Amorphous solids lack long-range order. Therefore identifying structural defects -- akin to dislocations in crystalline solids -- that carry plastic flow in these systems remains a daunting ...challenge. By comparing many different structural indicators in computational models of glasses, under a variety of conditions we carefully assess which of these indicators are able to robustly identify the structural defects responsible for plastic flow in amorphous solids. We further demonstrate that the density of defects changes as a function of material preparation and strain in a manner that is highly correlated with the macroscopic material response. Our work represents an important step towards predicting how and when an amorphous solid will fail from its microscopic structure.
β-cryptoxanthin is a dietary carotenoid for which there have been few studies on the safety and pharmacokinetics following daily oral supplementation.
90 healthy Asian women between 21 and 35 years ...were randomized into three groups: 3 and 6 mg/day oral β-cryptoxanthin, and placebo. At 2, 4, and 8 weeks of supplementation, plasma carotenoid levels were measured. The effects of β-cryptoxanthin on blood retinoid-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition were investigated.
β-cryptoxanthin supplementation for 8 weeks (3 and 6 mg/day) was found to be safe and well tolerated. Plasma β-cryptoxanthin concentration was significantly higher in the 6 mg/day group (9.0 ± 4.1 µmol/L) compared to 3 mg/day group (6.0 ± 2.6 µmol/L) (
< 0.03), and placebo (0.4 ± 0.1 µmol/L) (
< 0.001) after 8 weeks. Plasma all-trans retinol, α-cryptoxanthin, α-carotene, β-carotene, lycopene, lutein, and zeaxanthin levels were not significantly changed. No effects were found on blood retinol-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition.
Oral β-cryptoxanthin supplementation over 8 weeks lead to high plasma concentrations of β-cryptoxanthin, with no impact on other carotenoids, and was well tolerated in healthy women.
Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We ...investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients.
Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR).
Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS 95% confidence interval (CI) at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients.
EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy.
ACTRN12609000665235.
•EMR 5-year survival >50%.•Docetaxel + CF improves histological responses for MNR.•DCF + RT improves survival for MNR.
Purpose
Autologous full-thickness skin grafting (FTSG) has the potential to become an option in abdominal wall repair. An understanding of tissue remodelling in the extracellular matrix (ECM) is ...crucial as this interplay determines such parameters as tissue strength and flexibility. This cross-sectional preclinical laboratory study in mice provides information on the distribution of collagen types and matrix metalloproteinases (MMPs) in the ECM of FTSGs in the intraperitoneal and onlay positions compared with internal controls. The aim was to evaluate morphologic changes after tissue remodelling and repair in FTSGs applied in the two positions and to detect any adverse host response.
Methods
ECM components were evaluated as follows: qualitative examination of collagen bundle thickness using Picrosirius Red staining (collagen types I, III and IV); and evaluation of collagen types IV and V, as well as MMPs 1, 8 and 9 using immunohistochemical staining. Full-thickness grafts transplanted between female twin mice were examined as this best mimics autologous transplantation.
Results
At 8 weeks, FTSGs in the intraperitoneal position did not show any noticeable differences in morphologic appearance to those in the onlay position. Both intraperitoneal and onlay FTSGs showed increases in the amount of thick collagen bundles compared to internal controls. No correlation was seen between distribution of MMPs 1, 8 or 9 and distribution of collagen types I, III, IV or V.
Conclusion
This preclinical study shows that FTSGs in both intraperitoneal and onlay positions are possible application site options and, by extension, promising application site options for abdominal wall reinforcement in hernia surgery. Clinical studies in humans are required to confirm these findings.
Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we ...detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.
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•Characterization of long noncoding RNA transcriptome of neuroblastoma tumors•NBAT-1 is a biomarker for predicting the clinical outcome of the neuroblastomas•NBAT-1 epigenetically regulates cell proliferation and migration pathways•NBAT-1 is required for neuronal lineage commitment
Pandey et al. identify the long noncoding RNA NBAT-1 as a prognostic biomarker in neuroblastoma through transcriptome sequencing. NBAT-1 loss increases proliferation and impairs differentiation of neuronal precursors leading to more aggressive disease.
There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined.
We examined type ...2 immunity–associated gene expression in esophageal biopsy specimens, aiming to determine the degree of cytokine heterogeneity and its potential clinical significance.
Patients (n = 312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. In addition to histologic and endoscopic assessment, esophageal biopsy specimens were examined for expression of 96 genes within the EoE diagnostic panel.
Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, C-C motif chemokine ligand 26 (CCL26), thymic stromal lymphopoietin (TSLP), Charcot-Leyden crystal (CLC), C-C motif chemokine receptor 3 (CCR3), and CPA3. These groups differed in age (P < .02) and EoE diagnostic panel score (P < 1.08E–30) but not in eosinophil levels. The group V patients had the highest expression of IL5, TSLP, and CCL26 and genes associated with tissue remodeling, such as COL8A1, actin γ-2 (ACTG2), and tetraspanin 12 (TSPAN12). IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs 14 years P < .05). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III.
We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.
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Mice express S and M opsins that form visual pigments for the detection of light and visual signaling in cones. Here, we show that
S opsin transcription is higher than that of
M opsin, which supports ...ultraviolet (UV) sensitivity greater than midwavelength sensitivity. Surprisingly, most cones coexpress both S and M opsins in a common cone cell type throughout the retina. All cones express M opsin, but the levels are graded from dorsal to ventral. The levels of S opsin are relatively constant. However, in the far dorsal retina, S opsin is repressed stochastically, such that some cones express M opsin only. These observations indicate that two different mechanisms control M and S opsin expression. We suggest that a common cone type is patterned across the retinal surface to produce phenotypic cone subtypes.
Introduction
Synthetic non-resorbable mesh is almost standard in hernia surgery. However, several studies have showed negative effects of permanent implants such as chronic inflammation and ...complications involving different organs bordering the mesh. Such complications can raise the risk of chronic post-operative pain (CPP). Recently promising results regarding CPP have been published in patients with Lateral Inguinal Hernia (LIH) using a slowly resorbable mesh in Lichtenstein technique. For this reason the aim of the present study was to find the effect of a slowly resorbable implant on the long-term rate of hernia recurrence and chronic post-operative pain in patients with LIH repaired with TEP procedure.
Methods
Prospective pilot study of TEP repair using TIGR
®
Matrix Surgical Mesh in 35 primary LIH. At 3-year follow-up the Visual Analogue Scale (VAS) and the Inguinal Pain Questionnaire were employed to assess pain. Recurrence was determined by ultrasound and clinical examination.
Results
All patients completed the pain questionnaires but one patient did not attend the planned clinical examination for the 3-year follow-up. No patients had CPP, as defined in the World Guidelines for Groin Hernia Management. Almost all patients had lower VAS score in any activity 3 years following surgery in comparison to the preoperative period. Three patients (8.8%) suffered symptomatic recurrence during the 3-year follow-up.
Conclusion
TEP repair in patients with LIH using a synthetic long-term resorbable mesh was found to be encouraging respecting chronic post-operative pain at 3-year follow-up but at the cost of an increased risk of recurrence.
In amorphous materials, plasticity is localized and occurs as shear transformations. It was recently shown by Wu et al. that these shear transformations can be predicted by applying topological ...defect concepts developed for liquid crystals to an analysis of vibrational eigenmodes Z. W. Wu et al., Nat. Commun. 14, 2955 (2023)10.1038/s41467-023-38547-w. This study relates the -1 topological defects to the displacement fields expected of an Eshelby inclusion, which are characterized by an orientation and the magnitude of the eigenstrain. A corresponding orientation and magnitude can be defined for each defect using the local displacement field around each defect. These parameters characterize the plastic stress relaxation associated with the local structural rearrangement and can be extracted using the fit to either the global displacement field or the local field. Both methods provide a reasonable estimation of the molecular-dynamics-measured stress drop, confirming the localized nature of the displacements that control both long-range deformation and stress relaxation.In amorphous materials, plasticity is localized and occurs as shear transformations. It was recently shown by Wu et al. that these shear transformations can be predicted by applying topological defect concepts developed for liquid crystals to an analysis of vibrational eigenmodes Z. W. Wu et al., Nat. Commun. 14, 2955 (2023)10.1038/s41467-023-38547-w. This study relates the -1 topological defects to the displacement fields expected of an Eshelby inclusion, which are characterized by an orientation and the magnitude of the eigenstrain. A corresponding orientation and magnitude can be defined for each defect using the local displacement field around each defect. These parameters characterize the plastic stress relaxation associated with the local structural rearrangement and can be extracted using the fit to either the global displacement field or the local field. Both methods provide a reasonable estimation of the molecular-dynamics-measured stress drop, confirming the localized nature of the displacements that control both long-range deformation and stress relaxation.
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