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D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II–IIIB gastric cancer. The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II–IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4–41·7) in the chemotherapy and surgery group and 34·3 months (25·6–41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy and surgery group and 59% (53–64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44–0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. F Hoffmann-La Roche and Sanofi-Aventis.

Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. ImClone Systems.

Background This study aimed to analyze risk factors of operation-related complications after arthroscopic ganglionectomy in patients with volar wrist ganglions, including patients’ demographics and ganglions’ anatomical characteristics in MRI. We hypothesized that volar wrist ganglions, either located distal to the bifurcation of the radial artery or superficially expanded, would associate with complications after arthroscopic ganglionectomy. Methods This retrospective study included patients who had an arthroscopic ganglionectomy for volar wrist ganglion from Mar 2012 to Feb 2022 and followed up over one year. We reviewed medical records to gather patients’ demographics. The preoperative MRI was also examined to analyze the anatomical characteristics of the ganglion, involving axial location, superficial expansion, size, and presence of multiple lesions. The axial location was separated into two entities, whether located proximally or distally from the bifurcation of the radial artery. The superficial expansion was categorized into three depending on deep and superficial fascia penetration. For operation-related complications, we included the partial injury of the radial artery, median or dorsal branch of the radial nerve, and recurrence of ganglions after surgery. Results Forty-five patients were enrolled in this study. The partial injury of the radial artery occurred in four patients(8.9%); two were ligated, and others were repaired intraoperatively. The recurrence has occurred in two patients(4.4%). On univariate logistic regression analysis, these complications were associated with the anatomical location of the ganglion when it was distal to the bifurcation of the radial artery and concurrently penetrated up to the superficial fascia layer( p  = 0.035). The others were unrelated to complications, including revision surgery, multiple lesions, size, and anatomical locations unless it was concurrent. Conclusions The operation-related complications after arthroscopic volar wrist ganglionectomy are associated with its anatomical location when distal to the bifurcation of the radial artery and concurrently penetrated up to the superficial fascia layer. Trial registration Retrospectively registered.

Flammulina velutipes is a fungus with health and medicinal benefits that has been used for consumption and cultivation in East Asia. F. velutipes is also known to degrade lignocellulose and produce ethanol. The overlapping interests of mushroom production and wood bioconversion make F. velutipes an attractive new model for fungal wood related studies. Here, we present the complete sequence of the F. velutipes genome. This is the first sequenced genome for a commercially produced edible mushroom that also degrades wood. The 35.6-Mb genome contained 12,218 predicted protein-encoding genes and 287 tRNA genes assembled into 11 scaffolds corresponding with the 11 chromosomes of strain KACC42780. The 88.4-kb mitochondrial genome contained 35 genes. Well-developed wood degrading machinery with strong potential for lignin degradation (69 auxiliary activities, formerly FOLymes) and carbohydrate degradation (392 CAZymes), along with 58 alcohol dehydrogenase genes were highly expressed in the mycelium, demonstrating the potential application of this organism to bioethanol production. Thus, the newly uncovered wood degrading capacity and sequential nature of this process in F. velutipes, offer interesting possibilities for more detailed studies on either lignin or (hemi-) cellulose degradation in complex wood substrates. The mutual interest in wood degradation by the mushroom industry and (ligno-)cellulose biomass related industries further increase the significance of F. velutipes as a new model.

This study aimed (1) to provide a stepwise, reproducible description of a single-bone-tunnel, two-stranded, anchorless ligament-specific (‘en Masse’) repair for traumatic peripheral TFCC tears, and (2) to evaluate one-year clinical outcomes and exploratory prognostic factors in a retrospective consecutive case series. Forty-eight patients were retrospectively included. Postoperatively, ballottement testing revealed no detectable distal radioulnar joint (DRUJ) laxity ( p  < 0.001). The mean visual analog scale (VAS) pain score (7.2 to 1.9), grip strength (66.1% to 81.3%), Mayo wrist score (MWS, 64.3 to 81.9), and Disabilities of the Arm, Shoulder, and Hand (DASH) score (37.1 to 12.7) were improved postoperatively ( p  < 0.001). There were no surgery-related complications. On multivariable analysis, longer symptom duration ( p  = 0.031) and positive ulnar variance ( p  = 0.045) were associated with lower MWS; model fit was modest ( R 2 =0.224). Arthroscopic-assisted en Masse repair for peripheral TFCC tears was associated with improved clinical outcomes at one year or more after surgery, and postoperative ballottement testing revealed no detectable DRUJ laxity. Within this cohort, one-year follow-up precluded assessment of long-term durability; also, applicability to degenerative/chronic peripheral TFCC tears remains undetermined.

