples were collected up to 18 km downstream of the Casino deposit and as far as 30 km away in a drainage basin that does not contain any known porphyry Cu mineralization. Overall, a method combining the physical and chemical characteristics is effective in discriminating detrital tourmaline, including morphology (i.e., grain clusters), inclusion populations (i.e., lack of inclusions), crystal chemistry (i.e., Na-dominant X -site, Mg/Fe dominant Y -site, and OH−/O2− dominant W -site), and trace-element compositions (i.e., high Sr/Pb values and relatively low Zn/Cu values). Detrital tourmaline was evaluated on the basis of these parameters. Detrital grains are light brown to brown, sub- to euhedral, and range in texture from individual isolated grains to clusters of radiating aggregates. Tourmaline in the Casino deposit compositionally ranges from Fe-rich; 0.03–2.54 apfu , avg. 0.61 to Mg-rich, avg. 2.00 apfu , with a minor povondraite (Fe3+) component. Detrital tourmaline is similar in composition with Fe-rich; 0.03–3.73 apfu, avg. 1.04 to Mg-rich, 0.14–2.93 apfu , avg. 1.83 to tourmaline in bedrock at Casino. In both bedrock and detrital tourmaline, alkali- and alkaline-earth element concentrations are similar with Na > Ca > vacancy. The most relevant distinctions between tourmaline groups comes from grain morphology (i.e., clustered versus individual grains) and trace-element chemistry. A significant abundance of prospective porphyry Cu tourmaline grains (14 % of total recovered tourmaline in one sample) can be observed up to 18 km downstream from the Casino deposit (the current limit of sampling), while in drainages where there are no known porphyry Cu systems, tourmaline fitting these criteria is absent and reflect grains sourced from other geologic environments (e.g., pegmatitic, granitic, and metamorphic). This method provides a new addition to the indicator mineral toolbox for the exploration of porphyry Cu systems. • Detrital tourmaline from porphyry Cu systems can be distinguished from background grains. • Textures, major, and trace-element chemistry are required for effective classification. • Tourmaline morphology and inclusions can be just as effective as trace-elements for determining source. [ABSTRACT FROM AUTHOR]

Simple Summary: Oligometastatic prostate cancer has classically been defined as a small volume of prostate cancer spread as defined by imaging using CT, MRI, and bone scans. With development and integration of more sensitive functional imaging including PSMA-PET imaging more oligometastatic disease will be detected than was found with conventional imaging techniques. We are currently lacking data directing the best treatment course for these oligometastatic prostate cancer cases found on PET imaging who would have been defined as localized disease prior to PET imaging. Herein, we discuss the concept of stage migration and discuss current problems and challenges with the current definition of oligometastatic disease as imaging modalities have progressed in our field. Oligometastatic prostate cancer has traditionally been defined in the literature as a limited number of metastatic lesions (either to soft tissue or bone), typically based on findings seen on CT, MRI, and skeletal scintigraphy. Although definitions have varied among research studies, many important clinical trials have documented effective treatments and prognostication in patients with oligometastatic prostate cancer. In current clinical practice, prostate-specific membrane antigen (PSMA)-PET/CT is increasingly utilized for the initial staging of high-risk patients and, in many cases, detecting metastases that would have otherwise been undetected with conventional staging imaging. Thus, patients with presumed localized and/or oligometastatic prostate cancer undergo stage migration based on more novel molecular imaging. As a result, it is challenging to apply the data from the era before widespread PET utilization to current clinical practice and to relate current trials using PSMA-PET/CT for disease detection to older studies using conventional staging imaging alone. This manuscript aims to review the definition of oligometastatic prostate cancer, summarize important studies utilizing both PSMA-PET/CT and conventional anatomic imaging, discuss the concept of stage migration, and discuss current problems and challenges with the current definition of oligometastatic disease. [ABSTRACT FROM AUTHOR]

Human milk oligosaccharides (HMOs) form the third most abundant component of human milk and are known to convey several benefits to the neonate, including protection from viral and bacterial pathogens, training of the immune system, and influencing the gut microbiome. As HMO production during lactation is driven by enzymes that are common to other glycosylation processes, we adapted a model of mucin-type GalNAc-linked glycosylation enzymes to act on free lactose. We identified a subset of 11 enzyme activities that can account for 206 of 226 distinct HMOs isolated from human milk and constructed a biosynthetic reaction network that identifies 5 new core HMO structures. A comparison of monosaccharide compositions demonstrated that the model was able to discriminate between two possible groups of intermediates between major subnetworks, and to assign possible structures to several previously uncharacterised HMOs. The effect of enzyme knockouts is presented, identifying β-1,4-galactosyltransferase and β-1,3-N-acetylglucosaminyltransferase as key enzyme activities involved in the generation of the observed HMO glycosylation patterns. The model also provides a synthesis chassis for the most common HMOs found in lactating mothers. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% to 15% of patients with multiple myeloma (MM) are diagnosed with high-risk disease and have poor prognosis. Clinical trial data supports the combined use of selinexor, bortezomib, and dexamethasone (XVd) for treatment of patients with MM who have received at least 1 prior therapy. Information on the efficacy of XVd and of subsequent allogeneic stem cell transplantation (SCT) in heavily pretreated patients with high-risk MM is limited. Case Report: We present a case of a 58-year-old woman with high-risk MM (revised International Staging System Stage III; serum b2-microglobulin; 8.0 mg/L; and presence of del[17p]) who had received 8 prior treatment lines, and whose disease was refractory to ixazomib, bortezomib, and all immunomodulatory agents. Before initiating XVd (once weekly 1.3 mg/m2 bortezomib subcutaneously, 80 mg selinexor per os, and 40 mg dexamethasone per os), the patient had severely hypoplastic bone marrow and was transfusion dependent. After 1 cycle of XVd, she achieved a partial response, and after 4 cycles, a very good partial response (VGPR). No adverse reactions to selinexor were observed. Because of the VGPR, a haploidentical transplant was planned. At posttransplant week 4, the patient had become transfusion independent. She remained relapse-free for 13 months after initiating XVd. Maintenance treatment with lenalidomide was initiated, and following receipt of donor lymphocyte infusions due to loss of donor chimerism, the patient's light chain levels improved. Conclusions: This report presents the cytogenetics and management of a heavily pretreated patient with high-risk MM treated with SVd followed by SCT. [ABSTRACT FROM AUTHOR]

