Computational modeling of beam-customization devices for heavy-charged-particle radiotherapy

A model for beam customization with collimators and a range-compensating filter based on the phase-space theory for beam transport is presented for dose distribution calculation in treatment planning of radiotherapy with protons and heavier ions. Independent handling of pencil beams in conventional pencil-beam algorithms causes unphysical collimator-height dependence in the middle of large fields, which is resolved by the framework comprised of generation, transport, collimation, regeneration, range-compensation, and edge-sharpening processes with a matrix of pencil beams. The model was verified to be consistent with measurement and analytic estimation at a submillimeter level in penumbra of individual collimators with a combinational-collimated carbon-ion beam. The model computation is fast, accurate, and readily applicable to pencil-beam algorithms in treatment planning with capability of combinational collimation to make best use of the beam-customization devices.Comment: 16 pages, 5 figure

Rolling Contact Fatigue of Ceramics

High hardness, low coefficient of thermal expansion and high temperature capability are properties also suited to rolling element materials. Silicon nitride (Si{sub 3}N{sub 4}) has been found to have a good combination of properties suitable for these applications. However, much is still not known about rolling contact fatigue (RCF) behavior, which is fundamental information to assess the lifetime of the material. Additionally, there are several test techniques that are employed internationally whose measured RCF performances are often irreconcilable. Due to the lack of such information, some concern for the reliability of ceramic bearings still remains. This report surveys a variety of topics pertaining to RCF. Surface defects (cracks) in Si{sub 3}N{sub 4} and their propagation during RCF are discussed. Five methods to measure RCF are then briefly overviewed. Spalling, delamination, and rolling contact wear are discussed. Lastly, methods to destructively (e.g., C-sphere flexure strength testing) and non-destructively identify potential RCF-limiting flaws in Si{sub 3}N{sub 4} balls are described

First Observation of the Rare Decay Mode K-long -> e+ e-

In an experiment designed to search for and study very rare two-body decay modes of the K-long, we have observed four examples of the decay K-long -> e+ e-, where the expected background is 0.17+-0.10 events. This observation translates into a branching fraction of 8.7^{+5.7}_{-4.1} X 10^{-12}, consistent with recent theoretical predictions. This result represents by far the smallest branching fraction yet measured in particle physics.Comment: 9 pages, 3 figure

Extended Hemi-Hepatectomy with Portal Vein Reconstruction in a Patient with Situs Ambiguous

We report a case of far-advanced hepatocellular carcinoma (HCC) with situs ambiguous, complex visceral and vascular anomalies, who was successfully managed by extended hemi-hepatectomy. A 67-year-old man was referred to our hospital with a large liver mass. Abdominal ultrasonography, computed tomography and angiography revealed HCC with a diameter of 10 cm, with tumor thrombus in the main and first branch of the portal vein. Multiple complex anomalies in the abdomen were determined preoperatively. He had right-sided spleens-stomach-duodenum, liver at midline, inferior vena cava interruption with azygous continuation, and hepatic arterial anomaly. Extended left lobectomy of the liver with reconstruction of the portal vein was performed. Postoperatively, the patient recovered without major complications, and he was discharged on postoperative day 21. We report the first successful extended hepatectomy with portal vein reconstruction for HCC in a patient with rare situs anomalies

A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma

BACKGROUND: Unresectable biliary tract carcinoma is known to demonstrate a poor prognosis. We conducted a single arm phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) for advanced biliary tract malignancies basically on an outpatient basis. METHODS: Between February 1996 and September 2003, 42 patients were enrolled in this trial. LFP THERAPY: By using a total implanted CV-catheter system, 5-FU (160 mg/m(2)/day) was continuously infused over 24 hours for 7 consecutive days and CDDP (6 mg/m(2)/day) was infused for 30 minutes twice a week as one cycle. The administration schedule consisted of 4 cycles as one course. RESIST criteria (Response evaluation criteria for solid tumors) and NCI-CTC (National Cancer Institute-Common Toxicity Criteria) (ver.3.0) were used for evaluation of this therapy. The median survival time (MST) and median time to treatment failure (TTF) were calculated by the Kaplan-Meier method. RESULTS: Patients characteristics were: mean age 66.5(47–79): male 24 (54%): BDca (bile duct carcinoma) 27 GBca (Gallbladder carcinoma) 15: locally advanced 26, postoperative recurrence 16. The most common toxicity was anemia (26.2%). Neither any treatment related death nor grade 4 toxicity occurred. The median number of courses of LFP Therapy which patients could receive was two (1–14). All the patients are evaluable for effects with an over all response rates of 42.9% (95% confidence interval C.I.: 27.7–59.0) (0 CR, 18 PR, 13 NC, 11 PD). There was no significant difference regarding the anti tumor effects against both malignant neoplasms. Figure 2 Shows the BDca a longer MST and TTF than did GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant. The estimated MST and median TTF were 225 and 107 days, respectively. The BDca had a longer MST and TTF than GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant. CONCLUSION: LFP therapy appears to be useful modality for the clinical management of advanced biliary tract malignancy

Widespread Endogenization of Genome Sequences of Non-Retroviral RNA Viruses into Plant Genomes