The unique saddle articulation of the trapeziometacarpal joint allows for a wide range of motion necessary for routine function of the thumb. Inherently unstable characteristics of the joint can lead painful instability. In this study, we modified a surgical dorsal ligament reconstruction technique for restoring trapeziometacarpal joint stability. We evaluated and compared the biomechanical efficacy of our reconstruction technique with that of dorsoradial capsulodesis by creating a cadaveric model of rotational instability. Twenty-four specimens were subjected to dorsoradial capsulodesis ( n  = 12) or dorsoradial ligament reconstruction using the abductor pollicis longus (APL) ( n  = 12). The modified dorsoradial ligament reconstruction entailed detaching one distally based slip of the APL. The harvested tendon’s proximal end was passed through a bone tunnel created at the dorsoradial ridge of the trapezium. A suture anchor was inserted at the dorsal base of the metacarpal bone. The tendon stump was sutured to the metacarpal bone using fiber wire in figure-of-eight configuration. The load to failure of the trapeziometacarpal joint under compression was higher in the reconstruction group ( p  = 0.003). The improvement in the rotational arc (observed in all specimens) was significantly greater in the reconstruction group than the capsulodesis group ( p  = 0.003). Our technique reconstructs only the necessary ligament, requires a smaller incision and relatively simpler surgical procedure, and enables precise determination of the insertion and exit sites of the tendon, making it a promising treatment for trapeziometacarpal joint instability.

This paper presents an optimized design approach using nonlinear dynamic analysis and finite element methods to ensure the structural integrity of square-shaped containers made from ductile cast iron for intermediate- and low-level radioactive waste packaging. Ductile cast iron, with its spherical graphite structure, effectively distributes stress throughout the material, leading to a storage capacity increase of approximately 18%. Considering the critical need for containers that maintain integrity under extreme conditions like earthquakes, the design focuses on mitigating stress concentrations at the corners of square structures. Nonlinear dynamic analyses were conducted in five drop directions: three specified by ASTM-D5276 standards and two additional directions to account for different load patterns. Fractures were observed in four out of the five scenarios. For each direction where fractures occurred, equivalent loads causing similar displacement fields were applied to linear static models, which were then used for multi-load topology optimization. Three optimized models were derived, each increasing the volume by 1.4% to 1.6% compared to the original model, and the design that best met the structural integrity requirements during drop scenarios was selected. To further enhance the optimization process, weights were assigned to different load conditions based on numerical analysis results, balancing the impact of maximum stress, average stress, and plastic deformation energy. The final model, with its increased storage capacity and enhanced structural integrity, offers a practical solution for radioactive waste management, overcoming limitations in previous designs by effectively addressing complex load conditions.

Phytochromes are red and far-red photoreceptors that regulate plant growth and development under ambient light conditions. During phytochrome-mediated photomorphogenesis, phytochrome-interacting factors (PIFs) are the most important signaling partners that regulate the expression of light-responsive genes. However, the function of PIFs in monocots has not been studied well. In this study, using RNA interference (RNAi), we investigated the functions of BdPIL1 and BdPIL3 , two PIF-like genes identified in Brachypodium distachyon , which are closely related to Arabidopsis PIF1 and PIF3 . The expression of their genes is light-inducible, and both BdPIL1 and BdPIL3 proteins interact with phytochromes in an active form-specific manner. Transgenic Brachypodium seedlings with the RNAi constructs of BdPIL1 and BdPIL3 showed decreased coleoptile lengths and increased leaf growth when exposed to both red and far-red light. In addition, the transgenic plants were taller with elongated internodes than wild-type Bd21-3 plant, exhibiting late flowering. Moreover, RNA-seq analysis revealed downregulation of many genes in the transgenic plants, especially those related to the regulation of cell number, floral induction, and chlorophyll biosynthesis, which were consistent with the phenotypes of increased plant height, delayed flowering, and pale green leaves. Furthermore, we demonstrated the DNA-binding ability of BdPIL1 and BdPIL3 to the putative target promoters and that the DNA-binding was inhibited in the presence of phytochromes. Therefore, this study determines a molecular mechanism underlying phytochrome-mediated PIF regulation in Brachypodium, i.e., sequestration, and also elucidates the functions of BdPIL1 and BdPIL3 in the growth and development of the monocot plant.

Plant phytochromes are known as autophosphorylating serine/threonine protein kinases. However, the functional importance of their kinase activity is not fully elucidated. Previously, the kinase activity is shown to be necessary for the function of Avena sativa phytochrome A (AsphyA) using transgenic plants with mutants displaying reduced kinase activity, such as K411L and T418D. In this study, we isolated and analyzed two AsphyA mutants, K411R and T418V, that showed increased kinase activity. Transgenic phyA-201 plants with these mutants showed hypersensitive responses to far-red (FR) light, such as shorter hypocotyls and more expanded cotyledons than those of control plant (i.e., transgenic phyA-201 plant with wild-type AsphyA). Contrary to the mutants with reduced kinase activity, these mutants accelerated FR-induced phosphorylation and subsequent degradation of phytochrome-interacting factor 3 (PIF3) in Arabidopsis. Moreover, elongated hypocotyl 5 (HY5), a critical positive regulator of photoresponses in plants, accumulated in higher amounts in the transgenic plants under FR light than in the control plant. In addition, PIF1 degradation was accelerated in the transgenic plants. Consequently, the transgenic plants exhibit higher germination frequencies than the control plant. Collectively, our results demonstrate that the AsphyA mutants with increased kinase activity are hyperactive in plants, supporting a positive relationship between the kinase activity of phytochromes and photoresponses in plants.

BackgroundPoziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC).MethodsPatients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m2 infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks.ResultsIn the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8–21.9) and 29.5 weeks (95% CI 17.9–59.2), respectively.ConclusionsThe MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.