Timely crop planting is a foundation for climate-resilient rice-wheat systems of the Eastern Gangetic Plains—a global food insecurity and poverty hotspot. We hypothesize that the capacity of individual farmers to plant on time varies considerably, shaped by multifaceted enabling factors and constraints that are poorly understood. To address this knowledge gap, two complementary datasets were used to characterize drivers and decision processes that govern the timing of rice planting in this region. The first dataset was a large agricultural management survey (rice-wheat: n = 15,245; of which rice: n = 7597) from a broad geographic region that was analyzed by machine learning methods. The second dataset was a discussion-based survey (n = 112) from a more limited geography that we analyzed with graph theory tools to elicit nuanced information on planting decisions. By combining insights from these methods, we show for the first time that differences in rice planting times are primarily shaped by ecosystem and climate factors while social factors play a prominent secondary role. Monsoon onset, surface and groundwater availability, and land type determine village-scale mean planting times whereas, for resource-constrained farmers who tend to plant later ceteris paribus, planting is further influenced by access to farm machinery, seed, fertilizer, and labor. Also, a critical threshold for economically efficient pumping appears at a groundwater depth of around 4.5 m; below this depth, farmers do not irrigate and delay planting. Without collective action to spread risk through synchronous timely planting, ecosystem factors such as threats posed by pests and wild animals may further deter early planting by individual farmers. Accordingly, we propose a three-pronged strategy that combines targeted strengthening of agricultural input chains, agroadvisory development, and coordinated rice planting and wildlife conservation to support climate-resilient agricultural development in the Eastern Gangetic Plains. [ABSTRACT FROM AUTHOR]

Background: Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. Methods and materials: We performed a prospective trial that enrolled participants > 18 years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30 mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. Results: Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. Conclusions: These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT. [ABSTRACT FROM AUTHOR]

Introduction: For patients with high risk prostate cancer, conventionally fractionated treatment of the pelvic lymphatics and hypofractionated treatment to the prostate can be delivered simultaneously with dose painting. The purpose of this technical note is to highlight unexpected hot spots within the low dose lymphatic target volume as a clinical problem that we have observed with dose painting, and to describe a simple approach to account for this during treatment planning. Summary: We describe the creation of a control structure that can be incorporated into the optimization objective function. An upper constraint objective can be placed on the control structure such that heterogeneity within the plan is limited to the area near the high dose target volume and better emulates the dosimetry of a conventionally fractionated sequential boost plan. [ABSTRACT FROM AUTHOR]

Most rice farmers in Nepal's Terai region do not fully utilize irrigation during breaks in monsoon rainfall. This leads to yield losses despite abundant groundwater resources and ongoing expansion of diesel pumps and tubewell infrastructure. We investigate this puzzle by characterizing delay factors governing tubewell irrigation across wealth and precipitation gradients. After the decision to irrigate, different factors delay irrigation by roughly one week. While more sustainable and inexpensive energy for pumping may eventually catalyze transformative change, we identify near-term interventions that may increase rice farmers' resilience to water stress in smallholder-dominated farming communities based on prevailing types of irrigation infrastructure. [ABSTRACT FROM AUTHOR]

Objectives: There is emerging interest in models of care that focus on assessment and brief inpatient treatment (two to three days) including psychiatric emergency care centre units and short-stay units in Australia. We present the development of a functionally integrated Missenden Assessment Unit and six-bed short-stay unit in the new Professor Marie Bashir Centre at Royal Prince Alfred Hospital in inner-city Sydney. The focus was on collaboration between emergency, drug and alcohol and mental-health services in developing the short-stay unit and Missenden Assessment Unit with joint admission and resource use. We outline the models of care and findings from the 2016 evaluation following the initial two years of operation and consider ongoing challenges.Conclusion: The Missenden Assessment Unit provides an alternative point of presentation for mental-health drug and alcohol patients. The short-stay unit provides coordinated, therapeutic interventions. The Missenden Assessment Unit/short-stay unit reduced the burden of presentations to the emergency department while providing the opportunity for training and collaboration. Further refinement of the models of care should occur with policy development and via research. [ABSTRACT FROM AUTHOR]

We present atomistic molecular dynamics computer simulations of the bulk phases of a model liquid crystal system based on 8CB. The model differs from real 8CB because it employs a united-atom description to eliminate all hydrogen atoms, and neglects all long-range electrostatic interactions. Despite this simplification, the pressure-temperature phase diagram shows an order-disorder transition, in which isotropic, smectic, and nematiclike behaviors are observed. A detailed analysis of the inter- and intramolecular structures of the ordered phases is given, together with an examination of finite size effects and the equilibration times of the system. It is shown that, whereas a system may appear to be thermodynamically and mechanically equilibrated after a period of 10–15 ns, it is possible for an imprint of the starting configuration to persist for much longer time scales. In the present case, however, such an imprint does not appear to affect the observed phase behavior. [ABSTRACT FROM AUTHOR]

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs. [ABSTRACT FROM AUTHOR]

We analyze a class of norms defined via an optimal interpolation problem involving the composition of norms and a linear operator. This construction, known as infimal postcomposition in convex analysis, is shown to encompass various norms which have been used as regularizers in machine learning, signal processing, and statistics. In particular, these include the latent group lasso, the overlapping group lasso, and certain norms used for learning tensors. We establish basic properties of this class of norms and we provide dual norms. The extension to more general classes of convex functions is also discussed. A stochastic block-coordinate version of the Douglas-Rachford algorithm is devised to solve minimization problems involving these regularizers. A prominent feature of the algorithm is that it yields iterates that converge to a solution in the case of nonsmooth losses and random block updates. Finally, we present numerical experiments with problems employing the latent group lasso penalty. [ABSTRACT FROM AUTHOR]