Non-retroviral RNA virus sequences (NRVSs) have been found in the chromosomes of vertebrates and fungi, but not plants. Here we report similarly endogenized NRVSs derived from plus-, negative-, and double-stranded RNA viruses in plant chromosomes. These sequences were found by searching public genomic sequence databases, and, importantly, most NRVSs were subsequently detected by direct molecular analyses of plant DNAs. The most widespread NRVSs were related to the coat protein (CP) genes of the family Partitiviridae which have bisegmented dsRNA genomes, and included plant- and fungus-infecting members. The CP of a novel fungal virus (Rosellinia necatrix partitivirus 2, RnPV2) had the greatest sequence similarity to Arabidopsis thaliana ILR2, which is thought to regulate the activities of the phytohormone auxin, indole-3-acetic acid (IAA). Furthermore, partitivirus CP-like sequences much more closely related to plant partitiviruses than to RnPV2 were identified in a wide range of plant species. In addition, the nucleocapsid protein genes of cytorhabdoviruses and varicosaviruses were found in species of over 9 plant families, including Brassicaceae and Solanaceae. A replicase-like sequence of a betaflexivirus was identified in the cucumber genome. The pattern of occurrence of NRVSs and the phylogenetic analyses of NRVSs and related viruses indicate that multiple independent integrations into many plant lineages may have occurred. For example, one of the NRVSs was retained in Ar. thaliana but not in Ar. lyrata or other related Camelina species, whereas another NRVS displayed the reverse pattern. Our study has shown that single- and double-stranded RNA viral sequences are widespread in plant genomes, and shows the potential of genome integrated NRVSs to contribute to resolve unclear phylogenetic relationships of plant species

Tracing the Origin of the Fungal α1 Domain Places Its Ancestor in the HMG-Box Superfamily: Implication for Fungal Mating-Type Evolution

BACKGROUND: Fungal mating types in self-incompatible Pezizomycotina are specified by one of two alternate sequences occupying the same locus on corresponding chromosomes. One sequence is characterized by a gene encoding an HMG protein, while the hallmark of the other is a gene encoding a protein with an α1 domain showing similarity to the Matα1p protein of Saccharomyces cerevisiae. DNA-binding HMG proteins are ubiquitous and well characterized. In contrast, α1 domain proteins have limited distribution and their evolutionary origin is obscure, precluding a complete understanding of mating-type evolution in Ascomycota. Although much work has focused on the role of the S. cerevisiae Matα1p protein as a transcription factor, it has not yet been placed in any of the large families of sequence-specific DNA-binding proteins. METHODOLOGY/PRINCIPAL FINDINGS: We present sequence comparisons, phylogenetic analyses, and in silico predictions of secondary and tertiary structures, which support our hypothesis that the α1 domain is related to the HMG domain. We have also characterized a new conserved motif in α1 proteins of Pezizomycotina. This motif is immediately adjacent to and downstream of the α1 domain and consists of a core sequence Y-[LMIF]-x(3)-G-[WL] embedded in a larger conserved motif. CONCLUSIONS/SIGNIFICANCE: Our data suggest that extant α1-box genes originated from an ancestral HMG gene, which confirms the current model of mating-type evolution within the fungal kingdom. We propose to incorporate α1 proteins in a new subclass of HMG proteins termed MATα_HMG

Quantifying the Proteolytic Release of Extracellular Matrix-Sequestered VEGF with a Computational Model

BACKGROUND: VEGF proteolysis by plasmin or matrix metalloproteinases (MMPs) is believed to play an important role in regulating vascular patterning in vivo by releasing VEGF from the extracellular matrix (ECM). However, a quantitative understanding of the kinetics of VEGF cleavage and the efficiency of cell-mediated VEGF release is currently lacking. To address these uncertainties, we develop a molecular-detailed quantitative model of VEGF proteolysis, used here in the context of an endothelial sprout. METHODOLOGY AND FINDINGS: To study a cell's ability to cleave VEGF, the model captures MMP secretion, VEGF-ECM binding, VEGF proteolysis from VEGF165 to VEGF114 (the expected MMP cleavage product of VEGF165) and VEGF receptor-mediated recapture. Using experimental data, we estimated the effective bimolecular rate constant of VEGF165 cleavage by plasmin to be 328 M(-1) s(-1) at 25 degrees C, which is relatively slow compared to typical MMP-ECM proteolysis reactions. While previous studies have implicated cellular proteolysis in growth factor processing, we show that single cells do not individually have the capacity to cleave VEGF to any appreciable extent (less than 0.1% conversion). In addition, we find that a tip cell's receptor system will not efficiently recapture the cleaved VEGF due to an inability of cleaved VEGF to associate with Neuropilin-1. CONCLUSIONS: Overall, VEGF165 cleavage in vivo is likely to be mediated by the combined effect of numerous cells, instead of behaving in a single-cell-directed, autocrine manner. We show that heparan sulfate proteoglycans (HSPGs) potentiate VEGF cleavage by increasing the VEGF clearance time in tissues. In addition, we find that the VEGF-HSPG complex is more sensitive to proteases than is soluble VEGF, which may imply its potential relevance in receptor signaling. Finally, according to our calculations, experimentally measured soluble protease levels are approximately two orders of magnitude lower than that needed to reconcile levels of VEGF cleavage seen in pathological situations

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None