Abstract Hexokinase 1 and 2 have been shown to inhibit Bak- and Bax-mediated apoptosis, leading us to combine the histone deacetylase inhibitor romidepsin with clotrimazole or bifonazole, two compounds that reportedly decrease mitochondrial localization of hexokinases. Cancer cell lines derived from breast, kidney, lung, colon or ovarian cancers were treated with a short-term exposure to 25 ng/ml romidepsin combined with either clotrimazole or bifonazole. The combination of romidepsin with 25 µM clotrimazole or bifonazole resulted in increased annexin staining compared to cells treated with any of the drugs alone. Cell death was caspase-mediated, as the pan-caspase inhibitor Q-VD-OPh was found to inhibit apoptosis induced by the combination. A549 lung cancer cells or HCT-116 cells deficient in Bak and Bax were also resistant to apoptosis with the combination implicating the intrinsic apoptotic pathway. We found that a 24 h treatment with clotrimazole or bifonazole decreased total hexokinase 2 expression, resulting in a 76% or 60% decrease, respectively, of mitochondrial expression of hexokinase 2. Mitochondrial hexokinase 1 levels increased 2-fold or less. Our work suggests that the combination of a short-term romidepsin treatment with bifonazole or clotrimazole leads to increased apoptosis, most likely due to decreased mitochondrial expression of hexokinase 2. Highlights • Drug combinations are needed to overcome resistance to histone deacetylase inhibitors. • Clotrimazole and bifonazole decrease mitochondrial localization of hexokinases. • Romidepsin combined with clotrimazole or bifonazole leads to cancer cell apoptosis. • Targeting hexokinase 2 may increase the efficacy of histone deacetylase inhibitors. [ABSTRACT FROM AUTHOR]

Objective: To determine if magnetic resonance imaging (MRI)/ultrasound fusion-targeted prostate biopsy (TB) would lead to increased recommendations of aggressive radiotherapy treatments for higher risk prostate cancer compared to systematic biopsy (SB) results.Methods: Clinicopathologic data of 533 men who underwent both TB and SB from 2014 to 2017 was analyzed. TB was performed in addition to SB in patients with detection of MRI suspicious lesions. Three patient cohorts were established: (1) biopsy naïve (80/533, 15.0%), (2) active surveillance (185/533, 34.7%), and (3) prior negative biopsy (268/533, 50.3%). Cancer risk categorical criteria were established with recommended radiotherapy treatment for each. Variation of risk classification due to biopsy method for all patients and within each cohort was analyzed using either a chi-squared statistic or Fisher's exact test. McNemar's pairwise analyses were performed for all risk categories between TB and SB to assess the effects of TB on high-risk cancer identification and subsequent radiotherapy recommendations.Results: Number of patients within cancer risk categories (1. "No Cancer or Low-Risk"; 2. "More Favorable Intermediate-Risk"; 3. "Less Favorable Intermediate-Risk"; 4. "High-Risk") varied significantly based on TB and SB pathology among all patients combined (P <.0001), in cohort 2 (P = .0005), and in cohort 3 (P <0.0001). Further, among all patients, TB increased cancer risk classification and correspondingly would result in more aggressive radiotherapy recommendations: "No Cancer or Low-Risk" to "Less Favorable Intermediate-Risk" (30/343, P <0.0001) and "No Cancer or Low-Risk" to "High-Risk" (31/353, P <.0001).Conclusion: Among men with prostate cancer, TB commonly led to reclassification to a higher risk group, which is accompanied by more aggressive radiotherapy treatment recommendations when compared with SB findings alone. [ABSTRACT FROM AUTHOR]

Highlights • Mechanization provided more predictable profit and return on investment of inputs. • Applying inputs by hand disassociated fertilizer from end of season yield. • Chest-mounted spreader can be stop-gap between hand distributed inputs and zero-till. • Labor efficiency was roughly doubled by using chest-mounted spreader. • Chest-mounted spreader increased within and between-field uniformity of yield. Abstract Nepal is at a crossroads of diminishing farm-labor and inadequate investment into farming operations that, among other factors, have stagnated domestic wheat yield. Cultural and economic constraints have hindered the widespread adoption of more expensive precision agriculture technologies like zero-till that have the capacity to improve labor and farm input efficiencies. To capture the benefits from added precision of application but with the ability to fit within the current semi-mechanized seed bed preparation and tillage system, we introduced a low-cost, chest mounted seed and fertilizer. We found that simple mechanization caused yield efficiencies to be positive and significant for nitrogen and phosphate. Seed rates using this method were positively associated with seedling density. This led to both yield and profit being more predictable for farmers. Conversely, hand-applied inputs caused a disassociation between inputs and end of season yield and therefore added a large measure of risk to their farming operations. [ABSTRACT FROM AUTHOR]

The article offers information on the study of use of Radiation therapy (RT) for locally advanced head and neck cancer (LAHNC) complications. Topics discussed include experiment performed for detailed brain segmentation of treatment plans for a cohort of randomly-selected patients who received definitive RT for locally-advanced nasopharyngeal carcinoma and tonsillar carcinoma and results focuses concern for visual, motor, and memory domains in patients with nasopharyngeal carcinoma.

This study aimed to investigate the dynamics of the vaginal wall dose for interstitial brachytherapy (ISBT). A patient undergoing ISBT was selected as the patient case. The phantom case was generated to simulate the patient case in all regards with the exception of parallel needle positions. The vaginal wall was contoured as a 0.5-cm expansion around the vaginal surface of the obturator. The prescribed ISBT dose was 20 Gy in 4 fractions. Six treatment plans were generated by modifying relative dwell times and needle positions (DTNP). The volume of the vaginal wall receiving > 150% of prescription dose (V > 150% ) and D 2cc of the vaginal wall were compared among plans. The V > 150% was much larger in the patient case (49.3%) due to unparallel needles compared with the phantom case (14.3%) without modification (plan 1). Among the 6 plans, reduced dwell time (plan 3) and no dwell time (plans 5 and 6) on the vaginal surface needles had the lowest vaginal wall doses with the use of a central obturator needle in both cases. In comparison of patient case plans 1, 3, 5, and 6, V 150% was 49.2%, 19.0%, 21.3%, and 28.7%, respectively, and D 2cc was 41.15 Gy, 33.10 Gy, 36.51 Gy, and 34.37 Gy, respectively, which was limited around each loaded needle. Modification of DTNP is able to reduce the vaginal wall volume exceeding 150% of the prescription dose in the patient case. Understanding these dynamics of the vaginal wall dose will improve dose optimization of ISBT and may reduce vaginal morbidities. [ABSTRACT FROM AUTHOR]

Glycosyltransferases are a class of enzymes that catalyse the posttranslational modification of proteins to produce a large number of glycoconjugate acceptors from a limited number of nucleotide-sugar donors. The products of one glycosyltransferase can be the substrates of several other enzymes, causing a combinatorial explosion in the number of possible glycan products. The kinetic behaviour of systems where multiple acceptor substrates compete for a single enzyme is presented, and the case in which high concentrations of an acceptor substrate are inhibitory as a result of abortive complex formation, is shown to result in non-Michaelian kinetics that can lead to bistability in an open system. A kinetic mechanism is proposed that is consistent with the available experimental evidence and provides a possible explanation for conflicting observations on the β-1,4-galactosyltransferases. Abrupt switching between steady states in networks of glycosyltransferase-catalysed reactions may account for the observed changes in glycosyl-epitopes in cancer cells. [ABSTRACT FROM AUTHOR]

Charleshatchettite, CaNb4O10 (OH)2 ⋅ 8H2O, is a new mineral related to franconite and hochelagaite, discovered on a fracture surface of a nepheline syenite at Mont Saint -Hilaire, Québec, Canada. The mineral occurs in white globules (~0.15-0.20 mm in diameter) composed of radiating crystals with individual crystals having average dimensions of ~0.002 x 0.010 x 0.040 mm. Crystals are euhedral, bladed (flattened on [100]), and are transparent to translucent. The mineral is associated with albite, quartz, muscovite, pyrrhotite, pyrite, ancylite-(Ce), and siderite. Charleshatchettite is inferred to be biaxial (-) with α' = ~1.72(2) and γ' = ~1.82(2). Data from chemical analyses (SEM-EDS, n = 8): CaO 7.96 (7.04-8.63), MgO 0.24 (0.08-0.78), Al2O3 0.13 (b.d.-0.49), SiO2 1.04 (0.49-1.88), TiO2 3.64 (2.45-5.05), Nb2O5 68.07 (64.83-71.01), and H2O (calc) 22.96, total 104.04 wt% gives the average empirical formula: (Ca1.00Mg0.04)Σ1.04 (Nb3.62Ti0.32Si0.12Al0.02) Σ4.08O10(OH)2 ⋅ 8H2O (based on 20 anions). This is similar to that of hochelagaite (CaNb4O11 ⋅ nH2O), although the two are readily distinguished by their powder X -ray diffraction patterns. Results from single-crystal X -ray diffraction analysis give a = 21.151(4), b = 6.496(2), c = 12.714(3) Å, and β = 103.958(3)°, space group C2/c (no. 15). The crystal structure, refined to R = 5.64%, contains 1 Ca site, 2 distorted octahedral Nb sites, and 10 O sites. It consists of clusters of four edge-sharing Nb(O,OH)6 octahedra, linked through shared corners to adjacent clusters, forming layers of Nb(O,OH)6 octahedra. These alternate along [100] with layers composed of Ca(H2O)8 polyhedra, the two being linked together by H-bonding. Charleshatchettite is a late-stage mineral, interpreted to have developed through the interaction of low-T (<150 °C) aqueous fluids with an alkali-, Nb-rich precursor under slightly reducing conditions and a highly alkaline pH. The precursor mineral(s) is unknown but is considered to have been Nb-dominant, relatively unstable under slightly reducing as well as alkaline conditions, and likely itself would have been a product of near-complete Nb/Ta fractionation due to the paucity of Ta in charleshatchettite. Charleshatchettite is crystallochemically related to Sandia Octahedral Molecular Sieves [SOMS; Na2Nb2-xMxO6-x (OH)x ⋅ H2O with M = Ti, Zr, Hf], a group of synthetic compounds with strong ion exchange capabilities. [ABSTRACT FROM AUTHOR]

This paper combined experimentally-measured grinding wheel topography data taken around the entire circumference of the grinding wheel with a kinematic simulation of the grinding process. Several new methods were developed in order to create the resulting high-fidelity and computationally-efficient simulation. First a novel peak-removal technique was developed and applied to effectively remove erroneous peaks in the raw wheel topography data. Next a method was found to determine only the active cutting points on the wheel model by considering the kinematics of the grinding process. This new approach was able to reduce the simulation time from over twelve hours to about four seconds without losing any information about the cutting edge–workpiece interaction. The resulting predicted workpiece surface was then experimentally validated by carrying out a grinding experiment using the same grinding wheel used to develop the grinding wheel computer model and then measuring the resulting workpiece surface profile. Good agreement between simulated and experimental workpiece profiles was observed. Finally, the validated simulator was used to develop a kinematically-exact method to calculate the maximum uncut chip thickness and the simulation results were investigated for different depths of cut, wheel speeds and workpiece feeds. [ABSTRACT FROM AUTHOR]

Context: Accurate estimation of life expectancy in patients with brain metastases is critical for counseling and choosing appropriate therapy. Performance status is the single greatest determinant of overall survival in this population. However, current measures of performance status are subjective and often based on brief clinical encounters. Gait speed is an objective, reliable predictor of overall health and survival.Objective: The purpose of this study was to evaluate the relationship between gait speed and survival in patients with brain metastases.Methods: We conducted a retrospective review of all patients with documented gait speed and Karnofsky performance status seen in consultation for newly diagnosed brain metastases from 2014 to 2015. Gait speed was measured during neurological examination over 4 m at normal pace. Graded prognostic assessment scores were calculated from clinical information. The primary outcomes were overall survival and 30-day mortality.Results: Eighty-five of 88 patients (97%) met inclusion criteria. Overall, the median gait speed was 0.7 m/s (range 0-1.0 m/s). Gait speed was associated with increased overall survival in addition to graded prognostic assessment score. Median survival was longer in patients with normal gait speed (>0.6 m/s, 11.9 months) compared to those with slow gait speed (≤0.6 m/s, 4.5 months, P < 0.001) or who were nonambulatory (1.1 months, P < 0.001). Thirty-day mortality for normal, slow, and nonambulatory patients was 0%, 15%, and 42%, respectively. The graded prognostic assessment overestimated actual survival for nonambulatory patients (2.2 vs. 1.1 months) and underestimated for those with normal gait speed (4.4 vs. 11.9 months).Conclusion: Gait speed is associated with overall survival in patients with newly diagnosed brain metastases. Gait speed assessment is simple, objective, and may provide additional prognostic information to improve life expectancy estimation and management decisions. [ABSTRACT FROM AUTHOR]

Background: Eolambia caroljonesa is the most abundant dinosaur in the lower Cenomanian Mussentuchit Member of the Cedar Mountain Formation of Utah, and one of the most completely known non-hadrosaurid iguanodontians from North America. In addition to the large holotype and paratype partial skulls, copious remains of skeletally immature individuals, including three bonebeds, have been referred to E. caroljonesa. Nevertheless, aspects of the postcranial anatomy of this taxon, particularly the pelvic girdle, have remained ambiguous due to the lack of associated postcranial material of larger, more mature individuals. Methodology/Principal findings: Here we describe a recently discovered associated partial postcranial skeleton of a large Eolambia caroljonesa. This specimen, FMNH PR 3847, provides new anatomical data regarding the vertebral column and pelvic girdle, supplementing previous diagnoses and descriptions of E. caroljonesa. A new phylogenetic analysis incorporating information from FMNH PR 3847 places E. caroljonesa as a basal hadrosauromorph closely related to Protohadros byrdi from the Cenomanian Woodbine Formation of Texas. Histological analysis of FMNH PR 3847 reveals that it represents a subadult individual eight to nine years of age. Taphonomic analysis indicates that FMNH PR 3847 was preserved in a crevasse splay deposit, along with an unusual abundance of small crocodylomorph material. Conclusions/Significance: FMNH PR 3847 provides a wealth of new morphological data, adding to the anatomical and systematic characterization of Eolambia caroljonesa, and histological data, revealing new information on growth history in a basal hadrosauromorph. Taphonomic characterization of FMNH PR 3847 and associated vertebrate material will allow comparison with other vertebrate localities in the Mussentuchit Member of the Cedar Mountain Formation. [ABSTRACT FROM AUTHOR]

Nolzeite, Na(Mn,□)2[Si3(B,Si)O9(OH)2]·2H2O, is a new mineral found in altered sodalite syenite at the Poudrette quarry, La Vallée-du-Richelieu, Montérégie (formerly Rouville County), Québec, Canada. Crystals are colourless to pale green and are acicular with average dimensions of 5 μm×8 μm×55 μm. They occur as radiating to loose, randomly oriented groupings within vugs associated with aegirine, nepheline, sodalite, eudialyte-group minerals, analcime, natron, pyrrhotite, catapleiite, steedeite and the unidentified mineral, UK80. Nolzeite is non-pleochroic, biaxial, with nmin = 1.616(2) and nmax = 1.636(2) and has a positive elongation. The average of six chemical analyses gave the empirical formula: Na1.04(Mn1.69□0.24 Fe0.05Ca0.02)Σ=2.00(Si2.96S0.04)Σ=3.00(B0.70Si0.30)Σ=1.00O9(OH)2·2H2O based on 13 anions. The Raman spectrum shows six distinct bands occurring at ∼3600-3300 cm-1 and 1600-1500 cm-1 (O-H and H-O-H bending), 1300-1200 cm-1 (B-OH bending), 1030-800 cm-1 (Si-O-Si stretching) as well as 700-500 cm-1 and 400-50 cm-1 (Mn-O and Na-O bonding, respectively). The FTIR spectrum for nolzeite shows bands at ∼2800-3600 cm-1 (O-H) stretching, a moderately sharp band at 1631 cm-1 (H-O-H) bending, strong, sharp bands at ∼650-700 cm-1, ∼800-840 cm-1, and ∼900-1100 cm-1 (Si-O and B-O) bonds. Nolzeite is triclinic, crystallizing in space group P with a = 6.894(1), b = 7.632(2), c = 11.017(2) Å, α = 108.39(3), β = 99.03, γ = 103.05(3)°, V = 519.27 Å3, and Z = 2. The crystal structure was refined to R = 12.37% and wR2 = 31.07% for 1361 reflections (Fo > 4σFo). It is based on chains of tetrahedra with a periodicity of three (i.e. a dreier chain) consisting of three symmetrically independent SiO4 tetrahedra forming C-shaped clusters closed by BO2(OH)2 tetrahedra, producing single loop-branched dreier borosilicate chains. The chains are linked through shared corners to double chains of edge-sharing MnO5(OH) octahedra. Nolzeite is a chain silicate closely related to steedeite and members of the sérandite-pectolite series. Paragenetically, nolzeite is late-stage, probably forming under alkaline conditions and over a narrow range of low pressures and temperatures. [ABSTRACT FROM AUTHOR]

This paper describes the design and validation of an upgraded grinding wheel scanner system that controls the position of a Nanovea CHR-150 Axial Chromatism sensor along the x - and y -directions of the wheel surface to measure and characterize wheel surface topography. The scanner features a novel homing system that enables the wheel to be removed from the scanner, used on a grinding machine and then re-mounted and re-homed so that the same location on the wheel surface can be repeatedly measured and monitored. The average standard deviation for homing was 27.6 μm and 19.3 μm in the x - and y -directions, respectively, which is more than adequate for typical area scans of 25 mm 2 . After homing, the scanner was able to repeatedly measure features that were similar in size to an abrasive grain (∼200 μm diameter) with an average error of 9.3 μm and 5.9 μm in the x - and y -directions, respectively. The resulting topography measurements were compared with Scanning Electron Microscope images to demonstrate the accuracy of the scanner. A custom particle filter was developed to process the resulting data and a novel analysis technique involving the rate of change of measured area was proposed as a method for establishing the reference wheel surface from which desired wheel topography results can be reported such as the number of cutting edges, cutting edge width and cutting edge area as a function of radial depth. [ABSTRACT FROM AUTHOR]

Background: To assess the clinical outcomes in patients with greater than 4 newly diagnosed brain metastases treated with focal stereotactic radiotherapy alone. Methods: All patients with five or more brain metastases who received focal radiotherapy without whole brain radiation or resection were included in this retrospective analysis. Distant brain failure (DBF), overall survival (OS) and toxicity were reported. Results: Thirty-six patients met inclusion with median clinical follow-up of 6.3 months (range: 1.1, 51.4). Twenty-nine patients received stereotactic radiosurgery (SRS) to a median dose of 20 Gy (16-20), and 7 received fractionated stereotactic radiotherapy (FSRT) to a median dose of 30 Gy (25, 30) in five fractions. The median lesion number and total brain metastases volume was 6 (5, 14) and 1.55 cc (0.12, 32.96), respectively. The Kaplan-Meier estimate of DBF at six-month was 58%, and survival probability at 1 year was 49%. Twenty percent of patients experienced systemic death without CNS relapse. Eight percent experienced grade 3 toxicity with no grade 4 or 5 toxicity. Neither tumor volume nor number predicted DBF. Conclusions: DBF, OS and treatment toxicity were similar to historical controls with fewer than five metastases treated with focal radiation. Focal stereotactic radiotherapy alone without whole brain RT is a reasonable treatment strategy for five or more brain metastases. [ABSTRACT FROM AUTHOR]

Glycosylation is a common post-translational protein modification, in which glycans are built onto proteins through the sequential addition of monosaccharide units, in reactions catalysed by glycosyltransferases. Glycosylation influences the physicochemical and biological properties of proteins, with subsequent effects on subcellular and extracellular protein trafficking, cell–cell recognition, and ligand–receptor interactions. Glycan structures can be complex, as is the regulation of their biosynthesis, and it is only recently that the systems biology of metabolic flux control and glycosyltransferase networks has become a study in its own right. We review various models of glycosylation that have been proposed to date, based on current knowledge of Golgi structure and function, and consider how metabolic flux through glycosyltransferase networks regulates glycosylation events in the cell. [ABSTRACT FROM AUTHOR]

O-linked glycosylation is an important post-translational modification of mucin-type protein, changes to which are important biomarkers of cancer. For this study of the enzymes of O-glycosylation, we developed a shorthand notation for representing GalNAc-linked oligosaccharides, a method for their graphical interpretation, and a pattern-matching algorithm that generates networks of enzyme-catalysed reactions. Software for generating glycans from the enzyme activities is presented, and is also available online. The degree distributions of the resulting enzyme-reaction networks were found to be Poisson in nature. Simple graph-theoretic measures were used to characterise the resulting reaction networks. From a study of in-silico single-enzyme knockouts of each of 25 enzymes known to be involved in mucin O-glycan biosynthesis, six of them, β-1,4-galactosyltransferase (β4Gal-T4), four glycosyltransferases and one sulfotransferase, play the dominant role in determining O-glycan heterogeneity. In the absence of β4Gal-T4, all Lewis X, sialyl-Lewis X, Lewis Y and Sda/Cad glycoforms were eliminated, in contrast to knockouts of the N-acetylglucosaminyltransferases, which did not affect the relative abundances of O-glycans expressing these epitopes. A set of 244 experimentally determined mucin-type O-glycans obtained from the literature was used to validate the method, which was able to predict up to 98% of the most common structures obtained from human and engineered CHO cell glycoforms. [ABSTRACT FROM AUTHOR]

Torosaurus latus is an uncommon and contentious taxon of chasmosaurine ceratopsid known from several upper Maastrichtian units in western North America. We describe a partial parietal of To. latus from the Hell Creek Formation of Montana. Although the specimen’s ontogenetic maturity means that it cannot inform the ongoing debate over whether To. latus is the old adult form of the contemporary Triceratops, the specimen is one of the best-preserved To. latus parietals and supplements previous descriptions. [ABSTRACT FROM AUTHOR]

Purpose. To compare oncologic outcomes for patients with Gleason score (GS) ≥ 8 prostate adenocarcinoma treated with radical prostatectomy (RP) versus external beam radiotherapy combined with androgen deprivation (RT + ADT). Methods. Between 2001 and 2014, 121 patients with GS ≥ 8 were treated at our institution via RT + ADT (n=71) or RP (n=50) with ≥ 1 year of biochemical follow-up. Endpoints included biochemical failure (BF), distant metastasis, and initiation of salvage ADT. Results. The RT + ADT group was older, had higher biopsy GS, and had greater risk of lymph node involvement. All other pretreatment characteristics were similar between groups. Mean number of lymph nodes (LNs) sampled for patients undergoing RP was 8.2 (±6.18). Mean biochemical follow-up for all patients was 61 months. Five-year estimates of BF for the RT + ADT and RP groups were 7.2% versus 42.3%, (p<0.001). The RT + ADT group also had lower rates of distant metastasis (2% versus 7.8%) and salvage ADT (8% versus 33.8%). Conclusion. In this analysis, RT + ADT was associated with improved biochemical and metastatic control when compared to RP with limited LN sampling. How RT + ADT compares with more aggressive lymphadenectomy, as is currently our institutional standard, remains an important unanswered question. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of hypofractionated external beam radiation therapy (RT) on sexual function in patients treated for localized prostate cancer, and also to determine the effect of radiation dose to the penile bulb or crura of the corpus cavernosum on sexual function outcome. Materials and Methods Forty-one patients treated with hypofractionated RT without androgen deprivation were prescribed 67.6-70.2 Gy to the prostate, delivered in 26-28 fractions. The primary endpoint was erectile dysfunction (ED) category based on the Sexual Health Inventory for Men (SHIM) score closest to 2 years from RT. The penile bulb and crura were contoured and mean radiation dose calculated for each structure. Results The mean pretreatment SHIM score was 19.8, and the mean posttreatment SHIM score was 15.1. The ED category was decreased by ≥2 in 50% of patients with a mean penile bulb of >20 Gy compared with that in 9% of patients with a mean penile bulb dose of ≤20 Gy ( P = .003). Mean dose to the crura was highly correlated with mean dose to the penile bulb (Pearson correlation = 0.842; P <.001) but did not reach statistical significance as a predictor of ED after radiation. Conclusion Radiation dose to the penile bulb is predictive of posttreatment ED in patients treated with dose-escalated hypofractionated prostate RT. The cutpoint at which this effect was observed with this treatment is substantially lower than the previous reports. [ABSTRACT FROM AUTHOR]

Background Nearly all patients with malignant glioma will have disease recurrence. Our purpose was to define the treatment toxicity and efficacy of concurrent bevazicumab (BVZ) with hypofractionated stereotactic radiosurgery (SRS) of relatively larger targets for patients with recurrent MG. Methods A retrospective review of 21 patients with recurrent malignant glioma (18 glioblastoma, 3 WHO grade III glioma), treated at initial diagnosis with surgery and standard chemoradiation, was performed. All patients had concurrent BVZ with hypofractionatedSRS, 30 Gy in 5 fractions, with or without concurrent chemotherapy (temozolomide or CCNU). Results Median patient age was 54 years, median Karnofsky Performance Status was 80, and median target size was 4.3 cm (range, 3.4–7.5 cm). Eleven patients (52%) had previously failed BVZ. One patient had grade 3 toxicities (seizures, dysphasia), which resolved with inpatient admission and intravenous steroids/antiepileptics. Treatment-related toxicities were grade 3 (n = 1), grade 2 (n = 9), and grade 0–1 (n = 11). Kaplan-Meier median progression-free survival and overall survival estimates (calculated from start of SRS) for GBM patients (n = 18) were 11.0 and 12.5 months, respectively. Concurrent chemotherapy did not appear to show any statistically significant efficacy benefit or have any propensity for toxicity. Conclusion BVZ concurrent with hypofractionated SRS was well tolerated by this cohort of patients with relatively larger targets. Ongoing randomized trials with more moderate radiotherapy dosing may help establish the efficacy of this regimen, though intricacies of this approach, including patient selection, radiation target volume delineation/size, and optimal radiation dose, will need further evaluation. [ABSTRACT FROM PUBLISHER]

Protein N-glycosylation is a common post-translational modification that produces a complex array of branched glycan structures. The levels of branching, or antennarity, give rise to differential biological activities for single glycoproteins. However, the precise mechanism controlling the glycan branching and glycosylation network is unknown. Here, we constructed quantitative mathematical models of N-linked glycosylation that predicted new control points for glycan branching. Galactosyltransferase, which acts on N-acetylglucosamine residues, was unexpectedly found to control metabolic flux through the glycosylation pathway and the level of final antennarity of nascent protein produced in the Golgi network. To further investigate the biological consequences of glycan branching in nascent proteins, we glycoengineered a series of mammalian cells overexpressing human chorionic gonadotropin (hCG). We identified a mechanism in which galactosyltransferase 4 isoform regulated N-glycan branching on the nascent protein, subsequently controlling biological activity in an in vivo model of hCG activity. We found that galactosyltransferase 4 is a major control point for glycan branching decisions taken in the Golgi of the cell, which might ultimately control the biological activity of nascent glycoprotein. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To determine whether prostate-specific antigen (PSA) measurement after initiation of androgen deprivation therapy (ADT) but prior to the start of radiotherapy (RT) pPSA is an independent predictor of biochemical relapse-free survival (bRFS). We also sought to determine the effect, if any, of factors affecting bRFS for patients who did not achieve pPSA<0.5ng/mL. Methods and materials: A total of 105 patients with National Comprehensive Cancer Network intermediate- or high-risk prostate cancer treated with neoadjuvant ADT (median = 3.9mo) and external beam RT had pPSA data available and met the inclusion criteria. Pretreatment and treatment characteristics were included in a Cox proportional hazards model to determine effect on bRFS. Results: Median follow-up was 5.4 years. On multivariable analysis, pPSA≥0.5ng/mL was associated with worsened bRFS (hazard ratio [HR] = 2.7, P = 0.013). For the subgroup of patients with at most 1 high-risk factor, pPSA remained a statistically significant prognostic factor. For patients within this subgroup who had pPSA≥0.5ng/mL, the addition of pelvic RT was associated with a trend toward improved outcome (HR = 0.609, P = 0.083). Conclusion: For patients with intermediate- or high-risk prostate cancer receiving neoadjuvant ADT, achieving pPSA<0.5ng/mL was associated with improved rates of bRFS. Additionally, pPSA measurement may identify patients who may be able to benefit from escalated treatment such as pelvic RT. [Copyright &y& Elsevier]

Purpose To investigate added morbidity associated with the addition of pelvic elective nodal irradiation (ENI) to hypofractionated radiotherapy to the prostate. Methods and materials Two-hundred twelve patients, treated with hypofractionated radiotherapy to the prostate between 2004 and 2011, met the inclusion criteria for the analysis. All patients received 70 Gy to the prostate delivered over 28 fractions and 103 (49%) received ENI consisting of 50.4 Gy to the pelvic lymphatics delivered simultaneously in 1.8 Gy fractions. The mean dosevolume histograms were compared between the two subgroups defined by use of ENI, and various dose-volume parameters were analyzed for effect on late lower gastrointestinal (GI) and genitourinary (GU) toxicity. Results Acute grade 2 lower GI toxicity occurred in 38 (37%) patients receiving ENI versus 19 (17%) in those who did not (p = 0.001). The Kaplan-Meier estimate of grade ⩾ 2 lower GI toxicity at 3 years was 15.3% for patients receiving ENI versus 5.3% for those who did not (p = 0.026). Each rectal isodose volume was increased for patients receiving ENI up to 50 Gy (p ⩽ 0.021 for each 5 Gy increment). Across all patients, the absolute V70 of the rectum was the only predictor of late GI toxicity. When subgroups, defined by the use of ENI, were analyzed separately, rectal V70 was only predictive of late GI toxicity for patients who received ENI. For patients receiving ENI, V70 > 3 cc was associated with an increased risk of late GI events. Conclusions Elective nodal irradiation increases the rates of acute and late GI toxicity when delivered simultaneously with hypofractioanted prostate radiotherapy. The use of ENI appears to sensitize the rectum to hot spots, therefore we recommend added caution to minimize the volume of rectum receiving 100% of the prescription dose in these patients. [ABSTRACT FROM AUTHOR]

Since the publication of a list of enzymes classified according to the reactions that they catalysed, by Dixon and Webb in 1958, its content and presentation have undergone a number of significant changes. These have been necessitated by new information, as well as the need to improve clarity. The move from printed versions to the online environment, through the Explor Enz website, has allowed the process of adding newly reported enzymes to be automated and the information content to be enriched. Search and output facilities have also been enhanced. These and the problems attendant on the use of the Enzyme Commission classification system for some groups of enzymes are the subject of this review. [ABSTRACT FROM AUTHOR]

Purpose. To determine if high-risk prostate cancer responds differently to hypofractionation. Material and methods. One hundred and fifty-seven men with NCCN high-risk (T3, PSA > 20, or Gleason ≥ 8) clinically localized prostate cancer treated between 1998 and 2010 met the inclusion criteria for the analysis. Eighty-two were treated with conventional WPRT with a conventionally fractionated sequential boost to the prostate (cRT), with the prostate receiving 75-77 Gy in 1.8-2.0 Gy fractions. Seventy-five were treated with pelvic IMRT with a hypofractionated simultaneous boost to the prostate (hRT), with the prostate receiving 70 Gy in 2.5 Gy fractions. The dose to the pelvic lymph nodes was 45 Gy in the cRT group and 50.4 Gy in the hRT group, both at 1.8 Gy per fraction. Ninety-two percent received neoadjuvant hormonal ablation therapy, typically beginning two months prior to the start of RT. Results. Median follow-up was 6.5 years for men receiving cRT and 3.7 years for those receiving hRT. The actuarial rate of biochemical control at four years was 88% for cRT and 94% for hRT (p = 0.82). The rates of early rectal and urinary grade ≥ 2 toxicities were 35% (29 of 82) and 49% (40 of 82) for the cRT group and 36% (27 of 75) and 44% (33 of 75) for the hRT group. The actuarial rate of late grade ≥ 2 rectal toxicity at four years was 25% for the cRT group and 13% for the hRT group (p = 0.037). The rate of late grade 3 rectal complications was 4% (3 of 82) for patients receiving cRT and 1% (1 of 75) for patients receiving hRT. Conclusion. Initial follow-up indicates equivalent biochemical control between regimens. Patients receiving hRT experienced fewer late rectal complications. [ABSTRACT FROM AUTHOR]

Knowledge of the Michaelis–Menten parameters and their meaning in different circumstances is an essential prerequisite to understanding enzyme function and behaviour. The published literature contains an abundance of values reported for many enzymes. The problem concerns assessing the appropriateness and validity of such material for the purpose to which it is to be applied. This review considers the evaluation of such data with particular emphasis on the assessment of its fitness for purpose. [ABSTRACT FROM AUTHOR]

Background: Eolambia caroljonesa is known from copious remains from the lower Cenomanian Mussentuchit Member of the Cedar Mountain Formation in eastern Utah; however, the taxon has been only briefly described. Thus, we present herein a complete osteological description of Eolambia. Methodology/Principal Findings: The description of Eolambia presented here is based upon the holotype partial skeleton (CEUM 9758), paratype partial skull (CEUM 5212), and abundant disarticulated elements from two bonebeds that contain juvenile individuals. These remains allow the skeletal anatomy of Eolambia to be documented almost fully and a revised diagnosis to be proposed. Conclusions/Significance: The description provided here facilitates comparisons between Eolambia and other iguanodontians and allows Eolambia to be coded for additional characters in phylogenetic analyses. The close affinity between Eolambia and Probactrosaurus gobiensis from the Early Cretaceous of China supports previous hypotheses of faunal interchange between Asia and North America in the early Late Cretaceous. [ABSTRACT FROM AUTHOR]

The precise phylogenetic relationships of many non-hadrosaurid members of Iguanodontia, i.e., basal iguanodonts, have been unclear. Therefore, to investigate the global phylogeny of basal iguanodonts a comprehensive data matrix was assembled, including nearly every valid taxon of basal iguanodont. The matrix was analyzed in the program TNT, and the maximum agreement subtree of the resulting most parsimonious trees was then calculated in PAUP. Ordering certain multistate characters and omitting taxa through safe taxonomic reduction did not markedly improve resolution. The results provide some new information on the phylogeny of basal iguanodonts, pertaining especially to obscure or recently described taxa, and support some recent taxonomic revisions, such as the splitting of traditional "Camptosaurus" and "Iguanodon". The maximum agreement subtree also shows a close relationship between the Asian Probactrosaurus gobiensis and the North American Eolambia, supporting the previous hypothesis of faunal interchange between Asia and North America in the early Late Cretaceous. Nevertheless, the phylogenetic relationships of many basal iguanodonts remain ambiguous due to the high number of taxa removed from the maximum agreement subtree and poor resolution of consensus trees. [ABSTRACT FROM AUTHOR]

Purpose. To evaluate toxicity associated with the addition of elective nodal irradiation (ENI) to a hypofractionated regimen for the treatment of prostate cancer. Methods and Materials. Fifty-seven patients received pelvic image-guided IMRT to 50.4Gy in 28 fractions with a hypofractionated simultaneous boost to the prostate to 70Gy. Thirty-one patients received prostate-only treatment to 70Gy in 28 fractions. Results. Median followup was 41.1 months. Early grade =2 urinary toxicity rates were 49% (28 of 57) for patients receiving ENI and 58% (18 of 31) for those not (P = 0.61). Early grade =2 rectal toxicity rates were 40% (23 of 57) and 23% (7 of 31), respectively (P = 0.09). The addition of ENI resulted in a 21% actuarial rate of late grade =2 rectal toxicity at 4 years, compared to 0% for patients treated to the prostate only (P = 0.02). Retrospective daily dosimetry of patients experiencing late rectal toxicity revealed an average increase of 2.67% of the rectal volume receiving 70Gy compared to the original plan. Conclusions. The addition of ENI resulted in an increased risk of late rectal toxicity. Grade =2 late rectal toxicity was associated with worse daily rectal dosimetry compared to the treatment plan. [ABSTRACT FROM AUTHOR]

Background: Centrosaurine ceratopsids are well known from the middle Campanian Upper Two Medicine Formation of Montana. Four taxa have been named: Brachyceratops montanensis, Rubeosaurus ovatus, Einiosaurus procurvicornis, and Achelousaurus horneri. Rubeosaurus has been historically the most enigmatic of these taxa; only two specimens, the holotype caudal parietal bar and a referred incomplete skull, have been assigned to Rubeosaurus. Methodology/Principal Findings: A revised interpretation of the parietal processes of USNM 14765, the partial skeleton of a subadult centrosaurine formerly referred to Brachyceratops, indicates that it shares a P5 spike with the holotype of Rubeosaurus ovatus and should therefore be referred to that taxon. Brachyceratops is considered a nomen dubium. Conclusions/Significance: USNM 14765 provides additional anatomical information for Rubeosaurus ovatus. These new data are incorporated into a recent phylogenetic analysis of centrosaurine relationships; Rubeosaurus appears as the sister taxon of a clade composed of Einiosaurus, Achelousaurus, and Pachyrhinosaurus. [ABSTRACT FROM AUTHOR]

Abstract: Conventional wisdom suggests that soil water lost through transpiration by weeds can intensify crop drought stress, and that this is an important mechanism by which weed competition decreases yields and crop water productivity (CWP). To assess the impact of weed competition on soil water uptake and crop drought stress, a 3-year field experiment was conducted with maize (Zea mays L.) grown in monoculture and in combination with high-density stands of three troublesome weed species (Setaria faberi Herrm., Abutilon theophrasti Medic., and Amaranthus retroflexus L.). Independent of weed species type, when canopy light interception was largely unchanged by the presence of weeds, maize–weed mixtures did not deplete more soil water than maize grown in monoculture. Conversely, when early weed growth was vigorous, maize–weed mixtures intercepted more light early in the growing season and this resulted in higher initial rates of water depletion and drier soils. In both cases, measurements of stomatal conductance suggested that the internal water status of the maize was not significantly impacted by the presence of weeds as the soil dried. CWP was influenced by weed competition and in the most extreme case declined by almost 50% relative to monoculture maize (2.6kgm−3 vs. 5.0kgm−3). However, the impact of weeds on CWP was not uniform. Under low yield loss scenarios (ca. 10%), weeds had little impact on the soil water balance and CWP did not markedly decline relative to monoculture maize. Our results suggest that if weeds do not increase canopy light interception and are subordinate to lower parts of the canopy, high-density infestations can be retained in the field without increasing the probability of drought or substantially reducing CWP. [ABSTRACT FROM AUTHOR]